Biology subjects

Mitermite, M.

Publications and source records attributed to Mitermite, M..

3 recordsLinked to original sources

bioRxiv2026

Comparative multi-omics of the macrophage response to infection with Mycobacterium tuberculosis complex bacteria reveals pathogen-driven epigenomic reprogramming

BackgroundBovine tuberculosis (bTB) is a chronic infectious disease primarily caused by Mycobacterium bovis, which inflicts significant economic losses on the global livestock industry worldwide and can also cause tuberculosis (TB) disease in other mammalian species, including humans. Alveolar macrophages are the host cells targeted by the pathogen during the early stages of infection. While they play a crucial role in controlling infection, the exact nature of the host-pathogen interaction and the genetic and epigenetic factors that modulate infection outcome remain poorly understood. ResultsHere, we used transcriptomics (RNA-seq), chromatin accessibility (ATAC-seq), and chromatin configuration (ChIP-seq) analyses to examine the effects of intracellular mycobacterial infection on the bovine alveolar macrophage (bAM) transcriptome and epigenome. The primary focus was M. bovis infection, but we also conducted parallel comparative analyses using M. tuberculosis (the primary cause of human TB--hTB), M. bovis BCG (the vaccine strain), and gamma-irradiated (killed) M. bovis. Integration of RNA-seq, ChIP-seq, and ATAC-seq data revealed coordinated remodelling of chromatin accessibility and histone modification landscapes underpinning transcriptional activation of key immune and metabolic pathways in response to infection. The identification of candidate genes, including ERBB4, LRCH1, MRTFA, and RNPC3, through integrative analysis with a genome-wide association study (GWAS) for M. bovis infection susceptibility underscores the functional relevance of these regulatory networks. ConclusionsOur results demonstrate that M. bovis drives extensive reprogramming of the bAM epigenome, distinct from the responses elicited by other members of the M. tuberculosis complex (MTBC). The results of this multi-omics comparison provide new insights into the function of pivotal response genes and support the hypothesis that pathogen-driven epigenetic reprogramming of the bovine host macrophage is key to M. bovis survival. It also identifies molecular targets that may inform genome-enabled breeding strategies to enhance resilience to bTB in cattle.

genomics↗

bioRxiv2021

Macrophage Innate Training Induced by IL-4 Activation Enhances OXPHOS Driven Anti-Mycobacterial Responses

Macrophages are a highly adaptive population of innate immune cells. Polarization with IFN{gamma} and LPS into the "classically activated" M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis. By contrast, "alternatively activated" M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here we demonstrate that activation with IL-4 and IL-13 counterintuitively induces protective innate memory against mycobacterial challenge. In human and murine models, prior activation with IL-4/13 enhances pro-inflammatory cytokine secretion in response to a secondary stimulation with mycobacterial ligands. In our murine model, enhanced killing capacity is also demonstrated. Despite this switch in phenotype, IL-4/13 trained murine macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4/13 trained macrophages. Lastly, this work identifies that IL-10 attenuates protective IL-4/13 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection.

immunology↗

bioRxiv2020

Macrophage-specific responses to human- and animal-adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation

The Mycobacterium tuberculosis complex (MTBC) is a group of related pathogens that cause tuberculosis (TB) in mammals. MTBC species are distinguished by their ability to sustain in distinct host populations. While Mycobacterium bovis (Mbv) sustains transmission cycles in cattle and wild animals and causes zoonotic TB, M. tuberculosis (Mtb) affects human populations and seldom causes disease in cattle. However, the host and pathogen determinants driving host tropism between MTBC species are still unknown. Macrophages are the main host cell that encounters mycobacteria upon initial infection and we hypothesised that early interactions between the macrophage and mycobacteria influence species-specific disease outcome. To identify factors that contribute to host tropism, we analysed both blood-derived primary human and bovine macrophages (hM{phi} or bM{phi}, respectively) infected with Mbv and Mtb. We show that Mbv and Mtb reside in different cellular compartments and differentially replicate in hM{phi} whereas both Mbv and Mtb efficiently replicate in bM{phi}. Specifically, we show that out of the four infection combinations, only the infection of bM{phi} with Mbv promoted the formation of multinucleated cells (MNCs), a hallmark of tuberculous granulomas. Mechanistically, we demonstrate that both MPB70 from Mbv and extracellular vesicles released by Mbv-infected bM{phi} promote macrophage multi-nucleation. Importantly, we extend our in vitro studies to show that granulomas from Mbv-infected but not Mtb-infected cattle contained higher numbers of MNCs. Our findings implicate MNC formation in the contrasting pathology between Mtb and Mbv for the bovine host, and identify MPB70 from Mbv and extracellular vesicles from bM{phi} as mediators of this process.

microbiology↗