Biology subjects

Martinez-Martinez, Y. B.

Publications and source records attributed to Martinez-Martinez, Y. B..

5 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↗

bioRxiv2025

Loss of the PPE71-esxX-esxY-PPE38 locus drives adaptive transcriptional responses and hypervirulence of Mycobacterium tuberculosis Lineage 2

Mycobacterium tuberculosis (M.tb) is remarkable for its immense global disease burden and low mutation rate. Despite strong selective pressure, M.tb shows frequent deletions at the PPE71-38 locus, most notably in hypervirulent L2 Beijing strains. Here, we show that loss of the PPE71- 38 locus causes increased stress response gene expression and increased triglyceride levels. In addition, we demonstrate that re-introduction of PPE71 into the L2 strain HN878 suppresses the baseline elevation of these transcripts, while overexpression of PPE71 increases the localization of PE_PGRS proteins and lipoproteins to the M.tb outer mycomembrane. Mouse infection confirmed the hypervirulence of the PPE71-38 deletion strain and conversely showed that PPE71 overexpression attenuates M.tb. Our results indicate that loss of PPE71-38 is sufficient to drive an adaptive transcriptional response seen in M.tb L2 strains that likely contributes to the hypervirulence of this lineage.

microbiology↗

bioRxiv2025

Loss of the ESX-5 secretion locus in Mycobacterium tuberculosis reshapes the mycomembrane and enhances ESX-1 substrate secretion

The ESX-5 secretion system, uniquely found in slow-growing mycobacteria, is predicted to secrete over 150 proteins across the inner membrane of Mycobacterium tuberculosis (M.tb). Although many of these substrates are believed to promote M.tb virulence, most remain poorly characterized. Here, we use a complete locus deletion strain of ESX-5 in M.tb to examine the molecular changes caused by a broad loss in ESX-5 secretory substrates. We confirmed the selective loss of PE/PPE proteins secreted by ESX-5 into both the culture filtrate (CF) and outer mycomembrane (OMM) fractions of the M.tb {Delta}esx5 mutant. In examining other ESX systems, we found that ESX-1 substrate levels were increased in both the CF and OMM fractions of the {Delta}esx5 mutant. Conversely, the ESX-3 locus was transcriptionally repressed upon ESX-5 deletion. We noted that the {Delta}esx5 mutant had altered morphology in the form of wrinkled distortions of the bacterial surface. Likewise, we identified increased susceptibility of the {Delta}esx5 mutant to a variety of large (molecular weight >550 g/mol) antimicrobial compounds, suggesting that an intact ESX-5 system is required for M.tb to exclude such molecules. Our findings suggest that removing the ESX-5 system from M.tb fundamentally alters the properties of the mycobacterial OMM and impacts the expression and secretion activity of other ESX systems. Significance StatementMycobacterium tuberculosis (M.tb) uses the ESX-5 secretion system to export numerous proteins that shape host-pathogen interactions. Here, we found that deleting ESX-5 from M.tb not only prevented the secretion of many ESX-5 substrates but also impacted other ESX systems. The M.tb {Delta}esx5 mutant had increased ESX-1 substrate secretion but reduced ESX-3 expression. In addition, the M.tb {Delta}esx5 mutant displayed altered cell surface morphology and increased vulnerability to large antibiotic drugs, suggesting a critical role for ESX-5 for maintaining outer membrane integrity. These findings highlight ESX-5 as a central modulator of secretion and cell envelope composition with implications for drug targeting and vaccine development.

microbiology↗

bioRxiv2025

Elimination of senescent cells with senolytic host-directed therapy reduces tuberculosis progression in mice

By eliciting lung necrosis, which enhances aerosol transmission, Mycobacterium tuberculosis (Mtb) sustains its long-term survival as a human pathogen. In studying the human-like necrotic granuloma lesions characteristic of Mtb-infected B6.Sst1S mice, we found that lung myeloid cells display elevated senescence markers: cell cycle arrest proteins p21 and p16, the DNA damage marker {gamma}H2A.X, senescence-associated {beta}-galactosidase activity, and senescence-associated secretory phenotype (SASP). These markers were also elevated in Mtb-infected aged wild type (WT) mice but not in young WT mice. Global transcriptomics data revealed upregulation of pro-survival (PI3K, MAPK) and anti-apoptotic pathways in Mtb-infected B6.Sst1S macrophages. As senescent cells are terminally growth-arrested yet metabolically active cells that release tissue-damaging, immunosuppressive SASP, we treated Mtb-infected mice with a cocktail of three senolytic drugs (dasatinib, quercetin, and fisetin) designed to kill senescent cells. Senolytic drug treatment prolonged survival and reduced Mtb lung counts in B6.Sst1S and aged WT mice to a greater degree than young WT mice and concomitantly reduced lung senescence markers. These findings indicate that (1) Mtb infection may induce lung myeloid cells to enter a senescent state and that these cells may promote disease progression, and (2) senolytic drugs merit consideration for human clinical trials against tuberculosis (TB). Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/645957v2_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@1ce7eeeorg.highwire.dtl.DTLVardef@1ef55d4org.highwire.dtl.DTLVardef@1ebef03org.highwire.dtl.DTLVardef@98b61f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMtb lung infection results in recruitment of both restrictive and permissive myeloid cells to the nascent granuloma. C_LIO_LIMtb infection induces certain permissive myeloid cells to enter a senescent state, characterized by cell cycle arrest and they promote local immunosuppression. C_LIO_LITreatment with a Senolytic drug cocktail, which kills senescent cells, augments host resistance against Mtb proliferation, lethality and immunopathology. C_LI

microbiology↗