Biology subjects

Endsley, J. J.

Publications and source records attributed to Endsley, J. J..

4 recordsLinked to original sources

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↗

bioRxiv2024

DAMP-inducing Peptide Nanofibers and PAMP Combination Adjuvants Boost Functional Lung Tissue-resident Memory CD4+ T Cell Responses

Vaccine adjuvants are typically composed of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) that activate innate immune cells. Advances in basic immunology have demonstrated the need for various types of protective immunity, which are difficult to achieve with a single adjuvant. The FDA approval of multiple PAMP-DAMP combinations for clinical use has led to an increased momentum in the area in recent years. Here we report the use of DAMP-inducing peptide nanofibers (PNFs) and CL429 (PAMP) combinations as subunit boosters for Bacille Calmette-Guerin (BCG). We demonstrate that pulmonary boosting with PNFs and CL429 enhances the lung-resident memory phenotype, effector cytokine profiles, and transcription factor bias of antigen-specific CD4+T cell populations compared to PNFs alone. Importantly, the combination significantly improved the frequency of tissue-resident memory T (TRM) cells which, have been shown to provide superior protection compared to circulating memory T cells. Interestingly, the T helper (Th) subset profile was driven in part driven by the route of vaccination resulting in a Th17 bias via a mucosal route or a Th1 bias when delivered intravenously. We show that following pulmonary administration, lung-resident antigen presenting cells (APCs) efficiently internalize PNFs and upregulate important co-stimulatory markers that drive T cell priming and activation. Our findings suggest that heterologous booster vaccines composed of DAMP-inducing PNFs and PAMP combinations can engage innate and adaptive immunity for generating TRM cells that protect against TB and potentially other respiratory diseases.

bioengineering↗

bioRxiv2024

TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication

SARS-CoV-2 is a highly transmissible virus that causes COVID-19 disease. Mechanisms of viral pathogenesis include excessive inflammation and viral-induced cell death, resulting in tissue damage. We identified the host E3-ubiquitin ligase TRIM7 as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein. Trim7-/- mice exhibited increased pathology and virus titers associated with epithelial apoptosis and dysregulated immune responses. Mechanistically, TRIM7 ubiquitinates M on K14, which protects cells from cell death. Longitudinal SARS-CoV-2 sequence analysis from infected patients revealed that mutations on M-K14 appeared in circulating variants during the pandemic. The relevance of these mutations was tested in a mouse model. A recombinant M- K14/K15R virus showed reduced viral replication, consistent with the role of K15 in virus assembly, and increased levels of apoptosis associated with the loss of ubiquitination on K14. TRIM7 antiviral activity requires caspase-6 inhibition, linking apoptosis with viral replication and pathology.

microbiology↗