bims-bac4me 2024-02-18 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024‒02‒18
thirty papers selected by
Chun-Chi Chang, University Hospital Zurich

A pathway linking atopic dermatitis to skin microbes.
Recognition of yeast β-glucan particles triggers immunometabolic signaling required for trained immunity.
Microbiota encoded fatty-acid metabolism expands tuft cells to protect tissues homeostasis during Clostridioides difficile infection in the large intestine.
Longitudinal profiling of the microbiome at four body sites reveals core stability and individualized dynamics during health and disease.
Reduced Proliferative Capacity and Defense against Staphylococcus aureus in Human Nasal Mucosal Epithelium Lacking ZNF365.
Trained immunity-inducing vaccines: Harnessing innate memory for vaccine design and delivery.
Akkermansia muciniphila-induced trained immune phenotype increases bacterial intracellular survival and attenuates inflammation.
Complement in maternal milk shapes the infant microbiome.
A cross talk between microbial metabolites and host immunity: Its relevance for allergic diseases.
Spatiotemporal Clusters of ERK Activity Coordinate Cytokine-induced Inflammatory Responses in Human Airway Epithelial Cells.
The B7:CD28 family and friends: Unraveling coinhibitory interactions.
Monocyte-derived alveolar macrophages are key drivers of smoke-induced lung inflammation and tissue remodeling.
Genomic attributes of airway commensal bacteria and mucosa.
Role of Extracellular Vesicles in Immunity and Host Defense.
Diesel exhaust particle exposure exacerbates ciliary and epithelial barrier dysfunction in the multiciliated bronchial epithelium models.
Intestinal microbiota programming of alveolar macrophages influences severity of respiratory viral infection.
Host and microbial regulation of mitochondrial reactive oxygen species during mycobacterial infections.
Epithelial stem and progenitor cells of the upper airway.
Immunological aspects of probiotics for improving skin diseases: Influence on the Gut-Brain-Skin Axis.
Bacteriophage therapy for drug-resistant Staphylococcus aureus infections.
Defining signals that promote human alveolar type I differentiation.
Editorial: Synergistic combinatorial treatments to overcome antibiotic resistance.
The mucosal concept in chronic rhinosinusitis: Focus on the epithelial barrier.
Scrutinizing microbiome determinism: why deterministic hypotheses about the microbiome are conceptually ungrounded.
The phosphatidylinositol-5' phosphatase synaptojanin1 limits integrin-mediated invasion of Staphylococcus aureus.
Can Lacticaseibacillus rhamnosus CRL1505 postbiotic improve emergency myelopoiesis in immunocompromised mice?
TRPV4 Regulates the Macrophage Metabolic Response to Limit Sepsis-induced Lung Injury.
Keratinocyte integrin α3β1 induces expression of the macrophage stimulating factor, CSF-1, through a YAP/TEAD-dependent mechanism.
Constant Vigilance! Managing Threats to the Skin Barrier.
Pediatric human nose organoids demonstrate greater susceptibility, epithelial responses, and cytotoxicity than adults during RSV infection.

Cell Host Microbe. 2024 Feb 14. pii: S1931-3128(24)00013-1. [Epub ahead of print]32(2): 154-155

A pathway linking atopic dermatitis to skin microbes.

Jinfang Zhu.

Interactions between microbiota and host skin have an important impact on cutaneous immunity and inflammation. In this issue of Cell Host & Microbe, Cha et al. report that skin commensal bacteria-mediated priming of group 2 innate lymphoid cells in early life predisposes the mice to atopic dermatitis-like inflammation in adulthood.

DOI: https://doi.org/10.1016/j.chom.2024.01.009
iScience. 2024 Mar 15. 27(3): 109030

Recognition of yeast β-glucan particles triggers immunometabolic signaling required for trained immunity.

Cian J H Horneck Johnston, Anna E Ledwith, Mimmi L E Lundahl, Hugo Charles-Messance, Emer E Hackett, Simon D O'Shaughnessy, Jonah Clegg, Hannah Prendeville, John P McGrath, Aaron M Walsh, Sarah Case, Hollie Austen Byrne, Parth Gautam, Elaine Dempsey, Sinead C Corr, Frederick J Sheedy.

  Fungal β-glucans are major drivers of trained immunity which increases long-term protection against secondary infections. Heterogeneity in β-glucan source, structure, and solubility alters interaction with the phagocytic receptor Dectin-1 and could impact strategies to improve trained immunity in humans. Using a panel of diverse β-glucans, we describe the ability of a specific yeast-derived whole-glucan particle (WGP) to reprogram metabolism and thereby drive trained immunity in human monocyte-derived macrophages in vitro and mice bone marrow in vivo. Presentation of pure, non-soluble, non-aggregated WGPs led to the formation of the Dectin-1 phagocytic synapse with subsequent lysosomal mTOR activation, metabolic reprogramming, and epigenetic rewiring. Intraperitoneal or oral administration of WGP drove bone marrow myelopoiesis and improved mature macrophage responses, pointing to therapeutic and food-based strategies to drive trained immunity. Thus, the investment of a cell in a trained response relies on specific recognition of β-glucans presented on intact microbial particles through stimulation of the Dectin-1 phagocytic response.

Keywords:  Immunology; Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2024.109030
bioRxiv. 2024 Jan 31. pii: 2024.01.29.574039. [Epub ahead of print]

Microbiota encoded fatty-acid metabolism expands tuft cells to protect tissues homeostasis during Clostridioides difficile infection in the large intestine.

Tasia D Kellogg, Simona Ceglia, Benedikt M Mortzfeld, Abigail L Zeamer, Sage E Foley, Doyle V Ward, Shakti K Bhattarai, Beth A McCormick, Andrea Reboldi, Vanni Bucci.

Metabolic byproducts of the intestinal microbiota are crucial in maintaining host immune tone and shaping inter-species ecological dynamics. Among these metabolites, succinate is a driver of tuft cell (TC) differentiation and consequent type 2 immunity-dependent protection against invading parasites in the small intestine. Succinate is also a growth enhancer of the nosocomial pathogen Clostridioides difficile in the large intestine. To date, no research has shown the role of succinate in modulating TC dynamics in the large intestine, or the relevance of this immune pathway to C. difficile pathophysiology. Here we reveal the existence of a three-way circuit between commensal microbes, C. difficile and host epithelial cells which centers around succinate. Through selective microbiota depletion experiments we demonstrate higher levels of type 2 cytokines leading to expansion of TCs in the colon. We then demonstrate the causal role of the microbiome in modulating colonic TC abundance and subsequent type 2 cytokine induction using rational supplementation experiments with fecal transplants and microbial consortia of succinate-producing bacteria. We show that administration of a succinate-deficient Bacteroides thetaiotaomicron knockout (Δfrd) significantly reduces the enhanced type 2 immunity in mono-colonized mice. Finally, we demonstrate that mice prophylactically administered with the consortium of succinate-producing bacteria show reduced C. difficile -induced morbidity and mortality compared to mice administered with heat-killed bacteria or the vehicle. This effect is reduced in a partial tuft cell knockout mouse, Pou2f3 +/- , and nullified in the tuft cell knockout mouse, Pou2f3 -/- , confirming that the observed protection occurs via the TC pathway. Succinate is an intermediary metabolite of the production of short-chain fatty acids, and its concentration often increases during dysbiosis. The first barrier to enteric pathogens alike is the intestinal epithelial barrier, and host maintenance and strengthening of barrier integrity is vital to homeostasis. Considering our data, we propose that activation of TC by the microbiota-produced succinate in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by intestinal pathogens.

DOI: https://doi.org/10.1101/2024.01.29.574039
bioRxiv. 2024 Feb 01. pii: 2024.02.01.577565. [Epub ahead of print]

Longitudinal profiling of the microbiome at four body sites reveals core stability and individualized dynamics during health and disease.

Xin Zhou, Xiaotao Shen, Jethro S Johnson, Daniel J Spakowicz, Melissa Agnello, Wenyu Zhou, Monica Avina, Alexander Honkala, Faye Chleilat, Shirley Jingyi Chen, Kexin Cha, Shana Leopold, Chenchen Zhu, Lei Chen, Lin Lyu, Daniel Hornburg, Si Wu, Xinyue Zhang, Chao Jiang, Liuyiqi Jiang, Lihua Jiang, Ruiqi Jian, Andrew W Brooks, Meng Wang, Kévin Contrepois, Peng Gao, Sophia Miryam Schüssler-Fiorenza Rose, Thi Dong Binh Tran, Hoan Nguyen, Alessandra Celli, Bo-Young Hong, Eddy J Bautista, Yair Dorsett, Paula Kavathas, Yanjiao Zhou, Erica Sodergren, George M Weinstock, Michael P Snyder.

To understand dynamic interplay between the human microbiome and host during health and disease, we analyzed the microbial composition, temporal dynamics, and associations with host multi-omics, immune and clinical markers of microbiomes from four body sites in 86 participants over six years. We found that microbiome stability and individuality are body-site-specific and heavily influenced by the host. The stool and oral microbiome were more stable than the skin and nasal microbiomes, possibly due to their interaction with the host and environment. Also, we identified individual-specific and commonly shared bacterial taxa, with individualized taxa showing greater stability. Interestingly, microbiome dynamics correlated across body sites, suggesting systemic coordination influenced by host-microbial-environment interactions. Notably, insulin-resistant individuals showed altered microbial stability and associations between microbiome, molecular markers, and clinical features, suggesting their disrupted interaction in metabolic disease. Our study offers comprehensive views of multi-site microbial dynamics and their relationship with host health and disease.Study Highlights: The stability of the human microbiome varies among individuals and body sites.Highly individualized microbial genera are more stable over time.At each of the four body sites, systematic interactions between the environment, the host and bacteria can be detected.Individuals with insulin resistance have lower microbiome stability, a more diversified skin microbiome, and significantly altered host-microbiome interactions.

DOI: https://doi.org/10.1101/2024.02.01.577565
Int Arch Allergy Immunol. 2024 Feb 14. 1-14

Reduced Proliferative Capacity and Defense against Staphylococcus aureus in Human Nasal Mucosal Epithelium Lacking ZNF365.

Xiaoyun Du, Longgang Yu, Lin Wang, Xudong Yan, Bingqing Xu, Fangyu Chai, Danyang Li, Jiajia Zi, Jisheng Zhang, Yan Jiang.

  INTRODUCTION: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common chronic inflammatory disease of the nose characterized by barrier disruption and environmental susceptibility, and the deletion of ZNF365 may be a factor inducing these manifestations. However, there is no study on the mechanism of action between CRSwNP and ZNF365. Therefore, this study focuses on the effect of the zinc finger protein ZNF365 on the proliferation of nasal mucosal epithelial cells and their defense against Staphylococcus aureus (S. aureus).METHODS: Immunohistochemistry and Western blot were applied to verify the changes of ZNF365 expression in nasal polyp tissues and control tissues, as well as in primary epithelial cells. ZNF365 was knocked down in human nasal mucosa epithelial cell line (HNEpc), and the proliferation, migration, and transdifferentiation of epithelium were observed by immunofluorescence, QPCR, CCK8, and cell scratch assay. The changes of mesenchymal markers and TLR4-MAPK-NF-κB pathway were also observed after the addition of S. aureus.
RESULTS: ZNF365 expression was reduced in NP tissues and primary nasal mucosal epithelial cells compared to controls. Knockdown of ZNF365 in HNEpc resulted in decreased proliferation and migration ability of epithelial cells and abnormal epithelial differentiation (decreased expression of tight junction proteins). S. aureus stimulation further inhibited epithelial cell proliferation and migration, while elevated markers of epithelial-mesenchymal transition and inflammatory responses occurred.
CONCLUSION: ZNF365 is instrumental in maintaining the proliferative capacity of nasal mucosal epithelial cells and defending against the invasion of S. aureus. The findings suggest that ZNF365 may participate in the development of CRSwNP.

Keywords:  Chronic rhinosinusitis with nasal polyps; Epithelial-mesenchymal transition; Proliferative capacity; Staphylococcus aureus; ZNF365

DOI:  https://doi.org/10.1159/000536106
Clin Immunol. 2024 Feb 09. pii: S1521-6616(24)00041-X. [Epub ahead of print]261 109930

Trained immunity-inducing vaccines: Harnessing innate memory for vaccine design and delivery.

Ilayda Baydemir, Elisabeth A Dulfer, Mihai G Netea, Jorge Domínguez-Andrés.

  While the efficacy of many current vaccines is well-established, various factors can diminish their effectiveness, particularly in vulnerable groups. Amidst emerging pandemic threats, enhancing vaccine responses is critical. Our review synthesizes insights from immunology and epidemiology, focusing on the concept of trained immunity (TRIM) and the non-specific effects (NSEs) of vaccines that confer heterologous protection. We elucidate the mechanisms driving TRIM, emphasizing its regulation through metabolic and epigenetic reprogramming in innate immune cells. Notably, we explore the extended protective scope of vaccines like BCG and COVID-19 vaccines against unrelated infections, underscoring their role in reducing neonatal mortality and combating diseases like malaria and yellow fever. We also highlight novel strategies to boost vaccine efficacy, incorporating TRIM inducers into vaccine formulations to enhance both specific and non-specific immune responses. This approach promises significant advancements in vaccine development, aiming to improve global public health outcomes, especially for the elderly and immunocompromised populations.

Keywords:  BCG; Innate immunity; Non-specific effects; Trained immunity; Vaccines

DOI:  https://doi.org/10.1016/j.clim.2024.109930
Commun Biol. 2024 Feb 16. 7(1): 192

Akkermansia muciniphila-induced trained immune phenotype increases bacterial intracellular survival and attenuates inflammation.

Ainize Peña-Cearra, Ainhoa Palacios, Aize Pellon, Janire Castelo, Samuel Tanner Pasco, Iratxe Seoane, Diego Barriales, Jose Ezequiel Martin, Miguel Ángel Pascual-Itoiz, Monika Gonzalez-Lopez, Itziar Martín-Ruiz, Nuria Macías-Cámara, Naiara Gutiez, Sarai Araujo-Aris, Ana Mª Aransay, Héctor Rodríguez, Juan Anguita, Leticia Abecia.

The initial exposure to pathogens and commensals confers innate immune cells the capacity to respond distinctively upon a second stimulus. This training capacity might play key functions in developing an adequate innate immune response to the continuous exposure to bacteria. However, the mechanisms involved in induction of trained immunity by commensals remain mostly unexplored. A. muciniphila represents an attractive candidate to study the promotion of these long-term responses. Here, we show that priming of macrophages with live A. muciniphila enhances bacterial intracellular survival and decreases the release of pro- and anti-inflammatory signals, lowering the production of TNF and IL-10. Global transcriptional analysis of macrophages after a secondary exposure to the bacteria showed the transcriptional rearrangement underpinning the phenotype observed compared to acutely exposed cells, with the increased expression of genes related to phagocytic capacity and those involved in the metabolic adjustment conducing to innate immune training. Accordingly, key genes related to bacterial killing and pro-inflammatory pathways were downregulated. These data demonstrate the importance of specific bacterial members in the modulation of local long-term innate immune responses, broadening our knowledge of the association between gut microbiome commensals and trained immunity as well as the anti-inflammatory probiotic potential of A. muciniphila.

DOI: https://doi.org/10.1038/s42003-024-05867-6
Nat Rev Immunol. 2024 Feb 13.

Complement in maternal milk shapes the infant microbiome.

Maria Papatriantafyllou.

DOI: https://doi.org/10.1038/s41577-024-01006-8
Clin Transl Allergy. 2024 Feb;14(2): e12339

A cross talk between microbial metabolites and host immunity: Its relevance for allergic diseases.

Purevsuren Losol, Magdalena Wolska, Tomasz P Wypych, Lu Yao, Liam O'Mahony, Milena Sokolowska.

  BACKGROUND: Allergic diseases, including respiratory and food allergies, as well as allergic skin conditions have surged in prevalence in recent decades. In allergic diseases, the gut microbiome is dysbiotic, with reduced diversity of beneficial bacteria and increased abundance of potential pathogens. Research findings suggest that the microbiome, which is highly influenced by environmental and dietary factors, plays a central role in the development, progression, and severity of allergic diseases. The microbiome generates metabolites, which can regulate many of the host's cellular metabolic processes and host immune responses.AIMS AND METHODS: Our goal is to provide a narrative and comprehensive literature review of the mechanisms through which microbial metabolites regulate host immune function and immune metabolism both in homeostasis and in the context of allergic diseases.
RESULTS AND DISCUSSION: We describe key microbial metabolites such as short-chain fatty acids, amino acids, bile acids and polyamines, elucidating their mechanisms of action, cellular targets and their roles in regulating metabolism within innate and adaptive immune cells. Furthermore, we characterize the role of bacterial metabolites in the pathogenesis of allergic diseases including allergic asthma, atopic dermatitis and food allergy.
CONCLUSION: Future research efforts should focus on investigating the physiological functions of microbiota-derived metabolites to help develop new diagnostic and therapeutic interventions for allergic diseases.

Keywords:  allergy; immune metabolism; immune response; microbial metabolites; microbiome

DOI:  https://doi.org/10.1002/clt2.12339
bioRxiv. 2024 Feb 04. pii: 2024.02.03.578773. [Epub ahead of print]

Spatiotemporal Clusters of ERK Activity Coordinate Cytokine-induced Inflammatory Responses in Human Airway Epithelial Cells.

Nicholaus L DeCuzzi, Daniel Oberbauer, Kenneth J Chmiel, Michael Pargett, Justa M Ferguson, Devan Murphy, Amir A Zeki, John G Albeck.

RATIONALE: Spatially coordinated ERK signaling events ("SPREADs") transmit radially from a central point to adjacent cells via secreted ligands for EGFR and other receptors. SPREADs maintain homeostasis in non-pulmonary epithelia, but it is unknown whether they play a role in the airway epithelium or are dysregulated in inflammatory disease.OBJECTIVES: (1) To characterize the spatial heterogeneity of ERK activity in response to pro-inflammatory ligands, and (2) to assess the effects of pharmacological and metabolic regulators on cytokine-mediated SPREADs.
METHODS: Live-cell ERK biosensor activity and SPREAD events were measured in human bronchial epithelial cell lines (HBE1 and 16HBE) and primary human bronchial epithelial cells (pHBE), in both submerged and biphasic Air-Liquid Interface (ALI) culture conditions (i.e., differentiated cells). Cells were exposed to pro-inflammatory cytokines relevant to asthma and chronic obstructive pulmonary disease (COPD), and to pharmacological treatments (gefitinib, tocilizumab, hydrocortisone) and metabolic modulators (insulin, 2-deoxyglucose) to probe the airway epithelial mechanisms of SPREADs. Phospho-STAT3 immunofluorescence was used to measure localized inflammatory responses to IL-6.
MEASUREMENTS AND MAIN RESULTS: Pro-inflammatory cytokines significantly increased the frequency of SPREADs. Notably, differentiated pHBE cells display increased SPREAD frequency that coincides with airway epithelial barrier breakdown. SPREADs correlate with IL-6 peptide secretion and localized pSTAT3. Hydrocortisone, inhibitors of receptor signaling, and suppression of metabolic function decreased SPREADs and local STAT3 activation.
CONCLUSIONS: Pro-inflammatory cytokines modulate SPREADs in human airway epithelial cells via both secreted EGFR and IL6R ligands. SPREADs correlate with changes in epithelial barrier permeability, implying a role for spatiotemporal ERK signaling in barrier homeostasis and dysfunction during inflammation. The involvement of SPREADs in airway inflammation suggests a novel signaling mechanism that could be exploited clinically to supplement corticosteroid treatment for asthma and COPD.
One Sentence Summary: We demonstrate that proinflammatory cytokines cause spatiotemporally organized ERK signaling events called "SPREADs" in human airway epithelial cells, correlating with conditions that disrupt epithelial barrier function.
At a Glance Commentary: Scientific Knowledge on the Subject: Airway epithelial cells play a critical role in the innate immune response to pro-inflammatory conditions. This response must coordinate the recruitment of adaptive immune cells and permit their trans-epithelial migration. ERK signaling is required for these events and has been shown to modulate cell fate outcomes via temporally dynamic activity. Pro-inflammatory conditions may therefore rely on spatially and temporally specific ERK signaling to coordinate immune responses. However, the occurrence of spatially localized signaling events in the airway epithelium has not been investigated. What This Study Adds to the Field: Combining live-cell ERK biosensors with multiple human airway epithelial models, we demonstrate that pro-inflammatory cytokines induce spatially localized ERK signaling. In addition, we find that the common anti-inflammatory treatments tocilizumab, gefitinib, and hydrocortisone suppress cytokine-induced SPREADs. These findings suggest that localized ERK signaling coordinates the innate immune response via spatially restricted cytokine release and regulation of airway barrier permeability.

DOI: https://doi.org/10.1101/2024.02.03.578773
Immunity. 2024 Feb 13. pii: S1074-7613(24)00038-4. [Epub ahead of print]57(2): 223-244

The B7:CD28 family and friends: Unraveling coinhibitory interactions.

Kelly P Burke, Apoorvi Chaudhri, Gordon J Freeman, Arlene H Sharpe.

Immune responses must be tightly regulated to ensure both optimal protective immunity and tolerance. Costimulatory pathways within the B7:CD28 family provide essential signals for optimal T cell activation and clonal expansion. They provide crucial inhibitory signals that maintain immune homeostasis, control resolution of inflammation, regulate host defense, and promote tolerance to prevent autoimmunity. Tumors and chronic pathogens can exploit these pathways to evade eradication by the immune system. Advances in understanding B7:CD28 pathways have ushered in a new era of immunotherapy with effective drugs to treat cancer, autoimmune diseases, infectious diseases, and transplant rejection. Here, we discuss current understanding of the mechanisms underlying the coinhibitory functions of CTLA-4, PD-1, PD-L1:B7-1 and PD-L2:RGMb interactions and less studied B7 family members, including HHLA2, VISTA, BTNL2, and BTN3A1, as well as their overlapping and unique roles in regulating immune responses, and the therapeutic potential of these insights.

DOI: https://doi.org/10.1016/j.immuni.2024.01.013
Front Immunol. 2024 ;15 1325090

Monocyte-derived alveolar macrophages are key drivers of smoke-induced lung inflammation and tissue remodeling.

Christian T Wohnhaas, Kevin Baßler, Carolin K Watson, Yang Shen, Germán G Leparc, Cornelia Tilp, Fabian Heinemann, David Kind, Birgit Stierstorfer, Denis Delić, Thomas Brunner, Florian Gantner, Joachim L Schultze, Coralie Viollet, Patrick Baum.

  Smoking is a leading risk factor of chronic obstructive pulmonary disease (COPD), that is characterized by chronic lung inflammation, tissue remodeling and emphysema. Although inflammation is critical to COPD pathogenesis, the cellular and molecular basis underlying smoking-induced lung inflammation and pathology remains unclear. Using murine smoke models and single-cell RNA-sequencing, we show that smoking establishes a self-amplifying inflammatory loop characterized by an influx of molecularly heterogeneous neutrophil subsets and excessive recruitment of monocyte-derived alveolar macrophages (MoAM). In contrast to tissue-resident AM, MoAM are absent in homeostasis and characterized by a pro-inflammatory gene signature. Moreover, MoAM represent 46% of AM in emphysematous mice and express markers causally linked to emphysema. We also demonstrate the presence of pro-inflammatory and tissue remodeling associated MoAM orthologs in humans that are significantly increased in emphysematous COPD patients. Inhibition of the IRAK4 kinase depletes a rare inflammatory neutrophil subset, diminishes MoAM recruitment, and alleviates inflammation in the lung of cigarette smoke-exposed mice. This study extends our understanding of the molecular signaling circuits and cellular dynamics in smoking-induced lung inflammation and pathology, highlights the functional consequence of monocyte and neutrophil recruitment, identifies MoAM as key drivers of the inflammatory process, and supports their contribution to pathological tissue remodeling.

Keywords:  COPD; IRAK4 inhibitor; lung inflammation; monocyte-derived alveolar macrophages; neutrophils; single-cell RNA-sequencing; smoking; tissue remodeling

DOI:  https://doi.org/10.3389/fimmu.2024.1325090
Commun Biol. 2024 Feb 12. 7(1): 171

Genomic attributes of airway commensal bacteria and mucosa.

Leah Cuthbertson, Ulrike Löber, Jonathan S Ish-Horowicz, Claire N McBrien, Colin Churchward, Jeremy C Parker, Michael T Olanipekun, Conor Burke, Aisling McGowan, Gwyneth A Davies, Keir E Lewis, Julian M Hopkin, Kian Fan Chung, Orla O'Carroll, John Faul, Joy Creaser-Thomas, Mark Andrews, Robin Ghosal, Stefan Piatek, Saffron A G Willis-Owen, Theda U P Bartolomaeus, Till Birkner, Sarah Dwyer, Nitin Kumar, Elena M Turek, A William Musk, Jennie Hui, Michael Hunter, Alan James, Marc-Emmanuel Dumas, Sarah Filippi, Michael J Cox, Trevor D Lawley, Sofia K Forslund, Miriam F Moffatt, William O C Cookson.

Microbial communities at the airway mucosal barrier are conserved and highly ordered, in likelihood reflecting co-evolution with human host factors. Freed of selection to digest nutrients, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the initial results of systematic culture and whole-genome sequencing of the thoracic airway bacteria, identifying 52 novel species amongst 126 organisms that constitute 75% of commensals typically present in heathy individuals. Clinically relevant genes encode antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. Using whole-genome content we identify dysbiotic features that may influence asthma and chronic obstructive pulmonary disease. We match isolate gene content to transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways to sustain host interactions with microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosa in lung diseases of global significance.

DOI: https://doi.org/10.1038/s42003-024-05840-3
Immunol Invest. 2024 Feb 13. 1-16

Role of Extracellular Vesicles in Immunity and Host Defense.

Puja Kumari, Skylar S Wright, Vijay A Rathinam.

  Extracellular vesicles (EVs) are membrane-bound structures released by cells and have become significant players in immune system functioning, primarily by facilitating cell-to-cell communication. Immune cells like neutrophils and dendritic cells release EVs containing bioactive molecules that modulate chemotaxis, activate immune cells, and induce inflammation. EVs also contribute to antigen presentation, lymphocyte activation, and immune tolerance. Moreover, EVs play pivotal roles in antimicrobial host defense. They deliver microbial antigens to antigen-presenting cells (APCs), triggering immune responses, or act as decoys to neutralize virulence factors and toxins. This review discusses host and microbial EVs' multifaceted roles in innate and adaptive immunity, highlighting their involvement in immune cell development, antigen presentation, and antimicrobial responses.

Keywords:  Ectosomes; OMVs; exosomes; extracellular vesicles; microvesicles

DOI:  https://doi.org/10.1080/08820139.2024.2312896
Ecotoxicol Environ Saf. 2024 Feb 15. pii: S0147-6513(24)00165-9. [Epub ahead of print]273 116090

Diesel exhaust particle exposure exacerbates ciliary and epithelial barrier dysfunction in the multiciliated bronchial epithelium models.

Eunsook Park, Bu-Yeo Kim, Seahyoung Lee, Kuk Hui Son, Jihye Bang, Se Hyang Hong, Joong Won Lee, Kyung-Ok Uhm, Hyun-Jeong Kwak, Hyun Joung Lim.

  Airway epithelium, the first defense barrier of the respiratory system, facilitates mucociliary clearance against inflammatory stimuli, such as pathogens and particulates inhaled into the airway and lung. Inhaled particulate matter 2.5 (PM2.5) can penetrate the alveolar region of the lung, and it can develop and exacerbate respiratory diseases. Although the pathophysiological effects of PM2.5 in the respiratory system are well known, its impact on mucociliary clearance of airway epithelium has yet to be clearly defined. In this study, we used two different 3D in vitro airway models, namely the EpiAirway-full-thickness (FT) model and a normal human bronchial epithelial cell (NHBE)-based air-liquid interface (ALI) system, to investigate the effect of diesel exhaust particles (DEPs) belonging to PM2.5 on mucociliary clearance. RNA-sequencing (RNA-Seq) analyses of EpiAirway-FT exposed to DEPs indicated that DEP-induced differentially expressed genes (DEGs) are related to ciliary and microtubule function and inflammatory-related pathways. The exposure to DEPs significantly decreased the number of ciliated cells and shortened ciliary length. It reduced the expression of cilium-related genes such as acetylated α-tubulin, ARL13B, DNAH5, and DNAL1 in the NHBEs cultured in the ALI system. Furthermore, DEPs significantly increased the expression of MUC5AC, whereas they decreased the expression of epithelial junction proteins, namely, ZO1, Occludin, and E-cadherin. Impairment of mucociliary clearance by DEPs significantly improved the release of epithelial-derived inflammatory and fibrotic mediators such as IL-1β, IL-6, IL-8, GM-CSF, MMP-1, VEGF, and S100A9. Taken together, it can be speculated that DEPs can cause ciliary dysfunction, hyperplasia of goblet cells, and the disruption of the epithelial barrier, resulting in the hyperproduction of lung injury mediators. Our data strongly suggest that PM2.5 exposure is directly associated with ciliary and epithelial barrier dysfunction and may exacerbate lung injury.

Keywords:  Air-liquid interface; Ciliary function; Diesel exhaust particle; Mucociliary clearance; Normal human bronchial epithelial cell

DOI:  https://doi.org/10.1016/j.ecoenv.2024.116090
Cell Host Microbe. 2024 Jan 23. pii: S1931-3128(24)00006-4. [Epub ahead of print]

Intestinal microbiota programming of alveolar macrophages influences severity of respiratory viral infection.

Vu L Ngo, Carolin M Lieber, Hae-Ji Kang, Kaori Sakamoto, Michal Kuczma, Richard K Plemper, Andrew T Gewirtz.

  Susceptibility to respiratory virus infections (RVIs) varies widely across individuals. Because the gut microbiome impacts immune function, we investigated the influence of intestinal microbiota composition on RVI and determined that segmented filamentous bacteria (SFB), naturally acquired or exogenously administered, protected mice against influenza virus (IAV) infection. Such protection, which also applied to respiratory syncytial virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was independent of interferon and adaptive immunity but required basally resident alveolar macrophages (AMs). In SFB-negative mice, AMs were quickly depleted as RVI progressed. In contrast, AMs from SFB-colonized mice were intrinsically altered to resist IAV-induced depletion and inflammatory signaling. Yet, AMs from SFB-colonized mice were not quiescent. Rather, they directly disabled IAV via enhanced complement production and phagocytosis. Accordingly, transfer of SFB-transformed AMs into SFB-free hosts recapitulated SFB-mediated protection against IAV. These findings uncover complex interactions that mechanistically link the intestinal microbiota with AM functionality and RVI severity.

Keywords:  complement; gut-lung axis; inflammatory anergy; influenza; macrophages; phagocytosis; segmented filamentous bacteria

DOI:  https://doi.org/10.1016/j.chom.2024.01.002
Mitochondrion. 2024 Feb 13. pii: S1567-7249(24)00010-2. [Epub ahead of print] 101852

Host and microbial regulation of mitochondrial reactive oxygen species during mycobacterial infections.

Jin Kyung Kim, Eun-Kyeong Jo.

  Mycobacteria, including Mycobacterium tuberculosis (Mtb) and non-tuberculous mycobacteria (NTM), pose challenges in treatment due to their increased resistance to antibiotics. Following infection, mycobacteria and their components trigger robust innate and inflammatory immune responses intricately associated with the modulation of mitochondrial functions, including oxidative phosphorylation (OXPHOS) and metabolism. Certainly, mitochondrial reactive oxygen species (mtROS) are an inevitable by-product of OXPHOS and function as a bactericidal weapon; however, an excessive accumulation of mtROS are linked to pathological inflammation and necroptotic cell death during mycobacterial infection. Despite previous studies outlining various host pathways involved in regulating mtROS levels during antimicrobial responses in mycobacterial infection, our understanding of the precise mechanisms orchestrating the fine regulation of this response remains limited. Emerging evidence suggests that mycobacterial proteins play a role in targeting the mitochondria of the host, indicating the potential influence of microbial factors on mitochondrial functions within host cells. In this Review, we provide an overview of how both host and Mtb factors influence mtROS generation during infection. A comprehensive study of host and microbial factors that target mtROS will shed light on innovative approaches for effectively managing drug-resistant mycobacterial infections.

Keywords:  Infection; Mitochondria; Mycobacteria; Mycobacterial effectors; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.mito.2024.101852
Cells Dev. 2024 Feb 12. pii: S2667-2901(24)00006-8. [Epub ahead of print] 203905

Epithelial stem and progenitor cells of the upper airway.

Maral J Rouhani, Sam M Janes, Carla Kim.

  The upper airway acts as a conduit for the passage of air to the respiratory system and is implicated in several chronic diseases. Whilst the cell biology of the distal respiratory system has been described in great detail, less is known about the proximal upper airway. In this review, we describe the relevant anatomy of the upper airway and discuss the literature detailing the identification and roles of the progenitor cells of these regions.

Keywords:  Airway stem cells; Laryngeal stem cells; Lung stem cells; Nasal stem cells; Stem cells

DOI:  https://doi.org/10.1016/j.cdev.2024.203905
Biochem Biophys Res Commun. 2024 Feb 05. pii: S0006-291X(24)00168-2. [Epub ahead of print]702 149632

Immunological aspects of probiotics for improving skin diseases: Influence on the Gut-Brain-Skin Axis.

Ali Abdi, Parvin Oroojzadeh, Nassim Valivand, Roshanak Sambrani, Hajie Lotfi.

  The interplay between gut microbiota and human health, both mental and physical, is well-documented. This connection extends to the gut-brain-skin axis, linking gut microbiota to skin health. Recent studies have underscored the potential of probiotics and prebiotics to modulate gut microbiota, supported by in vivo and clinical investigations. In this comprehensive review, we explore the immunological implications of probiotics in influencing the gut-skin axis for the treatment and prevention of skin conditions, including psoriasis, acne, diabetic ulcers, atopic dermatitis, and skin cancer. Our analysis reveals that probiotics exert their effects by modulating cytokine production, whether administered orally or topically. Probiotics bolster skin defenses through the production of antimicrobial peptides and the induction of keratinocyte differentiation and regeneration. Yet, many questions surrounding probiotics remain unanswered, necessitating further exploration of their mechanisms of action in the context of skin diseases.

Keywords:  Gut-brain-skin axis; Probiotics; Skin diseases; Skin wound

DOI:  https://doi.org/10.1016/j.bbrc.2024.149632
Front Cell Infect Microbiol. 2024 ;14 1336821

Bacteriophage therapy for drug-resistant Staphylococcus aureus infections.

Kaixin Liu, Chao Wang, Xudong Zhou, Xudong Guo, Yi Yang, Wanying Liu, Rongtao Zhao, Hongbin Song.

  Drug-resistant Staphylococcus aureus stands as a prominent pathogen in nosocomial and community-acquired infections, capable of inciting various infections at different sites in patients. This includes Staphylococcus aureus bacteremia (SaB), which exhibits a severe infection frequently associated with significant mortality rate of approximately 25%. In the absence of better alternative therapies, antibiotics is still the main approach for treating infections. However, excessive use of antibiotics has, in turn, led to an increase in antimicrobial resistance. Hence, it is imperative that new strategies are developed to control drug-resistant S. aureus infections. Bacteriophages are viruses with the ability to infect bacteria. Bacteriophages, were used to treat bacterial infections before the advent of antibiotics, but were subsequently replaced by antibiotics due to limited theoretical understanding and inefficient preparation processes at the time. Recently, phages have attracted the attention of many researchers again because of the serious problem of antibiotic resistance. This article provides a comprehensive overview of phage biology, animal models, diverse clinical case treatments, and clinical trials in the context of drug-resistant S. aureus phage therapy. It also assesses the strengths and limitations of phage therapy and outlines the future prospects and research directions. This review is expected to offer valuable insights for researchers engaged in phage-based treatments for drug-resistant S. aureus infections.

Keywords:  antimicrobial resistance; bacteriophage therapy; bacteriophages; drug-resistant Staphylococcus aureus; infection

DOI:  https://doi.org/10.3389/fcimb.2024.1336821
Am J Physiol Lung Cell Mol Physiol. 2024 Feb 13.

Defining signals that promote human alveolar type I differentiation.

Yong Li, Y S Prakash, Qi Tan, Daniel J Tschumperlin.

  Alveolar type I (ATI) cells cover >95% of the lung's distal surface and facilitate gas exchange through their exceptionally thin shape. ATI cells in vivo are replenished by alveolar type II cell division and differentiation, but a detailed understanding of ATI biology has been hampered by the challenges in direct isolation of these cell due to their fragility, and incomplete understanding of the signaling interactions that promote differentiation of ATII to ATI cells. Here we explored the signals that maintain ATII versus promote ATI fates in 3D organoid cultures, and developed a human alveolar type I differentiation medium (hATIDM) suitable for generating ATI cells from either mixed distal human lung cells or purified ATII cells. This media adds bone morphogenetic protein 4 (BMP4) and removes epidermal growth factor (EGF), Wnt agonist CHIR99021, and transforming growth factor-beta (TGF-beta) inhibitor SB431542 from previously developed alveolar organoid culture media. We demonstrate that BMP4 promotes expression of the ATI marker gene AGER whereas CHIR99021 and SB431542 maintain expression of the ATII marker gene SFTPC. The human ATI spheroids generated with hATIDM express multiple molecular and morphological features reminiscent of human ATI cells. Our results demonstrate that signaling interactions among BMP, TGF-beta and Wnt signaling pathways in alveolar spheroids and distal lung organoids including IPF-organoids coordinate human ATII to ATI differentiation.

Keywords:  Alveolar epithelial cells; Differentiation; Organoids; Stem Cells; cell signal

DOI:  https://doi.org/10.1152/ajplung.00191.2023
Front Cell Infect Microbiol. 2024 ;14 1369264

Editorial: Synergistic combinatorial treatments to overcome antibiotic resistance.

Javier A Garza-Cervantes, Angel León-Buitimea.



Keywords:  antibiotic resistance; antimicrobial biopolymers; antimicrobial nanocomposites; antimicrobial nanoparticles; antimicrobial peptides; green synthesis; synergistic treatment

DOI:  https://doi.org/10.3389/fcimb.2024.1369264
J Allergy Clin Immunol. 2024 Jan 29. pii: S0091-6749(24)00083-6. [Epub ahead of print]

The mucosal concept in chronic rhinosinusitis: Focus on the epithelial barrier.

Bing Yan, Feng Lan, Jingyun Li, Chengshuo Wang, Luo Zhang.

  Chronic rhinosinusitis (CRS) is a common chronic nasal cavity and sinus disease, affecting a growing number of individuals worldwide. Recent advances have shifted our understanding of CRS pathophysiology from a physical obstruction model of ventilation and drainage to a mucosal concept that recognizes the complexities of mucosal immunological variations and cellular aberrations. A growing number of studies have demonstrated the alteration of the epithelial barrier during inflammatory states. Therefore, the current review has focused on the crucial role of epithelial cells within this mucosal framework in CRS, detailing the perturbed epithelial homeostasis, the impaired epithelial cell barrier, dysregulated epithelial cell repair processes, as well as enhanced interactions between epithelial cells and immune cells. Notably, the utilization of novel technologies, such as single-cell transcriptomics, has revealed the novel functions of epithelial barriers, such as inflammatory memory and neuroendocrine functions. Therefore, this review also emphasizes the importance of epithelial inflammatory memory and the necessity of further investigations into neuroendocrine epithelial cells and neurogenic inflammation in CRS. In the end, we contemplate the prospective benefits of epithelial cell-oriented biological treatments, which are currently under investigation in rigorous randomized, double-blind clinical trials in patients with CRSwNP.

Keywords:  Chronic rhinosinusitis; epithelial barrier; mucosal concept; type 2 immunity

DOI:  https://doi.org/10.1016/j.jaci.2024.01.015
Hist Philos Life Sci. 2024 Feb 12. 46(1): 12

Scrutinizing microbiome determinism: why deterministic hypotheses about the microbiome are conceptually ungrounded.

Javier Suárez.

  This paper addresses the topic of determinism in contemporary microbiome research. I distinguish two types of deterministic claims about the microbiome, and I show evidence that both types of claims are present in the contemporary literature. First, the idea that the host genetics determines the composition of the microbiome which I call "host-microbiome determinism". Second, the idea that the genetics of the holobiont (the individual unit composed by a host plus its microbiome) determines the expression of certain phenotypic traits, which I call "microbiome-phenotype determinism". Drawing on the stability of traits conception of individuality (Suárez in Hist Philos Life Sci 42:11, 2020) I argue that none of these deterministic hypotheses is grounded on our current knowledge of how the holobiont is transgenerationally assembled, nor how it expresses its phenotypic traits.

Keywords:  Causality; Hologenome; Microbiome heritability; Microbiota; Phylosymbiosis; Postgenomic determinism

DOI:  https://doi.org/10.1007/s40656-024-00610-0
Microbiol Spectr. 2024 Feb 15. e0200623

The phosphatidylinositol-5' phosphatase synaptojanin1 limits integrin-mediated invasion of Staphylococcus aureus.

Yong Shi, Petra Muenzner, Stefanie Schanz-Jurinka, Christof R Hauck.

  The gram-positive bacterium Staphylococcus aureus can invade non-professional phagocytic cells by associating with the plasma protein fibronectin to exploit host cell integrins. Integrin-mediated internalization of these pathogens is facilitated by the local production of phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) via an integrin-associated isoform of phosphatidylinositol-5' kinase. In this study, we addressed the role of PI-4,5-P2-directed phosphatases on internalization of S. aureus. ShRNA-mediated knockdown of individual phosphoinositide 5-phosphatases revealed that synaptojanin1 (SYNJ1) is counteracting invasion of S. aureus into mammalian cells. Indeed, shRNA-mediated depletion as well as genetic deletion of synaptojanin1 via CRISPR/Cas9 resulted in a gain-of-function phenotype with regard to integrin-mediated uptake. Surprisingly, the surface level of integrins was slightly downregulated in Synj1-KO cells. Nevertheless, these cells showed enhanced local accumulation of PI-4,5-P2 and exhibited increased internalization of S. aureus. While the phosphorylation level of the integrin-associated protein tyrosine kinase FAK was unaltered, the integrin-binding and -activating protein talin was enriched in the vicinity of S. aureus in synaptojanin1 knockout cells. Scanning electron microscopy revealed enlarged membrane invaginations in the absence of synaptojanin1 explaining the increased capability of these cells to internalize integrin-bound microorganisms. Importantly, the enhanced uptake by Synj1-KO cells and the exaggerated morphological features were rescued by the re-expression of the wild-type enzyme but not phosphatase inactive mutants. Accordingly, synaptojanin1 activity limits integrin-mediated invasion of S. aureus, corroborating the important role of PI-4,5-P2 during this process.IMPORTANCEStaphylococcus aureus, an important bacterial pathogen, can invade non-professional phagocytes by capturing host fibronectin and engaging integrin α5β1. Understanding how S. aureus exploits this cell adhesion receptor for efficient cell entry can also shed light on the physiological regulation of integrins by endocytosis. Previous studies have found that a specific membrane lipid, phosphatidylinositol-4,5-bisphosphate (PIP2), supports the internalization process. Here, we extend these findings and report that the local levels of PIP2 are controlled by the activity of the PIP2-directed lipid phosphatase Synaptojanin1. By dephosphorylating PIP2 at bacteria-host cell attachment sites, Synaptojanin1 counteracts the integrin-mediated uptake of the microorganisms. Therefore, our study not only generates new insight into subversion of cellular receptors by pathogenic bacteria but also highlights the role of host cell proteins acting as restriction factors for bacterial invasion at the plasma membrane.

Keywords:  5-bisphosphate; Staphylococcus aureus; integrin; internalization; phosphatase; phosphatidylinositol-4; synaptojanin1

DOI:  https://doi.org/10.1128/spectrum.02006-23
Microbes Infect. 2024 Feb 09. pii: S1286-4579(24)00031-5. [Epub ahead of print] 105311

Can Lacticaseibacillus rhamnosus CRL1505 postbiotic improve emergency myelopoiesis in immunocompromised mice?

Andrés Gramajo Lopez, Brenda Vasile, Yanina Kolling, Maximiliano Ivir, Florencia Gutiérrez, Susana Alvarez, Susana Salva.

  We evaluated whether viable and non-viable Lacticaseibacillus rhamnosus CRL1505 (Lr05V or Lr05NV, respectively) was able to improve emergency myelopoiesis induced by Streptococcus pneumoniae (Sp) infection. Adult Swiss-mice were orally treated with Lr05V or Lr05NV during five consecutive days. The Lr05V and Lr05NV groups and untreated control group received an intraperitoneal dose of cyclophosphamide (Cy-150 mg/kg). Then, the mice were nasally challenged with Sp (107 UFC/mice) on day 3 post-Cy injection. After the pneumococcal challenge, the innate and myelopoietic responses were evaluated. The control group showed a high susceptibility to pneumococcal infection, an impaired innate immune response and a decrease of hematopoietic stem cells (HSCs: Lin-Sca-1+c-Kit+), and myeloid multipotent precursors (MMPs: Gr-1+Ly6G+Ly6C-) in bone marrow (BM). However, lactobacilli treatments were able to significantly increase blood neutrophils and peroxidase-positive cells, while improving cytokine production and phagocytic activity of alveolar macrophages. This, in turn, led to an early Sp lung clearance compared to the control group. Furthermore, Lr05V was more effective than Lr05NV to increase growth factors in BM, which allowed an early HSCs and MMPs recovery with respect to the control group. Both Lr05V and Lr05NV were able to improve BM emergency myelopiesis and protection against respiratory pathogens in mice undergoing chemotherapy.

Keywords:  Cyclophosphamide; Emergency myelopoiesis; Immunobiotic; Lacticaseibacillus rhamnosus CRL1505; Postbiotic; Streptococcus pneumoniae

DOI:  https://doi.org/10.1016/j.micinf.2024.105311
Am J Respir Cell Mol Biol. 2024 Feb 12.

TRPV4 Regulates the Macrophage Metabolic Response to Limit Sepsis-induced Lung Injury.

Erica M Orsini, Sanjoy Roychowdhury, Mahesha Gangadhariah, Emily Cross, Susamma Abraham, Amanda Reinhardt, Megan E Grund, Julie Y Zhou, Olivia Stuehr, Bishnu Pant, Mitchell A Olman, Vidula Vachharajani, Rachel G Scheraga.

  Sepsis is a systemic inflammatory response that requires effective macrophage metabolic functions to resolve ongoing inflammation. Previous work showed that the mechanosensitive cation channel, transient receptor potential vanilloid 4 (TRPV4), mediates macrophage phagocytosis and cytokine production in response to lung infection. Here, we show that TRPV4 regulates glycolysis in a stiffness dependent manner by augmenting macrophage glucose uptake by GLUT1. In addition, TRPV4 is required for lipopolysaccharide (LPS)-induced phagolysosome maturation in a GLUT1-dependent manner. In a cecal slurry mouse model of sepsis, TRPV4 regulates sepsis-induced glycolysis as measured by bronchoalveolar lavage fluid (BALF) lactate and sepsis-induced lung injury as measured by BALF total protein and lung compliance. TRPV4 is necessary for bacterial clearance in the peritoneum to limit sepsis-induced lung injury. Interestingly, BALF lactate is increased in septic patients compared with healthy controls, supporting the relevance of lung cell glycolysis to human sepsis. These data show that macrophage TRPV4 is required for glucose uptake through GLUT1 for effective phagolysosome maturation to limit sepsis-induced lung injury. Our work presents TRPV4 as a potential target to protect the lung from injury in sepsis.

Keywords:  TRPV4; glycolysis; lung injury; macrophage; sepsis

DOI:  https://doi.org/10.1165/rcmb.2023-0456OC
Matrix Biol. 2024 Feb 08. pii: S0945-053X(24)00022-2. [Epub ahead of print]

Keratinocyte integrin α3β1 induces expression of the macrophage stimulating factor, CSF-1, through a YAP/TEAD-dependent mechanism.

Whitney M Longmate, Emily Norton, Giesse Albeche Duarte, Lei Wu, Mathieu R DiPersio, John M Lamar, C Michael DiPersio.

  The development of wound therapy targeting integrins is hampered by inadequate understanding of integrin function in cutaneous wound healing and the wound microenvironment. Following cutaneous injury, keratinocytes migrate to restore the skin barrier, and macrophages aid in debris clearance. Thus, both keratinocytes and macrophages are critical to the coordination of tissue repair. Keratinocyte integrins have been shown to participate in this coordinated effort by regulating secreted factors, some of which crosstalk to distinct cells in the wound microenvironment. Epidermal integrin α3β1 is a receptor for laminin-332 in the cutaneous basement membrane. Here we show that wounds deficient in epidermal α3β1 express less epidermal-derived macrophage colony-stimulating factor 1 (CSF-1), the primary macrophage-stimulating growth factor. α3β1-deficient wounds also have fewer wound-proximal macrophages, suggesting that keratinocyte α3β1 may stimulate wound macrophages through the regulation of CSF-1. Indeed, using a set of immortalized keratinocytes, we demonstrate that keratinocyte-derived CSF-1 supports macrophage growth, and that α3β1 regulates Csf1 expression through Src-dependent stimulation of Yes-associated protein (YAP)-Transcriptional enhanced associate domain (TEAD)-mediated transcription. Consistently, α3β1-deficient wounds in vivo display a substantially reduced number of keratinocytes with YAP-positive nuclei. Overall, our current findings identify a novel role for epidermal integrin α3β1 in regulating the cutaneous wound microenvironment by mediating paracrine crosstalk from keratinocytes to wound macrophages, implicating α3β1 as a potential target of wound therapy.

Keywords:  CSF-1; Integrin α3β1; YAP/TAZ; keratinocyte; macrophage; wound healing

DOI:  https://doi.org/10.1016/j.matbio.2024.02.003
Ann Allergy Asthma Immunol. 2024 Feb 13. pii: S1081-1206(24)00081-4. [Epub ahead of print]

Constant Vigilance! Managing Threats to the Skin Barrier.

Vanessa Chu, Peck Y Ong.

  OBJECTIVE: Skin barrier defects are one of the primary causes of atopic dermatitis (AD). The basis of skin barrier defects in AD is due to a deficiency in various barrier proteins including filaggrin, involucrin, claudins, and lipids including ceramide, fatty acids and cholesterol. This review updates a more detailed lipid dysregulation in the skin barrier of AD based on recent lipidomic analysis. The clinical implications, treatments, prevention and predictive capability of skin barrier defects are also reviewed. DATA;: Sources: Published literature obtained through PubMed searches. STUDY;: Selection: Studies relevant to the mechanisms, clinical implications, treatments, prevention and predictors of AD development.RESULTS: Skin barrier defects contribute to transepidermal water loss, infections, IgE sensitizations and cutaneous inflammation in AD. Preventive treatments include daily hydration and application of moisturizers. Since skin barrier defects precede the development of AD, they provide an opportunity for prediction and intervention.
CONCLUSION: Skin barrier defects play an important role in the co-morbidities of AD including infectious complications, disease flare and allergic diathesis. Current research focuses on prevention and prediction of AD development.

Keywords:  S. aureus; ceramide; eczema; filaggrin; food allergy; infants; lipid; lipidomic; moisturizer; skin barrier defects; skin tape strip

DOI:  https://doi.org/10.1016/j.anai.2024.02.004
bioRxiv. 2024 Feb 01. pii: 2024.02.01.578466. [Epub ahead of print]

Pediatric human nose organoids demonstrate greater susceptibility, epithelial responses, and cytotoxicity than adults during RSV infection.

Gina M Aloisio, Divya Nagaraj, Ashley M Murray, Emily M Schultz, Trevor McBride, Letisha Aideyan, Erin G Nicholson, David Henke, Laura Ferlic-Stark, Anubama Rajan, Amal Kambal, Hannah L Johnson, Elina Mosa, Fabio Stossi, Sarah E Blutt, Pedro A Piedra, Vasanthi Avadhanula.

Respiratory syncytial virus (RSV) is a common cause of respiratory infections, causing significant morbidity and mortality, especially in young children. Why RSV infection in children is more severe as compared to healthy adults is not fully understood. In the present study, we infect both pediatric and adult human nose organoid-air liquid interface (HNO-ALIs) cell lines with two contemporary RSV isolates and demonstrate how they differ in virus replication, induction of the epithelial cytokine response, cell injury, and remodeling. Pediatric HNO-ALIs were more susceptible to early RSV replication, elicited a greater overall cytokine response, demonstrated enhanced mucous production, and manifested greater cellular damage compared to their adult counterparts. Adult HNO-ALIs displayed enhanced mucus production and robust cytokine response that was well controlled by superior regulatory cytokine response and possibly resulted in lower cellular damage than in pediatric lines. Taken together, our data suggest substantial differences in how pediatric and adult upper respiratory tract epithelium responds to RSV infection. These differences in epithelial cellular response can lead to poor mucociliary clearance and predispose infants to a worse respiratory outcome of RSV infection.

DOI: https://doi.org/10.1101/2024.02.01.578466