Mycobacterium tuberculosis Rv2145c Promotes Intracellular Survival by STAT3 and IL-10 Receptor Signaling

Abstract

Although Mycobacterium tuberculosis (Mtb) is an intracellular pathogen in phagocytic cells, the factors and mechanisms by which they invade and persist in host cells are still not well understood. Characterization of the bacterial proteins modulating macrophage function is essential for understanding tuberculosis pathogenesis and bacterial virulence. Here we investigated the pathogenic role of the Rv2145c protein in stimulating IL-10 production. We first found that recombinant Rv2145c stimulated bone marrow-derived macrophages (BMDMs) to secrete IL-10, IL-6 and TNF-α but not IL-12p70 and to increase the expression of surface molecules through the MAPK, NF-κB, and TLR4 pathways and enhanced STAT3 activation and the expression of IL-10 receptor in Mtb-infected BMDMs. Rv2145c significantly enhanced intracellular Mtb growth in BMDMs compared with that in untreated cells, which was abrogated by STAT3 inhibition and IL-10 receptor (IL-10R) blockade. Expression of Rv2145c in Mycobacterium smegmatis (M. smegmatis) led to STAT3-dependent IL-10 production and enhancement of intracellular growth in BMDMs. Furthermore, the clearance of Rv2145c-expressing M. smegmatis in the lungs and spleens of mice was delayed, and these effects were abrogated by administration of anti-IL-10R antibodies. Finally, all mice infected with Rv2145c-expressing M. smegmatis died, but those infected with the vector control strain did not. Our data suggest that Rv2145c plays a role in creating a favorable environment for bacterial survival by modulating host signals.

Mycobacterium tuberculosis H37Rv Strain Increases the Frequency of CD3+TCR+ Macrophages and Affects Their Phenotype, but Not Their Migration Ability

“…Mtb virulence influences diverse macrophage functions to create a favorable environment for the survival of the bacteria. For example, specific proteins of virulent strains increase their sensitivity to an acid medium, reduce cell death, and enhance the production of interleukin (IL)-10 to inhibit the activation of a Th1 response [ 10 , 11 , 12 , 13 ]. Other reports have also demonstrated that non-pathogenic strains induce the production of TNF, whereas hypervirulent strains reduce its secretion [ 10 ].…”

How Mycobacterium tuberculosis builds a home: Single-cell analysis reveals M. tuberculosis ESX-1-mediated accumulation of anti-inflammatory macrophages in infected mouse lungs

“…In addition, alternative activation pathways (e.g. IL-10) [109][110][111] and TGF-beta signaling 112,113 have been shown to not only inhibit the anti-MTB activities of macrophages but also suppress lung T cell activation, suggesting that anti-inflammatory responses suppress both innate and adaptive responses to support MTB persistence in recruited macrophages during chronic infection. In our data, recruited macrophages demonstrated induction of oxidative stress and glycolysis, but simultaneously exhibited an ESX-1 dependent upregulation of immunosuppressive pathways both in vitro and in vivo.…”

A brief report on the of mycobacterial proteins regulated by the loss of PtkA in Mtb-H37Ra

“…It is known to modulate the host cytokine secretion of IL-10 and IL-17 and STAT3. (Park HS et.al. 2021; Samten B. et.al, 2016).…”