PPE2 protein of Mycobacterium tuberculosis may inhibit nitric oxide in activated macrophages

Abstract

Although the pathophysiological role of PE/PPE proteins of Mycobacterium tuberculosis is yet to be fully understood, recent evidence shows that these proteins play important roles in antigenic diversity, as well as in host-pathogen interactions and mycobacterial pathogenesis. Most of the PE/PPE proteins are highly expressed in pathogenic bacteria, pointing to their role in the pathogenesis of mycobacteria. Here, we provide an overview of our work in progress on a specific PPE protein, PPE2 (Rv0256c), which may inhibit nitric oxide (NO) production in activated macrophages. As NO and its by-products are considered to be toxic to bacilli, it is possible that the bacilli recruit Rv0256c in order to inhibit higher production of NO during infection.

The PPE2 protein of Mycobacterium tuberculosis translocates to host nucleus and inhibits nitric oxide production

“…This indicates a possible role of this protein in protecting the bacterium during NO stress. Indeed, earlier we found that PPE2 is a secretory protein and in infected macrophages, PPE2-null mutants allowed higher production of nitric oxide14. The potential mechanisms by which NO may affect antimicrobial activity are protean.…”

“…Therefore, it appears that pathogenic strains may employ certain defensive strategies to counter the toxic effects of NO and its different oxidation products. Our earlier studies demonstrated that macrophages infected with PPE2-null mutant M. tuberculosis can produce higher levels of NO as compared to macrophages infected with wild-type strain14 suggesting that PPE2 may help the bacteria to inhibit NO production and could be a virulent factor. In this manuscript, we found that PPE2 mimics a eukaryotic transcription factor that translocates into the nucleus and binds to upstream regulatory sequences of iNOS, modulating transcription driven by its promoter.…”

Mycobacterium tuberculosis PPE25 and PPE26 proteins expressed in Mycobacterium smegmatis modulate cytokine secretion in mouse macrophages and enhance mycobacterial survival

“…Interestingly, our results demonstrated that PPE25 and PPE26 proteins could promote or inhibit expression of iNOS. Similar to PPE26, Bhat et al also reported that the PPE2 protein of M. tuberculosis may inhibit nitric oxide in activated macrophages [5]. Since iNOS/NO plays an important role in antimycobacterial immunity, inhibition of NO production could contribute to mycobacteria subverting robust host immune responses.…”

Macrophage Takeover and the Host–bacilli interplay During Tuberculosis

“…A PPE protein of M. tuberculosis, PPE18 is found to strongly inhibit iNOS/NO by targeting the TLR2-p38 mitogen-activated protein kinase (MAPK) suppressor of cytokine signaling 3 cascades, resulting in inhibition of NF-κB signaling [17,123]. Another M. tuberculosis PPE2 protein is also predicted to inhibit iNOS transcription and NO production [124]. The bacteria also induce various genes to protect it from intracellular oxidative stress [125].…”