Biology subjects

Schmit, T.

Publications and source records attributed to Schmit, T..

4 recordsLinked to original sources

bioRxiv2026

TFAM Dependent Mitochondrial Fitness Limits CD8⁺ T Cell Immunopathology and Sustains Protective Immunity during Viral Pneumonia

During respiratory virus infection, CD8 T cells kill infected cells and establish antigen-specific memory, but mechanisms regulating these functions remain incompletely understood. Here, we identify mitochondrial transcription factor A (TFAM)-dependent mitochondrial fitness as a regulator of CD8 T cell function during influenza infection. Human CD8 T cells exhibited an age-associated decline in TFAM expression and mitochondrial function. To model this physiologically relevant decline and determine its consequences for antiviral immunity, we generated CD8 T cell-specific TFAM-haploinsufficient mice. TFAM insufficiency disrupted mitochondrial integrity and bioenergetics and increased mitochondrial DNA and oxidative stress. During influenza infection, TFAM-insufficient CD8 T cells exhibited increased cytotoxic and inflammatory activity associated with lung immunopathology without improved viral control. This early phenotype was followed by loss of effector function, diminished antigen-specific responses, reduced protection following adoptive transfer, and impaired heterosubtypic recall immunity. Thus, TFAM-dependent mitochondrial fitness is a cell-intrinsic regulator that limits immunopathology while sustaining recall immunity.

immunology↗

bioRxiv2025

NF-κB driven inflammation mediates loss of upper airway epithelial tolerance to Streptococcus pneumoniae during influenza co-infection

Streptococcus pneumoniae asymptomatically colonizes the human nasopharynx, where epithelial tolerance maintains mucosal homeostasis. However, influenza A virus (IAV) co-infection transforms this tolerogenic state into an inflammatory environment that promotes bacterial outgrowth and invasion. Here, we identify a TGF-{beta}1 dependent epithelial program that sustains mucosal tolerance during Spn colonization and demonstrate that IAV co-infection disrupts this pathway through IL-17RA-NF-{kappa}B driven inflammation in the nasopharynx. In a murine colonization model, TGF-{beta}1 blockade enhanced pro-inflammatory cytokine production and neutrophil recruitment, resulting in inflammation-driven Spn clearance. IAV co-infection suppressed epithelial TGF-{beta}1 signaling, increased TRAF6/NF-{kappa}B activation, and impaired tight junction integrity, leading to Spn dissemination. Mechanistically, IL-17RA signaling contributed to the hyperactivation of the TRAF6/NF-{kappa}B axis. Pharmacologic inhibition of TRAF6 or NF-{kappa}B restored epithelial barrier function and reduced Spn translocation in a human air-liquid interface nasopharyngeal epithelial model. These findings reveal a conserved epithelial signaling axis through which influenza disrupts mucosal tolerance and promotes Spn invasion, highlighting the canonical TRAF6-NF-{kappa}B pathway as a potential therapeutic target to preserve epithelial integrity and mitigate Spn infection during viral-bacterial co-infection of the upper respiratory tract.

immunology↗

bioRxiv2022

The chemokine receptor CXCR3 promotes CD8+ T cell-dependent lung pathology during influenza pathogenesis

While the role of CD8+ T cells in influenza clearance is established, their contribution to pathological lung injury is increasingly appreciated. To explore if protective versus pathological functions can be linked to CD8+ T cell subpopulations, we dissected their responses in influenza-infected murine lungs. Our single-cell RNASeq (scRNAseq) analysis revealed significant diversity in CD8+ T cell subpopulations during peak viral load vs. infection-resolved state. While enrichment of Cxcr3hi CD8+ T effector (Teff) subset was associated with a more robust cytotoxic response, both CD8+ Teff and CD8+ T central memory (TCM) exhibited equally potent effector potential. The scRNAseq analysis identified unique regulons regulating the cytotoxic response in CD8+ T cells. The neutralization of CXCR3 mitigated lung injury without affecting viral clearance. IFN-{gamma} was dispensable to regulate the cytotoxic response of Cxcr3hi CD8+ T cells. Collectively, our data imply that CXCR3 interception could have a therapeutic effect in preventing influenza-linked lung injury. TEASERThe CXCR3 expressing CD8+ T cell subset causes severe lung pathology and exacerbates disease severity without affecting viral clearance during influenza infection

immunology↗

bioRxiv2021

Cellular heterogeneity and molecular reprogramming of host response during influenza acute lung injury

Acute lung injury (ALI) caused by influenza A virus (IAV or influenza) manifests from dysregulated cellular interactions between hematopoietic and non-hematopoietic cells that develop into a pathologic host response. However, the lungs diverse cellular framework that dictates the pathologic host response and acute lung injury remains incompletely understood. We performed a single-cell RNA-seq (scRNA-seq) analysis of total lung cells in mice from severe influenza to examine the cellular heterogeneity and cell-specific regulation of host response. We observed that IAV infection resulted in significant myelopoiesis, predominantly monocyte, and macrophage subsets, which constituted over 50% of total immune cells. IAV infection resulted in the significant loss of endothelial and fibroblast cells, representing the most predominant non-hematopoietic cells and crucial to regulating inflammatory response and barrier integrity. We also show the cell-cell communication dynamics of interferon and chemokine signaling and global regulation of these responses in transition from homeostatic to IAV infection state. These data highlight a robust application of scRNA-seq technology in establishing the atlas of cellular heterogeneity from its homeostatic transition to infection state and the host response regulation in IAV-mediated lung pathology.

immunology↗