Huante, M. B. | bioRxiv Science

bioRxiv2025

IL-4 and TGF-β Regulate Inflammatory cytokines and Cellular Infiltration in the Lung in Mouse-adapted SARS-CoV-2 Infection

The pathology of severe COVID-19 is due to a hyperinflammatory immune response persisting after viral clearance. To understand how the immune response to SARS-CoV-2 is regulated to avoid severe COVID-19, we tested relevant immunoregulatory cytokines. TGF-{beta}, IL-10 and IL-4 were neutralized upon infection with mouse-adapted SARS-CoV-2 (CMA3p20), a model of mild disease; and lung inflammation was quantified by histology and flow cytometry at early and late time points. Mild weight loss, and lung inflammation including consolidation and alveolar thickening were evident 3 days post-infection (dpi) and inflammation persisted to 7 dpi. Coinciding with early monocytic infiltrates, CCL2 and granulocyte-colony stimulating factor (G-CSF) were transiently produced 3 dpi, while IL-12 and CCL5 persisted to 7 dpi, modeling viral and inflammatory phases of disease. Neutralization of TGF-{beta}, but not IL-10 or IL-4, significantly increased lung inflammatory monocytes and elevated serum but not lung IL-6. Neutralization of IL-4 prolonged weight loss and increased early perivascular infiltration without changing viral titer. Anti-IL-4 reduced expression of Arg1, a gene associated with alternative activation of macrophages. Neutralizing TGF-{beta} and IL-4 had differential effects on pathology after virus control. Lung perivascular infiltration was reduced 7 dpi by neutralization of IL-4 or TGF-{beta}, and peri-airway inflammation was affected by anti-TGF-{beta}, while alveolar infiltrates were not affected by either. Anti-IL-4 prolonged IL-12 to 7 dpi along with reduced IL-10 in lungs. Overall, the immunoregulatory cytokines TGF-{beta} and IL-4 dampen initial inflammation in this maSARS-CoV-2 infection, suggesting that promotion of immunoregulation could help patients in early stages of disease. Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/653138v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@14c34org.highwire.dtl.DTLVardef@1322a8dorg.highwire.dtl.DTLVardef@8792aborg.highwire.dtl.DTLVardef@ae513e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

HIV IMPAIRS AND EXPLOITS PULMONARY TH17 AND TH22 CELL-MEDIATED IMMUNE RESPONSES TO MYCOBACTERIUM TUBERCULOSIS

Tuberculosis (TB) kills an estimated 1.25 million people annually and is the leading cause of death in people with HIV (PWH) (1). The CD4+ T helper (Th) populations play significant roles in protective immunity to Mycobacterium tuberculosis (Mtb) and are essential hosts for HIV pathogenesis. Emerging evidence in blood and gastrointestinal mucosa of PWH suggests that, among Th cells, Th17 and Th22 may be preferentially depleted during HIV infection. Targeting of Th17 and Th22 cells by HIV could pose important and poorly understood risks for Mtb containment in those with co-infection. Mtb-driven activation of Th17 and Th22 immunity may also contribute to HIV proliferation and persistence. We employed a humanized mouse model of co-infection to assess changes in Th17 and Th22 frequency and function due to infection with HIV, Mtb, or both. In infected mice, Th17 cells were the predominant host for HIV in spleen and shown to be a source of HIV replication in pulmonary TB granulomas. Th17 cells were increased in lung of mice with TB or TB-HIV. Conversely, Th22 cells were reduced in mice with HIV or TB-HIV. Mtb infection increased the viral load in lung of co-infected mice while HIV suppressed the pulmonary Th17 family cytokine response to Mtb including IL-6, IL-22, IL-23, and IL-1{beta}. Differential transcriptome assessment demonstrated that HIV co-infection disrupted Th17 pathways activated by Mtb in lung. Overall, these results suggest that HIV may compromise Th22 immunity and exploit Th17 cells to promote viral pathogenesis in the setting of Mtb and HIV co-infection.

immunology↗