Biology subjects

Mabry, C. J.

Publications and source records attributed to Mabry, C. J..

6 recordsLinked to original sources

bioRxiv2026

Loss of Mitochondrial Respiratory Capacity Reshapes Myeloid Cell Function during Mycobacterium tuberculosis infection

Myeloid cells are essential mediators of host defense against Mycobacterium tuberculosis (Mtb), yet the metabolic programs that sustain their function during chronic infection remain poorly defined. Here, using scRNA-seq we identified a striking, coordinated decline in mitochondrial electron transport chain gene expression across diverse myeloid populations as Mtb disease progressed in mice. This transcriptional remodeling was associated with broad changes in immune and metabolic pathways, including reduced antigen presentation, interferon responses, protein synthesis, and glycolysis. Accordingly, loss of Complex I in macrophages (Ndufs4 knockdown) reduced MHC-II surface expression, dysregulated inflammatory gene expression, and limited control of Mtb replication. Finally, analysis of single-cell transcriptomic data from Mtb-exposed human household contacts identified an almost identical transcriptional program enriched in IGRA+ individuals, supporting a role for mitochondrial respiratory remodeling in human TB. Together, these findings demonstrate that mitochondrial bioenergetic competence is required to sustain macrophage effector function during chronic Mtb infection and suggest that mitochondrial restoration may boost protective responses in TB patients.

immunology↗

bioRxiv2026

Mycobacterium tuberculosis manipulates host inflammation and lipid metabolism through the SET1-interacting protein Rv1075c

A growing body of literature supports a critical role for nucleomodulins, proteins that traffic to host cell nuclei and manipulate nuclear processes, in intracellular bacterial pathogenesis. Here, we identify the Mycobacterium tuberculosis (Mtb) secreted protein Rv1075c as a nucleomodulin that targets a histone modifying protein complex in macrophages. We report that {Delta}Rv1075c Mtb infection elicits a blunted transcriptional response in inflammatory and lipid metabolism pathways and fails to induce foamy macrophage formation in the lungs of infected mice. Using an unbiased mass-spectrometry based approach, we found that Rv1075c interacts with components of the H3K4me3-depositing SET1 histone methyltransferase complex, and that this interaction is required for Rv1075c nuclear localization. Consistent with Rv1075c inhibiting SET1 activity, SET1 deficiency results in hyperinduction of inflammatory genes in activated macrophages. Together, these findings reveal a mechanism by which Mtb engages host chromatin machinery and support a model whereby Rv1075c exploits the SET1 complex to promote a host environment conducive to mycobacterial persistence.

microbiology↗

bioRxiv2026

Mitochondrial STAT3-mediated suppression of apoptosis constrains antimycobacterial immunity

Maintenance of mitochondrial homeostasis is required to balance the host-pathogen interface during Mycobacterium tuberculosis (Mtb) infection. Here, we identify the non-canonical TRIM family member Trim14 as a critical regulator of mitochondrial integrity in Mtb-infected macrophages. Specifically, we demonstrate that Trim14 preserves mitochondrial membrane polarization and limits macrophage apoptosis by controlling phosphorylation and mitochondrial targeting of Stat3. When targeted to mitochondria, Stat3 restricts opening of the mitochondrial permeability transition pore, which raises the macrophage threshold for apoptotic commitment. In vivo, loss of Trim14 enhances apoptosis of macrophages and dendritic cells, leading to augmented antimycobacterial immunity marked by increased CD8+ T cell activation and effector function. Together, these findings define a Trim14-mitochondrial Stat3 axis that suppresses host-protective apoptosis during Mtb infection and pinpoint mitochondrial Stat3 as a potential target for therapies aimed at boosting antimycobacterial immunity. HIGHLIGHTSO_LITrim14 raises the apoptotic threshold in Mtb-infected macrophages. C_LIO_LITrim14 controls phosphorylation and mitochondrial targeting of Stat3. C_LIO_LIReduced mitochondrial Stat3 promotes mPTP opening and apoptotic commitment. C_LIO_LITrim14 deficiency enhances apoptosis, CD8+ T cell immunity, and Mtb resistance. C_LI

immunology↗

bioRxiv2025

HnRNPA2B1 tunes antimycobacterial immune responses in macrophages through alternative splicing of Irgm1

Onset and progression of active tuberculosis disease result from upsetting the delicate balance between Mtb virulence and host defenses. Because it dynamically tunes the functional output of protein expression in cells, alternative splicing, a process by which different mRNAs can be gen-erated from a single gene, is positioned to play a critical role in maintaining an equilibrated Mtb-macrophage host-pathogen interface. To gain insight into how alternative splicing shapes anti-mycobacterial immune responses, we used RNA-sequencing and splicing-aware computational pipelines to quantify alternative splicing in Mtb-infected bone marrow-derived murine macro-phages. We found that [~]5% of expressed macrophage genes exhibit one or more splicing changes at 8h post-Mtb infection, highlighting alternative splicing as a key regulatory node in the macrophage response to Mtb. We next sought to identify RNA binding proteins that play an out-sized role in shaping the macrophage transcriptome during Mtb infection. We discovered that the splicing factor heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) promotes the early induction of inflammatory genes while dampening several type I interferon-stimulated genes in response to Mtb. HnRNPA2B1 also controls alternative splicing of many genes during Mtb infection, including Irgm1, a critical immunity-related GTPase. The balance of Irgm1-long vs. -short is differentially regulated in response to diverse inflammatory cues and macrophages overexpressing Irgm1-short are defective in autophagosomal targeting, lysosomal homeostasis, and restriction of Mtb replication. These data highlight a key role for AS in shaping the macro-phage transcriptome and pinpoint hnRNPA2B1 as a novel restriction factor in the cell-intrinsic response to Mtb. IMPORTANCEAlthough the process of making proteins from RNAs requires many steps (transcription, cap-ping/polyadenylation, pre-mRNA splicing, mRNA export, mRNA modifications, etc.), we know very little about how post-transcriptional steps contribute to host immune defenses. Here, we show that alternative splicing, the process of making different mature RNAs from a single pre-cursor RNA, is a prominent and dynamic feature of macrophage infection with the bacterial pathogen Mycobacterium tuberculosis (Mtb). We identify the splicing regulator hnRNPA2B1 as a key coordinator of early gene expression during Mtb infection, influencing pathways that pro-mote inflammation and help restrict bacterial growth. Notably, we report that hnRNPA2B1 con-trols the splicing of the antimycobacterial protein Irgm1 to generate different flavors of the pro-tein. Since only one Irgm1 flavor can restrict Mtb growth inside macrophages, maintaining the balance of these proteins in response to diverse inflammatory cues is important. By revealing how RNA processing shapes the macrophage response to Mtb, our work highlights an often-overlooked layer of immune regulation and opens new avenues for splicing-targeted therapies designed to boost Mtb killing in macrophages.

microbiology↗

bioRxiv2024

Necrosis drives susceptibility to Mycobacterium tuberculosis in POLG mtDNA mutator mice

The genetic and molecular determinants that underlie the heterogeneity of Mycobacterium tuberculosis (Mtb) infection outcomes in humans are poorly understood. Multiple lines of evidence demonstrate that mitochondrial dysfunction can exacerbate mycobacterial disease severity and mutations in some mitochondrial genes confer susceptibility to mycobacterial infection in humans. Here, we report that mutations in mitochondria DNA (mtDNA) polymerase gamma (POLG) potentiate susceptibility to Mtb infection in mice. PolgD257A mutator mtDNA mice fail to mount a protective innate immune response at an early infection timepoint, evidenced by high bacterial burdens, reduced M1 macrophages, and excessive neutrophil infiltration in the lungs. Immunohistochemistry reveals signs of enhanced necrosis in the lungs of Mtb-infected PolgD257A mice and PolgD257A mutator macrophages are hyper-susceptible to extrinsic triggers of necroptosis ex vivo. By assigning a role for mtDNA mutations in driving necrosis during Mtb infection, this work further highlights the requirement for mitochondrial homeostasis in mounting balanced immune responses to Mtb.

immunology↗

bioRxiv2023

The RNA binding protein, HNRNPA2B1, regulates IFNG signaling in macrophages

Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) is a well known RNA binding protein but the mechanisms by which it contributes to innate immune gene regulation are poorly understood. Here we report that HNRNPA2B1 functions in macrophages to regulate IFNG (IFN-{gamma}) signaling through alternative splicing of the IFNG receptor. Specific deletion of HNRNPA2B1 in macrophages resulted in altered cytokine responses in both an endotoxic shock model and following Salmonella infection. Interestingly, while HNRNPA2B1 can function as a viability gene, we observed increased macrophage and neutrophil numbers in the KO mice following LPS induced endotoxic shock. We also discovered that HNRNPA2B1 restricts replication of Salmonella enterica in vivo. Mechanistically, loss of HNRNPA2B1 resulted in an increase in NGO transcripts, which lack a start codon, of the IFNG receptor (Ifngr) leading to lower expression of the receptor at the cell surface impacting the downstream IFNG signaling cascade. Collectively, our data highlight an important role for HNRNPA2B1 in regulating IFNG signaling and restricting intracellular bacterial pathogens in macrophages.

immunology↗