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bioRxiv · 10.1101/2022.10.13.512188

Mycobacterium tuberculosis infection elevates SLIT2 expression to modulate oxidative stress responses in macrophages

Borbora, S. M.·Bhatt, S.·Balaji, K. N.
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Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of the pulmonary ailment, tuberculosis (TB), continues to thrive owing to a disorganized immune response against it by the host. Among other factors, the rewiring of distinct host signaling pathways is effectuated by the intracellular bacterium, resulting in pathogen-favorable outcomes. Oxidative stress build-up is a key cellular manifestation that occurs during mycobacterial infection. Enhanced oxidative stress is brought about by the cumulative effect of elevated reactive oxygen species generation as well as the inept ability of the cell to mitigate ROS levels. Here, we report the increased expression of the neuronal ligand, SLIT2, during mycobacterial infection in macrophages. By employing loss of function analysis using specific inhibitors, we attribute the heightened expression of SLIT2 to the Mtb-mediated phosphorylation of the p38/JNK pathways. Also, using chromatin immunoprecipitation (ChIP) analysis, we found reduced levels of the repressive H3K27me3 signature on the Slit2 promoter during mycobacterial infection. Furthermore, SLIT2 was found to promote the expression of cellular pantetheinase, Vanin1 (VNN1), that contributed to copious levels of ROS within the macrophage cellular milieu. Thus, we dissect essential molecular details leading to the robust expression of SLIT2 during Mtb infection while outlining the potential consequences of SLIT2 upregulation in infected macrophages. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/512188v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@352ec6org.highwire.dtl.DTLVardef@19209e5org.highwire.dtl.DTLVardef@c7c546org.highwire.dtl.DTLVardef@168ab61_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Borbora, S. M., Bhatt, S., Balaji, K. N.. 2022-10-14. Mycobacterium tuberculosis infection elevates SLIT2 expression to modulate oxidative stress responses in macrophages. https://doi.org/10.1101/2022.10.13.512188

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