bims-imesem 2026-06-28 papers

bims-imesem

Biomed News

on Immunemetabolism

Issue of 2026–06–28
nine papers selected by
Akshara Kulkarni , University of Cambridge

Reduced CARS2 expression elicits a low-grade pro-inflammatory signature in THP-1 macrophages.
Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.
Exploring Key Regulators of Mitochondrial Dynamics and Immune Response in SARS-CoV-2 Infection.
Neutrophil dynamics in viral infections: drivers of inflammation and targets for pro-resolving therapies.
Viral load-driven systemic immune exhaustion is an enabler of antibody breadth in HIV infection.
HIV-1 gp120-induced lysosomal stress responses are controlled by TRPML1 redox sensors.
Latent cytomegalovirus disrupts innate NK cell responses to P. falciparum and impairs parasite control in first infection in adults.
Immuno-cell metabolic changes in HIV-1 infection.
MAPK-activated protein kinase 2 orchestrates memory T-cell inflation in cytomegalovirus infection.

Front Immunol. 2026 ;17 1786365

Reduced CARS2 expression elicits a low-grade pro-inflammatory signature in THP-1 macrophages.

Anh-Thu Dang, Paulina Lau, Sébastien Soubeyrand, Ruth McPherson.

  Genome-wide association studies have linked CARS2 locus, encoding the mitochondrial cysteinyl aminoacyl-tRNA synthetase CARS2, to coronary artery disease. Moreover, we previously demonstrated that CARS2 suppression was associated with a pro-inflammatory expression profile in cell models. However, the mechanisms were largely unexplored. Here, we further examine the changes associated with CARS2 suppression through bioinformatic and experimental approaches. Analysis of transcriptomic data from CARS2-suppressed cells revealed the prominent establishment of an interferon-like response in unpolarized THP-1 macrophages, as well as possible NF-ΚB activation. This was not accompanied by significant activation of STAT1 or NF-ΚB phosphorylation, indicative of interferon pathway activation and NF-ΚB activity, respectively. Rather, an NF-ΚB activity reporter THP-1 model revealed that NF-ΚB activation was modestly diminished in CARS2-suppressed cells. Furthermore, suppression of CARS2, or a YARS2 control, similarly reduced radical oxygen species levels without affecting mitochondrial content or membrane potential. However, YARS2 suppression was not pro-inflammatory, suggesting that reduced ROS levels are insufficient to explain the CARS2 effect. Finally, reduced CARS2 levels did not alter the abundance of respiratory complexes or mitochondrial function. These results argue for an anti-inflammatory contribution of CARS2 in THP-1-derived macrophages, which extends beyond its canonical mitochondrial role.

Keywords:  CARS2; THP-1; inflammation; macrophage - cell; mitochondria; transcription analysis

DOI:  https://doi.org/10.3389/fimmu.2026.1786365
Cell Rep. 2026 Jun 26. pii: S2211-1247(26)00685-6. [Epub ahead of print]45(7): 117607

Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.

Tatsuki Yasuda, Aoi Ichikawa, Kenta Onoue, Emi Ogasawara, Takaya Ishihara, Hidetaka Kosako, Naotada Ishihara.

  Mitochondria are dynamic organelles that continuously remodel their morphology through fusion and fission in response to cellular cues. While this dynamic behavior is essential for diverse cellular functions, how mitochondrial dynamics influence innate immune responses remains incompletely understood. Here, we show that mitochondrial hyperfusion-induced by loss of the fission factor DRP1 or by cellular stress, including cycloheximide or doxorubicin treatment-is associated with activation of a RIG-I-MAVS-dependent innate immune response and BAX-dependent cytosolic release of mitochondrial RNA. Functionally, our data suggest that this pathway contributes to enhanced susceptibility to NK cell-mediated cytotoxicity in vitro and reduced tumor growth in a xenograft model. Collectively, our findings identify mitochondrial hyperfusion-induced mtRNA release as a mechanism that engages innate immune signaling downstream of impaired mitochondrial dynamics.

Keywords:  CP: immunology; DRP1; RIG-I; innate immunity; mitochondrial RNA; mitochondrial dynamics; mitochondrial hyperfusion; molecular biology

DOI:  https://doi.org/10.1016/j.celrep.2026.117607
Viruses. 2026 Jun 16. pii: 675. [Epub ahead of print]18(6):

Exploring Key Regulators of Mitochondrial Dynamics and Immune Response in SARS-CoV-2 Infection.

Thatiana Corrêa de Melo, Hellen Paula Valerio, Dilza Trevisan-Silva, Marcelo Medina de Souza, Amanda Teixeira de Melo, Miryam Paola Alvarez-Flores, Douglas Souza Oliveira, Renata Nascimento Gomes, Glaucia Maria Machado-Santelli, Beatriz Fumelli Monti Ribeiro, Viviane Fongaro Botosso, Soraia Attie Calil Jorge, Ana Marisa Chudzinski-Tavassi.

  Mitochondria are central hubs of antiviral immunity and cellular metabolism, yet the links between SARS-CoV-2-induced mitochondrial remodeling, antiviral gene regulation, and post-translational control remain incompletely understood. Here, we investigated mitochondrial-immune remodeling in SARS-CoV-2-infected lung-derived LC-HK2 cells at 48 and 96 h post-infection using confocal and high-content imaging, colocalization analysis, CellProfiler quantification, RT-qPCR, proteomics, cytokine profiling, and conditioned-medium analysis. Infection induced a time-dependent mitochondrial phenotype. At 48 hpi, cells displayed early mitochondrial stress and fission-associated signatures, including increased DRP1, transient upregulation of mitochondrial respiratory genes, and reduced MFN1/2. At 96 hpi, mitochondria shifted toward elongated perinuclear networks, accompanied by increased fusion/biogenesis markers and partial ISG15-MFN2 colocalization, indicating a spatial association between ISG15-related antiviral/stress responses and mitochondrial remodeling. Antiviral and ISG-related transcripts were consistently upregulated, but IFN-α2 secretion remained limited, suggesting partial uncoupling between antiviral transcriptional activation and downstream interferon output. SUMO2/3 was dynamically modulated and showed time-dependent colocalization with mitochondrial dynamics proteins and MAVS. Together, these data support a coordinated mitochondrial-immune regulatory axis involving mitochondrial remodeling, ISG15-associated responses, and SUMO-dependent regulation during SARS-CoV-2 infection.

Keywords:  ISG15; LC-HK2 cells; MAVS; MFN2; SARS-CoV-2; SUMO2/3; innate immunity; mitochondrial dynamics; post-translational modifications; proteomics

DOI:  https://doi.org/10.3390/v18060675
J Innate Immun. 2026 Jun 25. 1-41

Neutrophil dynamics in viral infections: drivers of inflammation and targets for pro-resolving therapies.

Filipe Resende, Felipe Emanuel Oliveira Rocha, Celso Martins Queiroz-Junior, Mauro Teixeira, Vivian Vasconcelos Costa.

BACKGROUND: Neutrophils are essential components of host defense, traditionally recognized for their well-described antimicrobial functions in bacterial infections. Far from being merely short-lived and functionally limited, emerging evidence demonstrates that neutrophils are also key players in viral infections. Through mechanisms such as degranulation and formation of NETs, neutrophils play an important role in virus-induced inflammation and pathogenesis. However, their persistence and hyperactivated states also contribute to tissue damage and failed resolution of acute inflammation.
SUMMARY: Here, we summarize recent data regarding the role of neutrophils in respiratory and arboviral infections, from clinical evidence to mechanistic insights available from the last ten years. Finally, we discuss emerging therapeutic strategies that target neutrophil fate and function to promote the resolution of inflammation.
KEY MESSAGES: Overall, although well characterized in some viral infections, for a few other viral diseases the role of neutrophils remains elusive. We highlight the importance of modulating neutrophils death in a timely and non-inflammatory manner, as some viruses influence apoptosis for their own benefit, favoring viral replication. For those infections, and also due to non-resolving inflammation provoked by these viruses, pro-resolving mediators certainly display a beneficial effect. Rather than broadly suppressing antiviral immunity, pro-resolving approaches aimed at recalibrating neutrophil activation, lifespan, and clearance may represent a promising and safer avenue for the treatment of viral diseases characterized by excessive and non-resolving inflammation.

DOI: https://doi.org/10.1159/000553213
bioRxiv. 2026 Jun 17. pii: 2026.06.05.730519. [Epub ahead of print]

Viral load-driven systemic immune exhaustion is an enabler of antibody breadth in HIV infection.

Izumi de Los Rios Kobara, Uma Mangalanathan, Soneida Deline-Caballero, Kassandra Pinedo, Mikayla Stabile, Camilo Andres Espinosa Bernal, Hannah L Itell, Vrasha Chohan, R Scott McClelland, Kishor Mandaliya, Julie Overbaugh, Catherine A Blish.

A broadly neutralizing response to a human immunodeficiency virus (HIV) vaccine is a major goal of the field, yet the determinants of antibody breadth remain poorly defined. Antibody responses to HIV evolve over years of infection, developing unusual features such as high mutation rates in the subset of individuals that acquire breadth. Using single-cell RNA sequencing, single-cell proteomics, and plasma neutralization assays in a longitudinal Kenyan cohort of treatment-naive women living with HIV, we identify systems-level immune correlates of antibody breadth. Broad and narrow neutralizers diverge early in infection along a viral load-driven axis with broad neutralizers exhibiting greater viral loads and CD4 T cell decline; concurrently, NK cells, CD8 T cells, and monocytes, broad neutralizers displayed greater magnitude of immune activation in early infection, followed by exhaustion in late infection. This functional decline may dampen NK cell-mediated pruning of T follicular helper cells, creating a permissive environment for sustained germinal center activity and antibody maturation. Narrow neutralizers, by contrast, maintain functional cellular immunity but lack the antigenic pressure and permissive exhaustive state associated with breadth. Together, these findings suggest that antibody breadth in HIV infection reflects failed viral control rather than a successful antiviral response with implications for vaccination and cure strategies that must balance cellular and humoral immunity.

DOI: https://doi.org/10.64898/2026.06.05.730519
Redox Rep. 2026 Dec 31. 31(1): 2679333

HIV-1 gp120-induced lysosomal stress responses are controlled by TRPML1 redox sensors.

Nirmal Kumar, Braelyn Liang, Jonathan D Geiger.

   BACKGROUND: Increased lysosomal stress responses (LSR) are commonly implicated in the pathogenesis of neurodegenerative disorders including HIV-1-associated neurocognitive disorders (HAND). The HIV-1 envelope glycoprotein gp120 causes LSR, increases levels of ferrous iron (Fe2+) in the cytosol and in mitochondria, disrupts the reactive species interactome (RSI), and increases neural cell death.
METHODS: Using SH-SY5Y human neuroblastoma and U87MG human astrocytoma cells treated with gp120 and pharmacological modulators, we evaluated redox signaling and LSR by redox-sensitive fluorescent probes, spinning-disk confocal microscopy, flow cytometry, Western blotting, and immunostaining.
RESULTS: Here, we report that TRPML1, an endolysosome redox-sensitive cation channel, is mechanistically involved in gp120-induced neurotoxicity. TRPML1 was activated by gp120-induced increases in cytosolic reactive oxygen species (ROS) and resulted in release of Fe2+ from endolysosomes in levels sufficient to increase cytosolic levels of Fe2+ and ROS as well as decrease levels of hydrogen sulfide (H2S). Reduced glutathione normally buffers intracellular Fe2+, but gp120 decreased endolysosome glutathione levels and disrupted this regulatory control mechanism thereby promoting TRPML1-mediated Fe2+ efflux from endolysosomes. TRPML1 redox activation led to changes to the RSI in endolysosomes including increased ROS, lipid peroxidation, nitric oxide, and sulfane sulfur as well as decreased H2S. These changes were accompanied by increased cysteine oxidation of luminal proteins and endolysosome deacidification. Pharmacological inhibition of TRPML1 or knocking down expression levels of TRPML prevented these effects.
CONCLUSION: Our findings suggest that TRPML1 redox activation controls gp120-induced endolysosome dysfunction and iron/redox imbalance, and further implicates TRPML1 in the pathogenesis of HAND.

Keywords:  HIV-1 gp120; TRPML1; lysosomal stress responses; reactive carbonyl species; reactive nitrogen species; reactive oxygen species; reactive species interactome; reactive sulfur species; redox sensor

DOI:  https://doi.org/10.1080/13510002.2026.2679333
PLoS Pathog. 2026 Jun;22(6): e1014372

Latent cytomegalovirus disrupts innate NK cell responses to P. falciparum and impairs parasite control in first infection in adults.

Reena Mukhiya, Jessica R Loughland, Nicholas L Dooley, Zuleima Pava, Damian A Oyong, Dean W Andrew, Julianne Hamelink, Kiana Berry, James S McCarthy, Bridget E Barber, J Alejandro Lopez, Christian R Engwerda, Michelle J Boyle.

NK cells are innate and adaptive responders to malaria, with functional responses underpinned by NK cell heterogeneity. One driver of NK cell heterogeneity is latent CMV infection. Latent CMV infection negatively impacts adaptive immunity to malaria, but whether CMV-mediated changes to the NK cell compartment also impact innate responses to malaria is unknown. We investigated the impact of latent CMV infection on innate NK cell responses to the malaria parasite in vitro in malaria naïve adults, and in vivo NK cell responses during a first controlled human malaria infection. We found that transcriptional activation of NK cells by parasites was attenuated in CMV seropositive individuals. Further, during a first malaria infection, markers of NK cell activation and cytotoxicity were reduced. This attenuated response was not restricted to a single NK phenotype but occurred across diverse NK cell phenotypes. Consistent with a global NK cell attenuation, IL12 production from myeloid cells, a response that supports NK cell activation on exposure to P. falciparum parasites, was lower in CMV infected individuals. Linking NK cell activation to clinical outcomes, NK cell perforin expression was associated with parasite control in CMV seronegative individuals during first malaria infection. Data highlight the interplay between pathogens and the host-immune response that influence clinical outcomes.

DOI: https://doi.org/10.1371/journal.ppat.1014372
Infect Dis Immun. 2025 Jul;5(3): 177-189

Immuno-cell metabolic changes in HIV-1 infection.

Linle Xu, Yufen Jiang, Xuexing Zheng, Hongbo Shi.

  Recent research has shown that metabolic processes within immune cells are essential for both human immunodeficiency virus 1 (HIV-1) infection and the immune response. Throughout HIV-1 infection-from acute stages to chronic infection and viral latency-immune cells experience shifts in energy demands and metabolic pathways, paralleling T-cell exhaustion. Dysregulated immune metabolism compromises immune cell function, leading to immune dysfunction and persistent inflammation. Therefore, metabolic alterations in immune cells constitute a critical mechanism in HIV-1 progression and chronic inflammation. This review specifically explores the metabolic profiles and roles of T cells, monocytes-macrophages, dendritic cells, natural killer cells, and B cells at different stages of HIV-1 infection, emphasizing the effects of HIV-1 on the metabolic pathways of diverse immune cell types. These insights offer valuable therapeutic strategies aimed at inhibiting viral replication, restoring immune function, and controlling disease progression.

Keywords:  DCs; Glycolysis; HIV-1; Metabolism; Monocyte–macrophages; T cells

DOI:  https://doi.org/10.1097/ID9.0000000000000159
J Immunol. 2026 Jun 07. pii: vkag170. [Epub ahead of print]215(6):

MAPK-activated protein kinase 2 orchestrates memory T-cell inflation in cytomegalovirus infection.

Eleni Panagioti, Xueyang Yu, Yi Wen Kong, Kristina Macakova, Noe B Mercado, Sean Edward Lawler, Michael B Yaffe, Charles H Cook.

  Memory T-cell inflation is a distinctive immunological phenomenon observed during persistent viral infections such as cytomegalovirus (CMV). Unlike conventional memory T-cell responses, which contract after infection resolution, a subset of CMV-specific T cells undergoes a progressive and sustained expansion, termed "inflation", which is thought to be critical for long-term immune surveillance. The molecular mechanisms that govern memory T-cell inflation remain incompletely understood, yet they are pivotal for understanding immune persistence and designing strategies against chronic viral infections. In this study, we investigated the role of MAPK-activated protein kinase 2 (MK2), a key downstream effector of p38 MAPK signaling, in regulating T-cell responses during murine CMV (MCMV) infection. Using MK2 knockout (MK2-KO) mice, we demonstrate that MK2 deficiency alters the dynamics of MCMV-specific CD8+ T-cell responses without impairing viral control or tissue replication. MK2 deficiency led to a reduction in noninflationary MCMV-specific CD8+ T cells during acute infection, followed by enhanced expansion of inflationary CD8+ T-cell subsets during latent infection. Furthermore, MK2-KO mice exhibited impaired effector differentiation, as evidenced by decreased expression of the terminal differentiation marker KLRG1 on MCMV-specific CD8+ T cells. Collectively, these findings identify MK2 as an important regulator of CD8+ T-cell magnitude, kinetics, and phenotype during both acute and latent MCMV infection. By demonstrating a role of MK2 in the regulation of memory T-cell inflation, this study provides new mechanistic insight into immune regulation with implications for vaccination, chronic infection, and immune aging.

Keywords:  CD8+ T cells; KLRG1; MK2; cytomegalovirus; memory inflation

DOI:  https://doi.org/10.1093/jimmun/vkag170