bims-bac4me 2024-08-25 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024‒08‒25
43 papers selected by
Chun-Chi Chang, University Hospital Zurich

Protocol for analyzing BCG-induced trained immunity in murine bone marrow-derived macrophages.
RORα negatively regulates BCG-induced trained immunity.
Cell-intrinsic regulation of phagocyte function by interferon lambda during pulmonary viral, bacterial super-infection.
The microbiota: a crucial mediator in gut homeostasis and colonization resistance.
BCG vaccination alters the epigenetic landscape of progenitor cells in human bone marrow to influence innate immune responses.
The miR-26a/SIRT6/HIF-1α axis regulates glycolysis and inflammatory responses in host macrophages during Mycobacterium tuberculosis infection.
Nasal microbiome dynamics: decoding the intricate nexus in the progression of respiratory and neurological diseases.
The Human Skin Microbiome in Health: CME Part 1.
Trained immunity is regulated by T cell-induced CD40-TRAF6 signaling.
Stem cells tightly regulate dead cell clearance to maintain tissue fitness.
Epigenetic programming of host lipid metabolism associated with resistance to TST/IGRA conversion after exposure to Mycobacterium tuberculosis.
Putting a cap on the glycome: Dissecting human sialyltransferase functions.
Alterations in the Skin Microbiome in Dermatologic Diseases and with External Exposures: CME Part 2.
Nasal symbiont Staphylococcus epidermidis restricts influenza A virus replication via the creation of a polyamine-deficient cellular environment.
Vaginal Lactobacillus fatty acid response mechanisms reveal a metabolite-targeted strategy for bacterial vaginosis treatment.
Mucins protect against Streptococcus pneumoniae virulence by suppressing pneumolysin expression.
Clinical immunity to malaria involves epigenetic reprogramming of innate immune cells.
Respiratory tract infections: an update on the complexity of bacterial diversity, therapeutic interventions and breakthroughs.
Effects of Latilactobacillus sakei LZ217 on Gastric Mucosal Colonization, Metabolic Interference, and Urease Expression in Helicobacter pylori Infection.
Influenza A virus infection activates caspase-8 to enhance innate antiviral immunity by cleaving CYLD and blocking TAK1 and RIG-I deubiquitination.
Hypoxia-inducible lipid droplet-associated protein (HILPDA) and cystathionine β-synthase (CBS) co-contribute to protecting intestinal epithelial cells from Staphylococcus aureus via regulating lipid droplets formation.
IFNε, IFNω and IFNλ: interferons defending the mucosa.
Myddosomes in Toll-like receptor signaling-one to bind and rule them all.
The probiotic strain Bacillus subtilis CU1 primes antimicrobial innate immune response and reduces low-grade inflammation: a clinical study.
The effect of intestinal flora metabolites on macrophage polarization.
A lactobacilli-based inhaled live biotherapeutic product attenuates pulmonary neutrophilic inflammation.
Airway Triage: Goodbye, difficult airway!
Disruption of glucose homeostasis by bacterial infection orchestrates host innate immunity through NAD+/NADH balance.
Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation.
The role of microbiota in nasopharyngeal cancer: Where do we stand?
Understanding Inflammatory Heterogeneity in NSAID-exacerbated Respiratory Disease.
Host immunomodulation strategies to combat pandemic-associated antimicrobial-resistant secondary bacterial infections.
A noninvasive BCG skin challenge model for assessing tuberculosis vaccine efficacy.
Cell-cell interactions and communication dynamics in lung fibrosis.
Less is more! Low amount of Fusobacterium nucleatum supports macrophage-mediated trophoblast functions in vitro.
Protection of stromal cell-derived factor-1 SDF-1/CXCL12 against proteases yields improved skin wound healing.
Deciphering the Therapeutic Potential of Myeloid-Specific JAK2 Inhibition in Acute Respiratory Distress Syndrome.
Granulocyte colony-stimulating factor mediates bone loss via the activation of IL-1β/JNK signaling pathway in murine Staphylococcus aureus-induced osteomyelitis.
Sialylation in the gut: From mucosal protection to disease pathogenesis.
Examining the Efficacy of Five Lactobacillus Species in Treating and Preventing Atopic Dermatitis: A Systemic Literature Review.
Translocation of probiotics via gut-lung axis enhanced pulmonary immunity of weaned piglets exposed to low concentrations of ammonia.
Tissue-scale in vitro epithelial wrinkling and wrinkle-to-fold transition.
Divergent effects of itaconate isomers on Coxiella burnetii growth in macrophages and in axenic culture.

STAR Protoc. 2024 Aug 17. pii: S2666-1667(24)00432-5. [Epub ahead of print]5(3): 103267

Protocol for analyzing BCG-induced trained immunity in murine bone marrow-derived macrophages.

Jin-Chuan Xu, Zhidong Hu, Xiao-Yong Fan.

  Bacillus Calmette-Guérin (BCG), the only licensed tuberculosis vaccine, provides non-specific protection against non-tuberculosis diseases that is mediated by trained immunity, a functional reprogramming mediated by innate immune memory. Here, we present a protocol for analyzing BCG-induced trained immunity in murine bone marrow-derived macrophages (BMDMs). We describe steps for preparing BCG single bacterial suspensions, isolating BMDM cells, and the training process. This protocol can assist researchers to conveniently utilize BMDM cells to study trained immunity. For complete details on the use and execution of this protocol, please refer to Xu et al.1.

Keywords:  Cell culture; Cell isolation; Immunology; Microbiology; Model Organisms

DOI:  https://doi.org/10.1016/j.xpro.2024.103267
Cell Immunol. 2024 Aug 15. pii: S0008-8749(24)00065-0. [Epub ahead of print]403-404 104862

RORα negatively regulates BCG-induced trained immunity.

Gizem Kilic, Vasiliki Matzaraki, Ozlem Bulut, Ilayda Baydemir, Anaisa V Ferreira, Katrin Rabold, Simone J C F M Moorlag, Valerie A C M Koeken, L Charlotte J de Bree, Vera P Mourits, Leo A B Joosten, Jorge Domínguez-Andrés, Mihai G Netea.

  Trained immunity is a long-lasting change in the responsiveness of innate immune cells, leading to a stronger response upon an unrelated secondary challenge. Epigenetic, transcriptional, and metabolic reprogramming contribute to the development of trained immunity. By investigating the impact of gene variants on trained immunity responses after Bacillus Calmette-Guérin (BCG) vaccination, we identified a strong association between polymorphisms in the RORA gene and BCG-induced trained immunity in PBMCs isolated from healthy human donors. RORα, encoded by the RORA gene in humans, is a nuclear receptor and a transcription factor, regulating genes involved in circadian rhythm, inflammation, cholesterol, and lipid metabolism. We found that natural RORα agonists in the circulation negatively correlate with the strength of trained immunity responses after BCG vaccination. Moreover, pharmacological inhibition of RORα in human PBMCs led to higher cytokine production capacity and boosted trained immunity induction by BCG. Blocking RORα activity also resulted in morphological changes and increased ROS and lactate production of BCG-trained cells. Blocking lactate dehydrogenase A (LDHA) and glycolysis with sodium oxamate reduced the cytokine production capacity of cells trained with a combination of BCG and the RORα agonist. In conclusion, this study highlights the potential role of RORα in trained immunity, and its impact on human vaccination and diseases should be further investigated.

Keywords:  BCG; Immunometabolism; RORA; Trained immunity

DOI:  https://doi.org/10.1016/j.cellimm.2024.104862
PLoS Pathog. 2024 Aug 23. 20(8): e1012498

Cell-intrinsic regulation of phagocyte function by interferon lambda during pulmonary viral, bacterial super-infection.

Danielle Antos, Olivia B Parks, Alexis M Duray, Nevil Abraham, Joshua J Michel, Saran Kupul, Rosemary Westcott, John F Alcorn.

Influenza infections result in a significant number of severe illnesses annually, many of which are complicated by secondary bacterial super-infection. Primary influenza infection has been shown to increase susceptibility to secondary methicillin-resistant Staphylococcus aureus (MRSA) infection by altering the host immune response, leading to significant immunopathology. Type III interferons (IFNs), or IFNλs, have gained traction as potential antiviral therapeutics due to their restriction of viral replication without damaging inflammation. The role of IFNλ in regulating epithelial biology in super-infection has recently been established; however, the impact of IFNλ on immune cells is less defined. In this study, we infected wild-type and IFNLR1-/- mice with influenza A/PR/8/34 followed by S. aureus USA300. We demonstrated that global IFNLR1-/- mice have enhanced bacterial clearance through increased uptake by phagocytes, which was shown to be cell-intrinsic specifically in myeloid cells in mixed bone marrow chimeras. We also showed that depletion of IFNLR1 on CX3CR1 expressing myeloid immune cells, but not neutrophils, was sufficient to significantly reduce bacterial burden compared to mice with intact IFNLR1. These findings provide insight into how IFNλ in an influenza-infected lung impedes bacterial clearance during super-infection and show a direct cell intrinsic role for IFNλ signaling on myeloid cells.

DOI: https://doi.org/10.1371/journal.ppat.1012498
Front Microbiol. 2024 ;15 1417864

The microbiota: a crucial mediator in gut homeostasis and colonization resistance.

Yiding Chen, Ling Xiao, Min Zhou, Hu Zhang.

  The gut microbiota is a complex and diverse community of microorganisms that colonizes the human gastrointestinal tract and influences various aspects of human health. These microbes are closely related to enteric infections. As a foreign entity for the host, commensal microbiota is restricted and regulated by the barrier and immune system in the gut and contributes to gut homeostasis. Commensals also effectively resist the colonization of pathogens and the overgrowth of indigenous pathobionts by utilizing a variety of mechanisms, while pathogens have developed strategies to subvert colonization resistance. Dysbiosis of the microbial community can lead to enteric infections. The microbiota acts as a pivotal mediator in establishing a harmonious mutualistic symbiosis with the host and shielding the host against pathogens. This review aims to provide a comprehensive overview of the mechanisms underlying host-microbiome and microbiome-pathogen interactions, highlighting the multi-faceted roles of the gut microbiota in preventing enteric infections. We also discuss the applications of manipulating the microbiota to treat infectious diseases in the gut.

Keywords:  colonization resistance; enteric infections; gut homeostasis; microbiota; mucosal immunity

DOI:  https://doi.org/10.3389/fmicb.2024.1417864
Immunity. 2024 Aug 14. pii: S1074-7613(24)00370-4. [Epub ahead of print]

BCG vaccination alters the epigenetic landscape of progenitor cells in human bone marrow to influence innate immune responses.

Sarah J Sun, Raúl Aguirre-Gamboa, L Charlotte J de Bree, Joaquin Sanz, Anne Dumaine, Walter J F M van der Velden, Leo A B Joosten, Shabaana Khader, Maziar Divangahi, Mihai G Netea, Luis B Barreiro.

  Although the Bacille-Calmette-Guérin (BCG) vaccine is used to prevent tuberculosis, it also offers protection against a diverse range of non-mycobacterial infections. However, the underlying protective mechanisms in humans are not yet fully understood. Here, we surveyed at single-cell resolution the gene expression and chromatin landscape of human bone marrow, aspirated before and 90 days after BCG vaccination or placebo. We showed that BCG alters both the gene expression and epigenetic profiles of human hematopoietic stem and progenitor cells (HSPCs). Changes in gene expression occurred primarily within uncommitted stem cells. By contrast, changes in chromatin accessibility were most prevalent within differentiated progenitor cells at sites influenced by Kruppel-like factor (KLF) and early growth response (EGR) transcription factors and were highly correlated (r > 0.8) with the interleukin (IL)-1β secretion capacity of paired peripheral blood mononuclear cells (PBMCs). Our findings shed light on BCG vaccination's profound and lasting effects on HSPCs and its influence on innate immune responses and trained immunity.

Keywords:  BCG vaccination; hematopoietic stem cells; innate immunity; single-cell genomics; trained immunity

DOI:  https://doi.org/10.1016/j.immuni.2024.07.021
FEBS Lett. 2024 Aug 18.

The miR-26a/SIRT6/HIF-1α axis regulates glycolysis and inflammatory responses in host macrophages during Mycobacterium tuberculosis infection.

Soumya Mal, Debayan Majumder, Pankaj Birari, Arun Kumar Sharma, Umesh Gupta, Kuladip Jana, Manikuntala Kundu, Joyoti Basu.

  Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis. Here, a macrophage infection model was used to unravel the role of the histone deacetylase sirtuin 6 (SIRT6) in Mtb-triggered regulation of the innate immune response. Mtb infection downregulated microRNA-26a and upregulated its target SIRT6. SIRT6 suppressed glycolysis and expression of HIF-1α-dependent glycolytic genes during infection. In addition, SIRT6 regulated the levels of intracellular succinate which controls stabilization of HIF-1α, as well as the release of interleukin (IL)-1β. Furthermore, SIRT6 inhibited inducible nitric oxide synthase (iNOS) and proinflammatory IL-6 but augmented anti-inflammatory arginase expression. The miR-26a/SIRT6/HIF-1α axis therefore regulates glycolysis and macrophage immune responses during Mtb infection. Our findings link SIRT6 to rewiring of macrophage signaling pathways facilitating dampening of the antibacterial immune response.

Keywords:  Mycobacterium tuberculosis; glycolysis; immunometabolism; innate immunity; macrophage response; sirtuin 6

DOI:  https://doi.org/10.1002/1873-3468.15001
Crit Rev Microbiol. 2024 Aug 19. 1-16

Nasal microbiome dynamics: decoding the intricate nexus in the progression of respiratory and neurological diseases.

Keerti Maheshwari, Rashi Gupta, Ruchika Sharma, Amanpreet Kaur, Atul Vashist, Geeta Aggarwal.

  In recent times, the nasal region has emerged as a distinctive and dynamic environment where a myriad of microbial communities establish residence from infancy, persisting as both commensal and opportunistic pathogens throughout the lifespan. Understanding the coexistence of microorganisms in respiratory mucosal layers, their potential for infections, and the underlying molecular mechanisms shaping these interactions is crucial for developing efficient diagnostic and therapeutic interventions against respiratory and neurodegenerative diseases. Despite significant strides in understanding the olfactory system's nexus with nasal microbiota, comprehensive correlations with neurological diseases still need to be discovered. The nasal microbiome, a sentinel in immune defense, orchestrates a delicate equilibrium that, when disrupted, can precipitate severe respiratory infections, including Chronic Rhinosinusitis, Chronic obstructive pulmonary disorder (COPD), and Asthma, and instigate a cascade effect on central nervous system diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Multiple sclerosis (MS). This review aims to redress this imbalance by meticulously exploring the anatomical and microbiological nuances of the nasal mucosal surface in health and disease. By delineating the molecular intricacies of these interactions, this review unravels the molecular mechanisms that govern the intricate nexus between nasal microbiota dysbiosis, olfactory dysfunction, and the progression of respiratory and neurological diseases.

Keywords:  Human nasal microbiome; neurological disease; nose-brain axis; olfactory system; respiratory disease

DOI:  https://doi.org/10.1080/1040841X.2024.2391488
J Am Acad Dermatol. 2024 Aug 19. pii: S0190-9622(24)02671-9. [Epub ahead of print]

The Human Skin Microbiome in Health: CME Part 1.

Margaret A MacGibeny, Susuana Adjei, Hunter Pyle, Christopher G Bunick, Mahmoud Ghannoum, Ayman Grada, Tamia Harris-Tryon, Stephen K Tyring, Heidi H Kong.

  Human skin is home to a myriad of microorganisms, including bacteria, viruses, fungi, and mites, many of which are considered commensal microbes that aid in maintaining the overall homeostasis or steady-state condition of the skin and contribute to skin health. Our understanding of the complexities of the skin's interaction with its microorganisms is evolving. This knowledge is based primarily on in vitro and animal studies, and more work is needed to understand how this knowledge relates to humans. Here, we introduce the concept of the skin microbiome and discuss skin microbial ecology, some intrinsic factors with potential influence on the human skin microbiome, and possible microbiome-host interactions. The second article of this two-part CME series describes how microbiome alterations may be associated with skin disease, how medications can affect the microbiome, and what microbiome-based therapies are under investigation.

Keywords:  Cutaneous and pilosebaceous ecology; microbial and host interactions; microbiota; skin microbiome

DOI:  https://doi.org/10.1016/j.jaad.2024.07.1498
Cell Rep. 2024 Aug 22. pii: S2211-1247(24)01015-5. [Epub ahead of print]43(9): 114664

Trained immunity is regulated by T cell-induced CD40-TRAF6 signaling.

Maaike M E Jacobs, Rianne J F Maas, Inge Jonkman, Yutaka Negishi, Willem Tielemans Zamora, Cansu Yanginlar, Julia van Heck, Vasiliki Matzaraki, Joost H A Martens, Marijke Baltissen, Michiel Vermeulen, Judit Morla-Folch, Anna Ranzenigo, William Wang, Martin Umali, Jordi Ochando, Johan van der Vlag, Luuk B Hilbrands, Leo A B Joosten, Mihai G Netea, Willem J M Mulder, Mandy M T van Leent, Musa M Mhlanga, Abraham J P Teunissen, Nils Rother, Raphaël Duivenvoorden.

  Trained immunity is characterized by histone modifications and metabolic changes in innate immune cells following exposure to inflammatory signals, leading to heightened responsiveness to secondary stimuli. Although our understanding of the molecular regulation of trained immunity has increased, the role of adaptive immune cells herein remains largely unknown. Here, we show that T cells modulate trained immunity via cluster of differentiation 40-tissue necrosis factor receptor-associated factor 6 (CD40-TRAF6) signaling. CD40-TRAF6 inhibition modulates functional, transcriptomic, and metabolic reprogramming and modifies histone 3 lysine 4 trimethylation associated with trained immunity. Besides in vitro studies, we reveal that single-nucleotide polymorphisms in the proximity of CD40 are linked to trained immunity responses in vivo and that combining CD40-TRAF6 inhibition with cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4-Ig)-mediated co-stimulatory blockade induces long-term graft acceptance in a murine heart transplantation model. Combined, our results reveal that trained immunity is modulated by CD40-TRAF6 signaling between myeloid and adaptive immune cells and that this can be leveraged for therapeutic purposes.

Keywords:  CD40-CD40L; CP: Immunology; T cells; innate immunity; monocytes; nanobiologics; trained immunity

DOI:  https://doi.org/10.1016/j.celrep.2024.114664
Nature. 2024 Aug 21.

Stem cells tightly regulate dead cell clearance to maintain tissue fitness.

Katherine S Stewart, Merve Deniz Abdusselamoglu, Matthew T Tierney, Anita Gola, Yun Ha Hur, Kevin A U Gonzales, Shaopeng Yuan, Alain R Bonny, Yihao Yang, Nicole R Infarinato, Christopher J Cowley, John M Levorse, Hilda Amalia Pasolli, Sourav Ghosh, Carla V Rothlin, Elaine Fuchs.

Billions of cells are eliminated daily from our bodies1-4. Although macrophages and dendritic cells are dedicated to migrating and engulfing dying cells and debris, many epithelial and mesenchymal tissue cells can digest nearby apoptotic corpses1-4. How these non-motile, non-professional phagocytes sense and eliminate dying cells while maintaining their normal tissue functions is unclear. Here we explore the mechanisms that underlie their multifunctionality by exploiting the cyclical bouts of tissue regeneration and degeneration during hair cycling. We show that hair follicle stem cells transiently unleash phagocytosis at the correct time and place through local molecular triggers that depend on both lipids released by neighbouring apoptotic corpses and retinoids released by healthy counterparts. We trace the heart of this dual ligand requirement to RARγ-RXRα, whose activation enables tight regulation of apoptotic cell clearance genes and provides an effective, tunable mechanism to offset phagocytic duties against the primary stem cell function of preserving tissue integrity during homeostasis. Finally, we provide functional evidence that hair follicle stem cell-mediated phagocytosis is not simply redundant with professional phagocytes but rather has clear benefits to tissue fitness. Our findings have broad implications for other non-motile tissue stem or progenitor cells that encounter cell death in an immune-privileged niche.

DOI: https://doi.org/10.1038/s41586-024-07855-6
mSystems. 2024 Aug 20. e0062824

Epigenetic programming of host lipid metabolism associated with resistance to TST/IGRA conversion after exposure to Mycobacterium tuberculosis.

Kimberly A Dill-McFarland, Jason D Simmons, Glenna J Peterson, Felicia K Nguyen, Monica Campo, Penelope Benchek, Catherine M Stein, Tomas Vaisar, Harriet Mayanja-Kizza, W Henry Boom, Thomas R Hawn.

  Mycobacterium tuberculosis (Mtb) exposure leads to a range of outcomes including clearance, latent TB infection (LTBI), and pulmonary tuberculosis (TB). Some heavily exposed individuals resist tuberculin skin test (TST) and interferon-gamma (IFNγ) release assay (IGRA) conversion (RSTR), which suggests that they employ IFNγ-independent mechanisms of Mtb control. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. Chromatin accessibility did not differ between uninfected RSTR and LTBI monocytes. By contrast, methylation significantly differed at 174 CpG sites and across 63 genomic regions. Consistent with previous transcriptional findings in this cohort, differential methylation was enriched in lipid- and cholesterol-associated pathways including the genes APOC3, KCNQ1, and PLA2G3. In addition, methylation was enriched in Hippo signaling, which is associated with cholesterol homeostasis and includes CIT and SHANK2. Lipid export and Hippo signaling pathways were also associated with gene expression in response to Mtb in RSTR as well as IFN stimulation in monocyte-derived macrophages (MDMs) from an independent healthy donor cohort. Moreover, serum-derived high-density lipoprotein from RSTR had elevated ABCA1-mediated cholesterol efflux capacity (CEC) compared to LTBI. Our findings suggest that resistance to TST/IGRA conversion is linked to regulation of lipid accumulation in monocytes, which could facilitate early Mtb clearance among RSTR subjects through IFNγ-independent mechanisms.IMPORTANCETuberculosis (TB) remains an enduring global health challenge with millions of deaths and new cases each year. Despite recent advances in TB treatment, we lack an effective vaccine or a durable cure. While heavy exposure to Mycobacterium tuberculosis often results in latent TB latent infection (LTBI), subpopulations exist that are either resistant to infection or contain Mtb with interferon-gamma (IFNγ)-independent mechanisms not indicative of LTBI. These resisters provide an opportunity to investigate the mechanisms of TB disease and discover novel therapeutic targets. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. We identify methylation signatures in host lipid and cholesterol pathways with potential relevance to early TB clearance before the sustained IFN responses indicative of LTBI. This adds to a growing body of literature linking TB disease outcomes to host lipids.

Keywords:  DNA methylation; Mycobacterium tuberculosis; chromatin remodeling; interferons; monocytes

DOI:  https://doi.org/10.1128/msystems.00628-24
Carbohydr Res. 2024 Aug 13. pii: S0008-6215(24)00221-0. [Epub ahead of print]544 109242

Putting a cap on the glycome: Dissecting human sialyltransferase functions.

Khadra A Mohamed, Stijn Kruf, Christian Büll.

  Human glycans are capped with sialic acids and these nine-carbon sugars mediate many of the biological functions and interactions of glycans. Structurally diverse sialic acid caps mark human cells as self and they form the ligands for the Siglec immune receptors and other glycan-binding proteins. Sialic acids enable host interactions with the human microbiome and many human pathogens utilize sialic acids to infect host cells. Alterations in sialic acid-carrying glycans, sialoglycans, can be found in every major human disease including inflammatory conditions and cancer. Twenty sialyltransferase family members in the Golgi apparatus of human cells transfer sialic acids to distinct glycans and glycoconjugates. Sialyltransferases catalyze specific reactions to form unique sialoglycans or they have shared functions where multiple family members generate the same sialoglycan product. Moreover, some sialyltransferases compete for the same glycan substrate, but create different sialic acid caps. The redundant and competing functions make it difficult to understand the individual roles of the human sialyltransferases in biology and to reveal the specific contributions to pathobiological processes. Recent insights hint towards the existence of biosynthetic rules formed by the individual functions of sialyltransferases, their interactions, and cues from the local Golgi environment that coordinate sialoglycan biosynthesis. In this review, we discuss the current structural and functional understanding of the human sialyltransferase family and we review recent technological advances that enable the dissection of individual sialyltransferase activities.

Keywords:  Cell-based glycan array; Sialic acids; Sialoglycans; Sialome; Sialyltransferase

DOI:  https://doi.org/10.1016/j.carres.2024.109242
J Am Acad Dermatol. 2024 Aug 20. pii: S0190-9622(24)02672-0. [Epub ahead of print]

Alterations in the Skin Microbiome in Dermatologic Diseases and with External Exposures: CME Part 2.

Margaret A MacGibeny, Susuana Adjei, Hunter Pyle, Christopher G Bunick, Mahmoud Ghannoum, Ayman Grada, Tamia Harris-Tryon, Stephen K Tyring, Heidi H Kong.

  In Part I of our CME we reviewed the skin microbiome in healthy individuals. Part II reviews the evolving understanding of alterations in the skin microbiome in specific human diseases. We also discuss how the skin microbiome can change with environmental exposures and medications such as antibiotics as well as ongoing research on microbiome-based interventions.

Keywords:  antibiotics; antimicrobial resistance; fecal microbiota transplantation; inflammatory skin diseases; microbiome-based therapeutics; prebiotics; probiotics

DOI:  https://doi.org/10.1016/j.jaad.2024.07.1499
Commun Biol. 2024 Aug 22. 7(1): 1031

Nasal symbiont Staphylococcus epidermidis restricts influenza A virus replication via the creation of a polyamine-deficient cellular environment.

Ara Jo, Kyeong-Seog Kim, Jina Won, Haeun Shin, Sujin Kim, Bora Kim, Da Jung Kim, Joo-Youn Cho, Hyun Jik Kim.

Studies on the immune-regulatory roles played by the commensal microbes residing in the nasal mucosa consider the contribution of antiviral immune responses. Here, we sought to identify the nasal microbiome, Staphylococcus epidermidis-regulated antiviral immune responses and the alteration of polyamine metabolites in nasal epithelium. We found that polyamines were required for the life cycle of influenza A virus (IAV) and depletion of polyamines disturbed IAV replication in normal human nasal epithelial (NHNE) cells. Inoculation of S. epidermidis also suppressed IAV infection and the concentration of polyamines including putrescine, spermidine, and spermine was completely attenuated in S. epidermidis-inoculated NHNE cells. S. epidermidis activated the enzyme involved in the production of ornithine from arginine and downregulated the activity of the enzyme involved in the production of putrescine from ornithine in nasal epithelium. S. epidermidis also induced the activation of enzymes that promote the extracellular export of spermine and spermidine in NHNE cells. Our findings demonstrate that S. epidermidis is shown to be able of creating an intracellular environment lacking polyamines in the nasal epithelium and promote the balance of cellular polyamines in favor of the host to restrict influenza virus replication.

DOI: https://doi.org/10.1038/s42003-024-06706-4
Cell. 2024 Aug 14. pii: S0092-8674(24)00823-7. [Epub ahead of print]

Vaginal Lactobacillus fatty acid response mechanisms reveal a metabolite-targeted strategy for bacterial vaginosis treatment.

Meilin Zhu, Matthew W Frank, Christopher D Radka, Sarah Jeanfavre, Jiawu Xu, Megan W Tse, Julian Avila Pacheco, Jae Sun Kim, Kerry Pierce, Amy Deik, Fatima Aysha Hussain, Joseph Elsherbini, Salina Hussain, Nondumiso Xulu, Nasreen Khan, Vanessa Pillay, Caroline M Mitchell, Krista L Dong, Thumbi Ndung'u, Clary B Clish, Charles O Rock, Paul C Blainey, Seth M Bloom, Douglas S Kwon.

  Bacterial vaginosis (BV), a common syndrome characterized by Lactobacillus-deficient vaginal microbiota, is associated with adverse health outcomes. BV often recurs after standard antibiotic therapy in part because antibiotics promote microbiota dominance by Lactobacillus iners instead of Lactobacillus crispatus, which has more beneficial health associations. Strategies to promote L. crispatus and inhibit L. iners are thus needed. We show that oleic acid (OA) and similar long-chain fatty acids simultaneously inhibit L. iners and enhance L. crispatus growth. These phenotypes require OA-inducible genes conserved in L. crispatus and related lactobacilli, including an oleate hydratase (ohyA) and putative fatty acid efflux pump (farE). FarE mediates OA resistance, while OhyA is robustly active in the vaginal microbiota and enhances bacterial fitness by biochemically sequestering OA in a derivative form only ohyA-harboring organisms can exploit. OA promotes L. crispatus dominance more effectively than antibiotics in an in vitro BV model, suggesting a metabolite-based treatment approach.

Keywords:  Lactobacillus; bacterial vaginosis; female genital tract; metabolism; vaginal microbiome; women’s health

DOI:  https://doi.org/10.1016/j.cell.2024.07.029
J Clin Invest. 2024 Aug 22. pii: e182769. [Epub ahead of print]

Mucins protect against Streptococcus pneumoniae virulence by suppressing pneumolysin expression.

Jade Bath, Elisabet Bjånes, Cengiz Goekeri, Jeff Hsiao, Deniz Uzun, Geraldine Nouailles, Victor Nizet, Katharina Ribbeck.



Keywords:  Bacterial infections; Glycobiology; Infectious disease; Microbiology

DOI:  https://doi.org/10.1172/JCI182769
PNAS Nexus. 2024 Aug;3(8): pgae325

Clinical immunity to malaria involves epigenetic reprogramming of innate immune cells.

Jason Nideffer, Maureen Ty, Michele Donato, Rek John, Richard Kajubi, Xuhuai Ji, Felistas Nankya, Kenneth Musinguzi, Kathleen Dantzler Press, Nora Yang, Kylie Camanag, Bryan Greenhouse, Moses Kamya, Margaret E Feeney, Grant Dorsey, Paul J Utz, Bali Pulendran, Purvesh Khatri, Prasanna Jagannathan.

The regulation of inflammation is a critical aspect of disease tolerance and naturally acquired clinical immunity to malaria. Here, we demonstrate using RNA sequencing and epigenetic landscape profiling by cytometry by time-of-flight, that the regulation of inflammatory pathways during asymptomatic parasitemia occurs downstream of pathogen sensing-at the epigenetic level. The abundance of certain epigenetic markers (methylation of H3K27 and dimethylation of arginine residues) and decreased prevalence of histone variant H3.3 correlated with suppressed cytokine responses among monocytes of Ugandan children. Such an epigenetic signature was observed across diverse immune cell populations and not only characterized active asymptomatic parasitemia but also correlated with future long-term disease tolerance and clinical immunity when observed in uninfected children. Pseudotime analyses revealed a potential trajectory of epigenetic change that correlated with a child's age and recent parasite exposure and paralleled the acquisition of clinical immunity. Thus, our data support a model whereby exposure to Plasmodium falciparum induces epigenetic changes that regulate excessive inflammation and contribute to naturally acquire clinical immunity to malaria.

DOI: https://doi.org/10.1093/pnasnexus/pgae325
Arch Microbiol. 2024 Aug 17. 206(9): 382

Respiratory tract infections: an update on the complexity of bacterial diversity, therapeutic interventions and breakthroughs.

Avani Panickar, Anand Manoharan, Anand Anbarasu, Sudha Ramaiah.

  Respiratory tract infections (RTIs) have a significant impact on global health, especially among children and the elderly. The key bacterial pathogens Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, Staphylococcus aureus and non-fermenting Gram Negative bacteria such as Acinetobacter baumannii and Pseudomonas aeruginosa are most commonly associated with RTIs. These bacterial pathogens have evolved a diverse array of resistance mechanisms through horizontal gene transfer, often mediated by mobile genetic elements and environmental acquisition. Treatment failures are primarily due to antimicrobial resistance and inadequate bacterial engagement, which necessitates the development of alternative treatment strategies. To overcome this, our review mainly focuses on different virulence mechanisms and their resulting pathogenicity, highlighting different therapeutic interventions to combat resistance. To prevent the antimicrobial resistance crisis, we also focused on leveraging the application of artificial intelligence and machine learning to manage RTIs. Integrative approaches combining mechanistic insights are crucial for addressing the global challenge of antimicrobial resistance in respiratory infections.

Keywords:  Antimicrobial resistance; Genomics; Respiratory tract infections; Structural bioinformatics; Systems biology; Therapeutics

DOI:  https://doi.org/10.1007/s00203-024-04107-z
Helicobacter. 2024 Jul-Aug;29(4):29(4): e13130

Effects of Latilactobacillus sakei LZ217 on Gastric Mucosal Colonization, Metabolic Interference, and Urease Expression in Helicobacter pylori Infection.

Chenlan Xia, Ziqi Chen, Yongqiang Chen, Fangtong Wei, Shiying Wu, Qingqing Zhou, Ping Li, Qing Gu.

  Emerging evidence suggests differential antagonism of lactic acid-producing bacteria (LAB) to Helicobacter pylori, posing challenges to human health and food safety due to unclear mechanisms. This study assessed 21 LAB strains from various sources on H. pylori growth, urease activity, and coaggregation. Composite scoring revealed that Latilactobacillus sakei LZ217, derived from fresh milk, demonstrates strong inhibitory effects on both H. pylori growth and urease activity. L. sakei LZ217 significantly reduced H. pylori adherence of gastric cells in vitro, with inhibition ratios of 47.62%. Furthermore, in vivo results showed that L. sakei LZ217 alleviated H. pylori-induced gastric mucosa damage and inflammation in mice. Metabolomic exploration revealed metabolic perturbations in H. pylori induced by L. sakei LZ217, including reduced amino acid levels (e.g., isoleucine, leucine, glutamate, aspartate, and phenylalanine) and impaired carbohydrate and nucleotide synthesis, contributing to the suppression of ureA (28.30%), ureE (84.88%), and ureF (59.59%) expressions in H. pylori. This study underscores the efficacy of LAB against H. pylori and highlights metabolic pathways as promising targets for future interventions against H. pylori growth and colonization.

Keywords:   Helicobacter pylori ; Latilactobacillus sakei LZ217; gastric mucosa damage; in vitro and in vivo; metabolites; urease

DOI:  https://doi.org/10.1111/hel.13130
Cell Mol Life Sci. 2024 Aug 19. 81(1): 355

Influenza A virus infection activates caspase-8 to enhance innate antiviral immunity by cleaving CYLD and blocking TAK1 and RIG-I deubiquitination.

Huidi Yu, Yuling Sun, Jingting Zhang, Wenhui Zhang, Wei Liu, Penggang Liu, Kaituo Liu, Jing Sun, Hailiang Liang, Pinghu Zhang, Xiaoquan Wang, Xiufan Liu, Xiulong Xu.

  Caspase-8, an aspartate-specific cysteine protease that primarily functions as an initiator caspase to induce apoptosis, can downregulate innate immunity in part by cleaving RIPK1 and IRF3. However, patients with caspase-8 mutations or deficiency develop immunodeficiency and are prone to viral infections. The molecular mechanism underlying this controversy remains unknown. Whether caspase-8 enhances or suppresses antiviral responses against influenza A virus (IAV) infection remains to be determined. Here, we report that caspase-8 is readily activated in A549 and NL20 cells infected with the H5N1, H5N6, and H1N1 subtypes of IAV. Surprisingly, caspase-8 deficiency and two caspase-8 inhibitors, Z-VAD and Z-IETD, do not enhance but rather downregulate antiviral innate immunity, as evidenced by decreased TBK1, IRF3, IκBα, and p65 phosphorylation, decreased IL-6, IFN-β, MX1, and ISG15 gene expression; and decreased IFN-β production but increased virus replication. Mechanistically, caspase-8 cleaves and inactivates CYLD, a tumor suppressor that functions as a deubiquitinase. Caspase-8 inhibition suppresses CYLD cleavage, RIG-I and TAK1 ubiquitination, and innate immune signaling. In contrast, CYLD deficiency enhances IAV-induced RIG-I and TAK1 ubiquitination and innate antiviral immunity. Neither caspase-3 deficiency nor treatment with its inhibitor Z-DEVD affects CYLD cleavage or antiviral innate immunity. Our study provides evidence that caspase-8 activation in two human airway epithelial cell lines does not silence but rather enhances innate immunity by inactivating CYLD.

Keywords:  CYLD; Caspase-8; Influenza A virus; Innate immunity; RIPK1

DOI:  https://doi.org/10.1007/s00018-024-05392-z
Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Aug 22. pii: S1388-1981(24)00108-2. [Epub ahead of print]1869(8): 159558

Hypoxia-inducible lipid droplet-associated protein (HILPDA) and cystathionine β-synthase (CBS) co-contribute to protecting intestinal epithelial cells from Staphylococcus aureus via regulating lipid droplets formation.

Shaodong Fu, Rui Yu, Bo Yang, Xiangan Han, Yuanyuan Xu, Jinfeng Miao.

  Despite Staphylococcus aureus (S. aureus) being a highly studied zoontic bacterium, its enteropathogenicity remains elusive. Herein, our findings demonstrated that S. aureus infection led to the accumulation of lipid droplets (LDs) in intestinal epithelial cells, accompanied by marked elevation inflammatory response that ultimately decreases intracellular bacterial load. The aforestated phenomenon may be partly attributed to the up-regulation of hypoxia-inducible lipid droplet-associated protein (HILPDA) and the concomitant down-regulation of cystathionine β-synthase (CBS) protein. Moreover, S. aureus infection up-regulated the expression of HILPDA, thereby promoting LDs accumulation, and down-regulated that of CBS, consequently inhibiting microsomal triglyceride transfer protein (MTTP) expression. This process may suppress the transport of LDs to the extracellular environment, further contributing to the formation of intracellular LDs. In summary, the results of this study provide significant insights into the intricate mechanisms through which the host organism combats pathogens and maintains the balance of sulfur and lipid metabolism. These findings not only enhance our understanding of the host's defense mechanisms but also offer promising avenues for the development of novel strategies to combat intestinal infectious diseases.

Keywords:  Cystathionine β-synthase; HILPDA; Intestinal epithelial cells; MTTP; Staphylococcus aureus

DOI:  https://doi.org/10.1016/j.bbalip.2024.159558
Curr Opin Immunol. 2024 Aug 21. pii: S0952-7915(24)00046-3. [Epub ahead of print]89 102456

IFNε, IFNω and IFNλ: interferons defending the mucosa.

Jasmine J M Chuah, Nicole K Campbell.

The unconventional type I interferons IFNε and IFNω and type III interferon IFNλ are gradually emerging as tissue-specific cytokines in defence of mucosal tissues. This review provides an overview of the distinct features and functions that define these IFNs as protective factors in the respiratory, gastrointestinal and reproductive tracts, highlighting their immunoregulatory roles against pathogens while maintaining tolerance against commensal microbes. In particular, we discuss recent advances in our understanding of the constitutively expressed IFNε and its role in protecting against mucosal infections, inflammation and cancers. We identify an emerging theme for this unique cytokine as a key contributor to the 'first line of defence' against pathogens and maintenance of mucosal tissue homeostasis, primarily through its regulation of immune cell populations.

DOI: https://doi.org/10.1016/j.coi.2024.102456
Immunol Cell Biol. 2024 Aug 19.

Myddosomes in Toll-like receptor signaling-one to bind and rule them all.

Carmen D Mathmann, Thomas E Schultz, Leslie C Domínguez Cadena, Antje Blumenthal.

  Toll-like receptors (TLRs) are innate immune sensors for the presence of pathogens and endogenous danger signals. TLR activation results in conserved intracellular signaling events that orchestrate inflammation and antimicrobial defense. While the identity and interplay of key TLR signaling components are well established, how these largely cytosolic proteins are physically connected is not well understood. For the activation of conserved intracellular signaling events, most TLRs engage the adapter MyD88 (myeloid differentiation primary response 88), which assembles into higher-order protein complexes, myddosomes. In their recent publication, Fisch et al. present evidence that oligomeric myddosomes detach from initiating TLRs and evolve into larger scaffolds that dynamically assemble not only proximal but also distal cytosolic elements required to execute the entire cascade of the TLR-MyD88 signaling pathway. Coinciding with decline in TLR signaling over time, myddosomes progressively recruit autophagy machinery that mediates myddosome clearance. These findings expand the current understanding of TLR signaling by positioning myddosomes as the central structural element that physically assembles the key executors and regulators of TLR-MyD88-dependent intracellular signaling cascades.

Keywords:  Myddosomes; Toll‐like receptors; macrophages; signaling

DOI:  https://doi.org/10.1111/imcb.12816
Benef Microbes. 2024 Aug 14. 1-20

The probiotic strain Bacillus subtilis CU1 primes antimicrobial innate immune response and reduces low-grade inflammation: a clinical study.

F Mourey, P Scholtens, J-F Jeanne, B Rodriguez, A Decherf, F Machuron, A Kardinaal, T Scheithauer, M Porbahaie, E Narni-Mancinelli, A Crinier.

LifeinU™ Bacillus subtilis CU1 (BSCU1) has been previously shown to be effective in stimulating mucosal immune responses and supporting resistance to common infectious disease episodes in the elderly. The current clinical study aimed at exploring potential pathways by which BSCU1 could beneficially modulate the immune system and contribute to protection against infection in the general population. A total of 88 participants from three different age groups were supplemented with BSCU1 (2 × 109 cfu/day) for 4 weeks. The effect of the intervention on mucosal immunity was assessed by faecal sIgA levels. In addition, a series of complementary immunoassays were selected, including immune phenotyping, gene expression, basal cytokine levels, cytokine levels in lipopolysaccharide (LPS)-stimulated whole blood and phagocytosis assay. Although no significant effect was observed on faecal sIgA levels after intervention, BSCU1 showed a positive effect on a consistent set of markers of the peripheral innate immune system in adults and the elderly. Percentages of peripheral blood myeloid cells as well as the expression of the activation marker CD69 on monocytes were significantly increased after probiotic intervention. BSCU1 supplementation resulted in significant enrichment of clusters of genes involved in response to type I interferon and phagocytosis pathway. Consistently, ex vivo stimulation of whole blood with LPS resulted in a statistically significant increase in pro-inflammatory cytokines (interleukin (IL)-1beta, IL-6, interferon-gamma, IL-12, tumour necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1alpha, IL-8) and phagocytosis assays showed increased capacity of monocytes to engulf bacteria as well as higher phagosome maturation. BSCU1 supplementation also had a positive effect on low-grade inflammation as significant reduction in basal levels of several serum cytokines (IL-10, TNF-alpha, MIP-1alpha, IL-8) were observed in the elderly subgroup. Overall, BSCU1 primed immune cells for a better response to microbial challenges and reduced low-grade inflammation associated with aging. Registered at ClinicalTrials.gov with the identifier NCT05403398.

DOI: https://doi.org/10.1163/18762891-bja00028
Heliyon. 2024 Aug 15. 10(15): e35755

The effect of intestinal flora metabolites on macrophage polarization.

Hengzhong Lun, Peilong Li, Juan Li, Fenfen Liu.

  Intestinal flora metabolites played a crucial role in immunomodulation by influencing host immune responses through various pathways. Macrophages, as a type of innate immune cell, were essential in chemotaxis, phagocytosis, inflammatory responses, and microbial elimination. Different macrophage phenotypes had distinct biological functions, regulated by diverse factors and mechanisms. Advances in intestinal flora sequencing and metabolomics have enhanced understanding of how intestinal flora metabolites affect macrophage phenotypes and functions. These metabolites had varying effects on macrophage polarization and different mechanisms of influence. This study summarized the impact of gut microbiota metabolites on macrophage phenotype and function, along with the underlying mechanisms associated with different metabolites produced by intestinal flora.

Keywords:  Intestinal flora metabolites; Macrophage; Polarization

DOI:  https://doi.org/10.1016/j.heliyon.2024.e35755
Nat Commun. 2024 Aug 19. 15(1): 7113

A lactobacilli-based inhaled live biotherapeutic product attenuates pulmonary neutrophilic inflammation.

Teodora Nicola, Nancy Wenger, Xin Xu, Michael Evans, Luhua Qiao, Gabriel Rezonzew, Youfeng Yang, Tamas Jilling, Camilla Margaroli, Kristopher Genschmer, Kent Willis, Namasivayam Ambalavanan, J Edwin Blalock, Amit Gaggar, Charitharth Vivek Lal.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity. Exposure to noxious stimuli such as hyperoxia, volutrauma, and infection in infancy can have long-reaching impacts on lung health and predispose towards the development of conditions such as chronic obstructive pulmonary disease (COPD) in adulthood. BPD and COPD are both marked by lung tissue degradation, neutrophil influx, and decreased lung function. Both diseases also express a change in microbial signature characterized by firmicute depletion. However, the relationship between pulmonary bacteria and the mechanisms of downstream disease development has yet to be elucidated. We hypothesized that murine models of BPD would show heightened acetylated proline-glycine-proline (Ac-PGP) pathway and neutrophil activity, and through gain- and loss-of-function studies we show that Ac-PGP plays a critical role in driving BPD development. We further test a inhaled live biotherapeutic (LBP) using active Lactobacillus strains in in vitro and in vivo models of BPD and COPD. The Lactobacillus-based LBP is effective in improving lung structure and function, mitigating neutrophil influx, and reducing a broad swath of pro-inflammatory markers in these models of chronic pulmonary disease via the MMP-9/PGP (matrix metalloproteinase/proline-glycine-proline) pathway. Inhaled LBPs show promise in addressing common pathways of disease progression that in the future can be targeted in a variety of chronic lung diseases.

DOI: https://doi.org/10.1038/s41467-024-51169-0
Indian J Anaesth. 2024 Aug;68(8): 677-679

Airway Triage: Goodbye, difficult airway!

Johannes M Huitink.

DOI: https://doi.org/10.4103/ija.ija_505_24
Cell Rep. 2024 Aug 20. pii: S2211-1247(24)00999-9. [Epub ahead of print]43(9): 114648

Disruption of glucose homeostasis by bacterial infection orchestrates host innate immunity through NAD+/NADH balance.

Jingjing Tang, Xiao Wang, Shukun Chen, Tianyuan Chang, Yanchao Gu, Fuhua Zhang, Jing Hou, Yi Luo, Mengyuan Li, Jianan Huang, Mohua Liu, Lei Zhang, Yao Wang, Xihui Shen, Lei Xu.

  Metabolic reprogramming is crucial for activating innate immunity in macrophages, and the accumulation of immunometabolites is essential for effective defense against infection. The NAD+/NADH (ratio of nicotinamide adenine dinucleotide and its reduced counterpart) redox couple serves as a critical node that integrates metabolic pathways and signaling events, but how this metabolite couple engages macrophage activation remains unclear. Here, we show that the NAD+/NADH ratio serves as a molecular signal that regulates proinflammatory responses and type I interferon (IFN) responses divergently. Salmonella Typhimurium infection leads to a decreased NAD+/NADH ratio by inducing the accumulation of NADH. Further investigation shows that an increased NAD+/NADH ratio correlates with attenuated proinflammatory responses and enhanced type I IFN responses. Conversely, a decreased NAD+/NADH ratio is linked to intensified proinflammatory responses and restrained type I IFN responses. These results show that the NAD+/NADH ratio is an essential cell-intrinsic factor that orchestrates innate immunity, which enhances our understanding of how metabolites fine-tune innate immunity.

Keywords:  CP: Immunology; CP: Metabolism; IFN; LPS; NAD(+)/NADH ratio; Salmonella Typhimurium; immunometabolites; lipopolysaccharide; metabolic reprogramming; proinflammatory responses; type I interferon

DOI:  https://doi.org/10.1016/j.celrep.2024.114648
Nat Commun. 2024 Aug 22. 15(1): 7241

Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation.

Kuei-Pin Chung, Chih-Ning Cheng, Yi-Jung Chen, Chia-Lang Hsu, Yen-Lin Huang, Min-Shu Hsieh, Han-Chun Kuo, Ya-Ting Lin, Yi-Hsiu Juan, Kiichi Nakahira, Yen-Fu Chen, Wei-Lun Liu, Sheng-Yuan Ruan, Jung-Yien Chien, Maria Plataki, Suzanne M Cloonan, Peter Carmeliet, Augustine M K Choi, Ching-Hua Kuo, Chong-Jen Yu.

Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS.

DOI: https://doi.org/10.1038/s41467-024-51683-1
Oral Oncol. 2024 Aug 16. pii: S1368-8375(24)00300-2. [Epub ahead of print]158 106982

The role of microbiota in nasopharyngeal cancer: Where do we stand?

Sumel Ashique, Mohammad Houshyari, Anas Islam, Radheshyam Pal, Shakira Ghazanfar, Farzad Taghizadeh-Hesary.

  Nasopharyngeal carcinoma (NPC) is a common head and neck cancer with a poor prognosis. One of the crucial challenges regarding NPC is its pathogenesis. Recent findings highlight the significance of host microbiota in the development of NPC, affected locally by nasopharyngeal microbiota or remotely by oral microbiota. The oral microbiota can migrate to the nasopharyngeal space, thereby impacting the composition of the nasopharyngeal microbiota. Specific bacterial strains have been linked to the development of nasopharyngeal cancer, including Neisseria, Staphylococcus, Leptotrichia, Staphylococcaceae, Granulicatella, Corynebacterium, Fusobacterium, and Prevotella. Several mechanisms have been proposed to elucidate how microbiota dysbiosis contributes to the development of NPC, including triggering tumor-promoting inflammation, reactivating the Epstein-Barr virus (EBV), inducing oxidative stress, weakening the immune system, and worsening tumor hypoxia. In addition, the composition of nasopharyngeal microbiota and the number of tumor-infiltrating microbiota can influence the prognosis and treatment response in patients with NPC. To the best of our knowledge, this is the first review discussing the impacts of the host microbiota on nasopharyngeal cancer pathogenesis, progression, and treatment response.

Keywords:  Dysbiosis; Epstein-Barr virus; Microbiota; Nasopharyngeal carcinoma; Oxidative stress; Probiotics; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.oraloncology.2024.106982
J Allergy Clin Immunol Pract. 2024 Aug 19. pii: S2213-2198(24)00844-4. [Epub ahead of print]

Understanding Inflammatory Heterogeneity in NSAID-exacerbated Respiratory Disease.

Justin H Turner, Atsushi Kato.



Keywords:  Cytokine; Inflammatory heterogeneity; Lipid mediators; NSAID-ERD

DOI:  https://doi.org/10.1016/j.jaip.2024.07.035
Int J Antimicrob Agents. 2024 Aug 19. pii: S0924-8579(24)00224-3. [Epub ahead of print] 107308

Host immunomodulation strategies to combat pandemic-associated antimicrobial-resistant secondary bacterial infections.

Srimathi Raghavan, Kwang-Sun Kim.

  The incidence of secondary bacterial infections has increased in recent decades owing to various viral pandemics. These infections further increase the morbidity and mortality rates associated with viral infections and remain a significant challenge in clinical practice. Intensive antibiotic therapy has mitigated the threat of such infections; however, overuse and misuse of antibiotics have resulted in poor outcomes, such as inducing the emergence of bacterial populations with antimicrobial resistance (AMR) and reducing the therapeutic options for this crisis. Several antibiotic substitutes have been suggested and employed; however, they have certain limitations and novel alternatives are urgently required. This review highlights host immunomodulation as a promising strategy against secondary bacterial infections to overcome AMR. The definition and risk factors of secondary bacterial infections, features and limitations of currently available therapeutic strategies, host immune responses, and future perspectives for treating such infections are discussed.

Keywords:  antibiotics; antimicrobial resistance; extracellular vesicle; immunomodulation; nanoantibiotics; secondary bacterial infection; viral infection

DOI:  https://doi.org/10.1016/j.ijantimicag.2024.107308
PLoS Biol. 2024 Aug 19. 22(8): e3002766

A noninvasive BCG skin challenge model for assessing tuberculosis vaccine efficacy.

Nitya Krishnan, Miles Priestman, Iria Uhía, Natalie Charitakis, Izabella T Glegola-Madejska, Thomas M Baer, Albin Tranberg, Alan Faraj, Ulrika Sh Simonsson, Brian D Robertson.

We report here on the characterisation in mice of a noninvasive bacille Calmette-Guérin (BCG) skin challenge model for assessing tuberculosis (TB) vaccine efficacy. Controlled human infection models (CHIMs) are valuable tools for assessing the relevant biological activity of vaccine candidates, with the potential to accelerate TB vaccine development into the clinic. TB infection poses significant constraints on the design of a CHIM using the causative agent Mycobacterium tuberculosis (Mtb). A safer alternative is a challenge model using the attenuated vaccine agent Mycobacterium bovis BCG as a surrogate for Mtb, and intradermal (skin) challenge as an alternative to pulmonary infection. We have developed a unique noninvasive imaging system based on fluorescent reporters (FluorBCG) to quantitatively measure bacterial load over time, thereby determining a relevant biological vaccine effect. We assessed the utility of this model to measure the effectiveness of 2 TB vaccines: the currently licenced BCG and a novel subunit vaccine candidate. To assess the efficacy of the skin challenge model, a nonlinear mixed effect model was built describing the decline of fluorescence over time. The model-based analysis identified that BCG vaccination reduced the fluorescence readout of both fluorophores compared to unvaccinated mice (p < 0.001). However, vaccination with the novel subunit candidate did not alter the fluorescence decline compared to unvaccinated mice (p > 0.05). BCG-vaccinated mice that showed the reduced fluorescent readout also had a reduced bacterial burden in the lungs when challenged with Mtb. This supports the fluorescence activity in the skin as a reflection of vaccine induced functional pulmonary immune responses. This novel noninvasive approach allows for repeated measurements from the challenge site, providing a dynamic readout of vaccine induced responses over time. This BCG skin challenge model represents an important contribution to the ongoing development of controlled challenge models for TB.

DOI: https://doi.org/10.1371/journal.pbio.3002766
Chin Med J Pulm Crit Care Med. 2024 Jun;2(2): 63-71

Cell-cell interactions and communication dynamics in lung fibrosis.

Ting Xie, Jiurong Liang, Barry Stripp, Paul W Noble.

  Cell-cell interactions are essential components of coordinated cell function in lung homeostasis. Lung diseases involve altered cell-cell interactions and communication between different cell types, as well as between subsets of cells of the same type. The identification and understanding of intercellular signaling in lung fibrosis offer insights into the molecular mechanisms underlying these interactions and their implications in the development and progression of lung fibrosis. A comprehensive cell atlas of the human lung, established with the facilitation of single-cell RNA transcriptomic analysis, has enabled the inference of intercellular communications using ligand-receptor databases. In this review, we provide a comprehensive overview of the modified cell-cell communications in lung fibrosis. We highlight the intricate interactions among the major cell types within the lung and their contributions to fibrogenesis. The insights presented in this review will contribute to a better understanding of the molecular mechanisms underlying lung fibrosis and may guide future research efforts in developing targeted therapies for this debilitating disease.

Keywords:  Cell–cell interaction; Lung fibrosis; Lung homeostasis; Targeted therapies

DOI:  https://doi.org/10.1016/j.pccm.2024.04.001
Front Immunol. 2024 ;15 1447190

Less is more! Low amount of Fusobacterium nucleatum supports macrophage-mediated trophoblast functions in vitro.

Rebekka Einenkel, Jens Ehrhardt, Marek Zygmunt, Damián Oscar Muzzio.

  F. nucleatum, involved in carcinogenesis of colon carcinomas, has been described as part of the commensal flora of the female upper reproductive tract. Although its contribution to destructive inflammatory processes is well described, its role as commensal uterine bacteria has not been thoroughly investigated. Since carcinogenesis shares similar mechanisms with early pregnancy development (including proliferation, invasion, blood supply and the induction of tolerance), these mechanisms induced by F. nucleatum could play a role in early pregnancy. Additionally, implantation and placentation require a well-balanced immune activation, which might be suitably managed by the presence of a limited amount of bacteria or bacterial residues. We assessed the effect of inactivated F. nucleatum on macrophage-trophoblast interactions. Monocytic cells (THP-1) were polarized into M1, M2a or M2c macrophages by IFN-γ, IL-4 or TGF-β, respectively, and subsequently treated with inactivated fusobacteria (bacteria:macrophage ratio of 0.1 and 1). Direct effects on macrophages were assessed by viability assay, flow cytometry (antigen presentation molecules and cytokines), qPCR (cytokine expression), in-cell Western (HIF and P-NF-κB) and ELISA (VEGF secretion). The function of first trimester extravillous trophoblast cells (HTR-8/SVneo) in response to macrophage-conditioned medium was microscopically assessed by migration (scratch assay), invasion (sprouting assay) and tube formation. Underlying molecular changes were investigated by ELISA (VEGF secretion) and qPCR (matrix-degrading factors and regulators). Inflammation-primed macrophages (M1) as well as high bacterial amounts increased pro-inflammatory NF-κB expression and inflammatory responses. Subsequently, trophoblast functions were impaired. In contrast, low bacterial stimulation caused an increased HIF activation and subsequent VEGF-A secretion in M2c macrophages. Accordingly, there was an increase of trophoblast tube formation. Our results suggest that a low-mass endometrial/decidual microbiome can be tolerated and while it supports implantation and further pregnancy processes.

Keywords:  Fusobacterium nucleatum; HIF-1α; VEGF-A; decidual macrophages; endometrial microbiome; extravillous trophoblast; implantation; placental microbiome

DOI:  https://doi.org/10.3389/fimmu.2024.1447190
Front Immunol. 2024 ;15 1359497

Protection of stromal cell-derived factor-1 SDF-1/CXCL12 against proteases yields improved skin wound healing.

Rafaela Vaz Sousa Pereira, Mostafa EzEldeen, Estefania Ugarte-Berzal, Jennifer Vandooren, Erik Martens, Mieke Gouwy, Eva Ganseman, Jo Van Damme, Patrick Matthys, Jan Jeroen Vranckx, Paul Proost, Ghislain Opdenakker.

  SDF-1/CXCL12 is a unique chemotactic factor with multiple functions on various types of precursor cells, all carrying the cognate receptor CXCR4. Whereas individual biological functions of SDF-1/CXCL12 have been well documented, practical applications in medicine are insufficiently studied. This is explained by the complex multifunctional biology of SDF-1 with systemic and local effects, critical dependence of SDF-1 activity on aminoterminal proteolytic processing and limited knowledge of applicable modulators of its activity. We here present new insights into modulation of SDF-1 activity in vitro and in vivo by a macromolecular compound, chlorite-oxidized oxyamylose (COAM). COAM prevented the proteolytic inactivation of SDF-1 by two inflammation-associated proteases: matrix metalloproteinase-9/MMP-9 and dipeptidylpeptidase IV/DPPIV/CD26. The inhibition of proteolytic inactivation was functionally measured by receptor-mediated effects, including intracellular calcium mobilization, ERK1/2 phosphorylation, receptor internalization and chemotaxis of CXCR4-positive cells. Protection of SDF-1/CXCL12 against proteolysis was dependent on electrostatic COAM-SDF-1 interactions. By in vivo experiments in mice, we showed that the combination of COAM with SDF-1 delivered through physiological fibrin hydrogel had beneficial effect for the healing of skin wounds. Collectively, we show that COAM protects SDF-1 from proteolytic inactivation, maintaining SDF-1 biological activities. Thus, protection from proteolysis by COAM represents a therapeutic strategy to prolong SDF-1 bioavailability for wound healing applications.

Keywords:  COAM; CXCL12; SDF-1; chemokine; proteolysis; wound healing

DOI:  https://doi.org/10.3389/fimmu.2024.1359497
Mucosal Immunol. 2024 Aug 20. pii: S1933-0219(24)00089-8. [Epub ahead of print]

Deciphering the Therapeutic Potential of Myeloid-Specific JAK2 Inhibition in Acute Respiratory Distress Syndrome.

Shupei Gao, Wenjuan Li, Zhiwen Huang, Jeffrey A Deiuliis, Zachary Braunstein, Xinxin Liu, Xinlu Li, Mohammadreza Kosari, Jun Chen, Xinwen Min, Handong Yang, Quan Gong, Zheng Liu, Yingying Wei, Ziyang Zhang, Lingli Dong, Jixin Zhong.

  Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by severe inflammation and pulmonary dysfunction. Despite advancements in critical care, effective pharmacological interventions for ARDS remain elusive. While Janus kinase 2 (JAK2) inhibitors have emerged as an innovative treatment for numerous autoinflammatory diseases, their therapeutic potential in ARDS remains unexplored. In this study, we investigated the contribution of JAK2 and its underlying mechanisms in ARDS utilizing myeloid-specific JAK2 knockout murine models alongside a pharmacological JAK2 inhibitor. Notably, myeloid-specific JAK2 knockout led to a notable attenuation of ARDS induced by intratracheal administration of LPS, accompanied by reduced levels of neutrophils and inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and lung tissue. Intriguingly, the ameliorative effects were abolished upon the depletion of monocyte-derived alveolar macrophages (Mo-AMs) rather than tissue-resident alveolar macrophages (TR-AMs). JAK2 deficiency markedly reversed LPS-induced activation of STAT5 in macrophages. Remarkably, pharmacological JAK2 inhibition using baricitinib failed to substantially alleviate neutrophils infiltration, implying that specific inhibition of JAK2 in Mo-AMs is imperative for ARDS amelioration. Collectively, our data suggest that JAK2 may mitigate ARDS progression through the JAK2 pathway in Mo-AMs, underscoring JAK2 in alveolar macrophages, particularly Mo-AMs, as a promising therapeutic target for ARDS treatment.

Keywords:  ARDS; JAK2; Macrophage; STAT5; Therapeutic intervention

DOI:  https://doi.org/10.1016/j.mucimm.2024.08.008
Int Immunopharmacol. 2024 Aug 19. pii: S1567-5769(24)01480-2. [Epub ahead of print]141 112959

Granulocyte colony-stimulating factor mediates bone loss via the activation of IL-1β/JNK signaling pathway in murine Staphylococcus aureus-induced osteomyelitis.

Mingrui Song, Mingye Deng, Ziyue Peng, Fangfang Dai, Yutian Wang, Wen Shu, Xuyou Zhou, Jinye Zhang, Yilong Hou, Bin Yu.

  Staphylococcus aureus (S. aureus)-induced bone loss is a significant challenge in the treatment of osteomyelitis. Our previous study was the first to confirm that granulocyte colony-stimulating factor (G-CSF) mediates S. aureus-induced bone loss. However, the underlying mechanism remains unknown. The objective of this study was to elucidate this. We found G-CSF mediated BMSC senescence and increased IL-1β concentration of serum and bone marrow in mice after S. aureus infection. Furthermore, we demonstrated that G-CSF promoted the expression of IL1b in murine bone marrow-derived neutrophils. Notably, we identified that IL-1β mediated BMSC (bone marrow mesenchymal stromal cell) senescence in mice after S. aureus infection. Importantly, IL-1β neutralizing antibody effectively alleviated BMSC senescence and bone loss caused by S. aureus infection in mice. In terms of molecular mechanism, we found IL-1β induced BMSC senescence by JNK/P53 and JNK/BCL2 pathways. Collectively, G-CSF promotes IL-1β production which induces BMSC senescence via JNK/P53 and JNK/BCL2 pathways, leading to S. aureus-induced bone loss. This study identified novel targets for preventing and treating S. aureus-induced bone loss in osteomyelitis.

Keywords:  BMSC senescence; Bone loss; G-CSF; IL-1β; JNK; Osteomyelitis

DOI:  https://doi.org/10.1016/j.intimp.2024.112959
Carbohydr Polym. 2024 Nov 01. pii: S0144-8617(24)00697-0. [Epub ahead of print]343 122471

Sialylation in the gut: From mucosal protection to disease pathogenesis.

Xueni Ma, Muyang Li, Xiaochun Wang, Guoqing Qi, Lina Wei, Dekui Zhang.

  Sialylation, a crucial post-translational modification of glycoconjugates, entails the attachment of sialic acid (SA) to the terminal glycans of glycoproteins and glycolipids through a tightly regulated enzymatic process involving various enzymes. This review offers a comprehensive exploration of sialylation within the gut, encompassing its involvement in mucosal protection and its impact on disease progression. The sialylation of mucins and epithelial glycoproteins contributes to the integrity of the intestinal mucosal barrier. Furthermore, sialylation regulates immune responses in the gut, shaping interactions among immune cells, as well as their activation and tolerance. Additionally, the gut microbiota and gut-brain axis communication are involved in the role of sialylation in intestinal health. Altered sialylation patterns have been implicated in various intestinal diseases, including inflammatory bowel disease (IBD), colorectal cancer (CRC), and other intestinal disorders. Emerging research underscores sialylation as a promising avenue for diagnostic, prognostic, and therapeutic interventions in intestinal diseases. Potential strategies such as sialic acid supplementation, inhibition of sialidases, immunotherapy targeting sialylated antigens, and modulation of sialyltransferases have been utilized in the treatment of intestinal diseases. Future research directions will focus on elucidating the molecular mechanisms underlying sialylation alterations, identifying sialylation-based biomarkers, and developing targeted interventions for precision medicine approaches.

Keywords:  Colorectal cancer; Gut; Inflammatory bowel disease; Mucosal protection; Sialylation

DOI:  https://doi.org/10.1016/j.carbpol.2024.122471
Cureus. 2024 Jul;16(7): e64833

Examining the Efficacy of Five Lactobacillus Species in Treating and Preventing Atopic Dermatitis: A Systemic Literature Review.

Imina Emokpae, Deanna L Tobia, Saskia D Stamm, Petra Lundy, Derek S Weimer, Michelle Demory Beckler.

  Probiotics have garnered increasing attention, particularly within the realm of atopic dermatitis (AD). Although classified as dietary supplements by the Food and Drug Administration, probiotics are being explored for their potential to modify immune system responses and aid in disease recovery. This review aims to provide a current understanding of probiotics, specifically various lactobacilli strains, as a therapeutic option in preventing and treating AD. The concept of the gut-skin axis has gained substantial recognition, emphasizing the complex relationship between the gut microbiome and skin health. Dysfunctional gut barriers and metabolites produced by gut microorganisms can exert profound influences on skin conditions, including AD. Lactobacilli species are particularly noteworthy for their resilience and stability within the gastrointestinal tract, making these bacteria ideal candidates for probiotic supplementation. Various lactobacilli strains (Lactobacillus salivarius, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus reuteri, and Lactobacillus rhamnosus) were included in this study due to their current uses in mitigating AD symptomatology. This systemic review article aims to shed light on the potential of probiotics as a therapeutic approach for AD, highlighting their stellar safety profile and promising therapeutic efficacy. Given the compelling preliminary findings and the constraints associated with conventional treatments, probiotics, particularly lactobacilli strains, emerge as a considerable alternative or adjuvant option for individuals grappling with AD. Further exploration is imperative to establish probiotics as a promising therapeutic option, providing renewed hope for those seeking effective strategies for managing AD.

Keywords:  atopic dermatitis; dermatology; eczema; lactobacillus; medicine; microbiology; microbiome; nutrition; nutrition and dermatology; probiotics

DOI:  https://doi.org/10.7759/cureus.64833
Ecotoxicol Environ Saf. 2024 Aug 19. pii: S0147-6513(24)00897-2. [Epub ahead of print]284 116821

Translocation of probiotics via gut-lung axis enhanced pulmonary immunity of weaned piglets exposed to low concentrations of ammonia.

Jiajun Yang, Jing Wang, Peng Shang, Zongliang Liu, Bo Zhang, Dongsheng Yang, Hao Zhang.

  OBJECTIVE: Lactobacillus salivarius is a probiotic bacteria strain in human and animal diets. The administration of probiotics to weaned piglets may improve their growth by optimizing the gastrointestinal bacterial composition. To further investigate the effect of bacterial communication between the gastrointestinal tract and lungs on bodily immunity, we reared weaned piglets in a low-ammonia gas environment. L. salivarius was supplemented to explore its effects on pulmonary immunity and its potential for bacterial translocation.RESULTS: One hundred sixty weaned piglets were allocated to four groups: L. salivarius-supplemented, L. reuteri-supplemented, control, and antibiotic drug (aureomycin)-supplemented. The feeding duration was 28 d. The body weights of piglets administered a strain of Lactobacillus were better than those of the control (P < 0.01). The transcription level of immune factors interleukin 2 (IL-2), IL-4, interferon α (IFN-α), and tumor necrosis factor α (TNF-α) in cells of the ileum and lung was significantly higher (P < 0.01). Lung and ileal mucus tissues were isolated to sequence the bacterial composition, which suggested a higher richness in the lungs at the phylum level, which was not significant in the ileum. Functional bacteria were more abundant in the ileum and lungs. The proportion of the genera of Lactobacillus, Prevotella, Actinobacillus, and Prevotellaceae_ NK3B31_group increased in two tissues, and a lower ratio of Streptococcus, Escherichia-Shigella, and mycoplasma was detected. The correlation between the microbial genus composition and the levels of immune factors suggests that the abundance of Lactobacillus plays the same positive role in the lungs and ileum. Mycoplasmas play a negative role in ileal and pulmonary immunity. More Lactobacillus reuteri and anaerobic probiotic bacteria were detected in the lungs.
CONCLUSION: The colonization of Lactobacillus salivarius and Lactobacillus reuteri in the membrane of the ileum optimized the ileal microbial composition, enrolled other probiotic bacteria translating to the lung, improved the abundance of pulmonary microbiota, and enhanced immunity after exposure to low concentrations of ammonia.

Keywords:  Ileum; Immunity; Lactobacillus; Lung; Microbiota; Weaned Piglet

DOI:  https://doi.org/10.1016/j.ecoenv.2024.116821
Nat Commun. 2024 Aug 19. 15(1): 7118

Tissue-scale in vitro epithelial wrinkling and wrinkle-to-fold transition.

Jaeseung Youn, Dohui Kim, Hyunsu Kwak, Anna Lee, Dong Sung Kim.

Although epithelial folding is commonly studied using in vivo animal models, such models exhibit critical limitations in terms of real-time observation and independent control of experimental parameters. Here, we develop a tissue-scale in vitro epithelial bilayer folding model that incorporates an epithelium and extracellular matrix (ECM) hydrogel, thereby emulating various folding structures found in in vivo epithelial tissue. Beyond mere folding, our in vitro model realizes a hierarchical transition in the epithelial bilayer, shifting from periodic wrinkles to a single deep fold under compression. Experimental and theoretical investigations of the in vitro model imply that both the strain-stiffening of epithelium and the poroelasticity of ECM influence the folded structures of epithelial tissue. The proposed in vitro model will aid in investigating the underlying mechanism of tissue-scale in vivo epithelial folding relevant to developmental biology and tissue engineering.

DOI: https://doi.org/10.1038/s41467-024-51437-z
Front Immunol. 2024 ;15 1427457

Divergent effects of itaconate isomers on Coxiella burnetii growth in macrophages and in axenic culture.

Md Nur A Alam Siddique, Fabian Kellermeier, Martha Ölke, Mingming Zhao, Konrad Büssow, Peter J Oefner, Anja Lührmann, Katja Dettmer, Roland Lang.

  Aconitate decarboxylase-1 (ACOD1) is expressed by activated macrophages and generates itaconate that exerts anti-microbial and immunoregulatory effects. ACOD1-itaconate is essential for macrophage-mediated control of the intracellular pathogen Coxiella (C.) burnetii, which causes Q fever. Two isomers of itaconate, mesaconate and citraconate, have overlapping yet distinct activity on macrophage metabolism and inflammatory gene expression. Here, we found that all three isomers inhibited the growth of C. burnetii in axenic culture in ACCM-2 medium. However, only itaconate reduced C. burnetii replication efficiently in Acod1-/- macrophages. In contrast, addition of citraconate strongly increased C. burnetii replication in Acod1+/- macrophages, whereas mesaconate weakly enhanced bacterial burden in Acod1-/- macrophages. Analysis of intracellular isomers showed that exogenous citraconate and mesaconate inhibited the generation of itaconate by infected Acod1+/- macrophages. Uptake of added isomers into Acod1-/- macrophages was increased after infection for itaconate and mesaconate, but not for citraconate. Mesaconate, but not citraconate, competed with itaconate for uptake into macrophages. Taken together, inhibition of itaconate generation by macrophages and interference with the uptake of extracellular itaconate could be identified as potential mechanisms behind the divergent effects of citraconate and mesaconate on C. burnetii replication in macrophages or in axenic culture.

Keywords:  ACOD1; IRG1; citraconate; infection; itaconate; mesaconate; transport; uptake

DOI:  https://doi.org/10.3389/fimmu.2024.1427457