Mycobacterium tuberculosis PE_PGRS18 enhances the intracellular survival of M. smegmatis via altering host macrophage cytokine profiling and attenuating the cell apoptosis

Abstract

Mycobacterium tuberculosis PE/PPE family proteins, named after the presence of conserved PE (Pro-Glu) and PPE (Pro-Pro-Glu) domains at N-terminal, are prevalent in M. tuberculosis genome. The function of most PE/PPE family proteins remains elusive. To characterize the function of PE_PGRS18, the encoding gene was heterologously expressed in M. smegmatis, a nonpathogenic mycobacterium. The recombinant PE_PGRS18 is cell wall associated. M. smegmatis PE_PGRS18 recombinant showed differential response to stresses and altered the production of host cytokines IL-6, IL-1β, IL-12p40 and IL-10, as well as enhanced survival within macrophages largely via attenuating the apoptosis of macrophages. In summary, the study firstly unveiled the role of PE_PGRS18 in physiology and pathogenesis of mycobacterium.

PE_PGRS3 ofMycobacterium tuberculosisis specifically expressed at low phosphate concentration, and its arginine-rich C-terminal domain mediates adhesion and persistence in host tissues when expressed inMycobacterium smegmatis

“…Here, the enhanced persistence in the spleen tissue of the Ms recombinant strain expressing PE_PGRS3 compared with the parental strain and the Ms expressing PE_PGRS3ΔCT did not correlate with an increase in the inflammatory parameters as indicated by the cytokines secreted and lack of spleen enlargement. Other PE_PGRSs proteins have been shown to promote increased persistence in host tissues when expressed in Ms while attenuating, rather than inducing, inflammation (Deng et al, ; Yang et al, ), highlighting the fact that different PE_PGRSs may induce different mechanisms to manipulate host responses and enhance bacterial persistence. Our results indicate a key role for the ≈ 80 amino acids long, arginine‐rich, C‐terminal domain of PE_PGRS3 in TB pathogenesis.…”

“…The expression of the recombinant protein in Mycobacterium smegmatis ( Ms ), which does not possess any pe_pgrs or an ESX‐5 secretion system, has been widely used to investigate these proteins, and the results obtained have provided some relevant information. For example, PE_PGRS60 and PE_PGRS61 were shown to bind extracellular components (Monu & Meena, ); PE_PGRS33 was shown to interact with TLR2 to mediate inflammatory responses and entry in macrophages (Palucci et al, ; Zumbo et al, ); PE_PGRS18 and PE_PGRS41 were shown to increase mycobacteria survival within macrophages by interfering with innate host immune responses (Deng et al, ; Yang et al, ); PE_PGRS47 inhibited autophagy and interfered with the MHC Class II antigen presentation pathway (Saini et al, ); PE_PGRS17, PE_PGRS30, PE_PGRS33, and PE_PGRS62 were shown to modulate cytokines secretion (Chatrath, Gupta, Dixit, & Garg, ; Chen, Zhao, Li, & Xie, ; Huang et al, ; Zumbo et al, ).…”

Intelligent Mechanisms of Macrophage Apoptosis Subversion by Mycobacterium

“…Mtb PE_PGRS family proteins are the most abundant cell wall anchored proteins that are implicated in bacilli adhesion, invasion, and survival within macrophages and dendritic cells [23]. PE_PGRS62, PE_PGRS41, and PE_PGRS18 contribute actively to revoke macrophage apoptosis [24][25][26].…”

“…PE_PGRS18 also inhibits THP-1 apoptosis. However the underlying molecular mechanisms are still unknown [26].…”

Molecular Basis Underlying Host Immunity Subversion by Mycobacterium tuberculosis PE/PPE Family Molecules

“…P roline-glutamic acid/proline-proline-glutamic acid (PE/PPE) family proteins exclusive to mycobacteria accounts for nearly 10% of the Mycobacterium tuberculosis (MTB) genome encoding capability (Phelan et al, 2016;Yang et al, 2017;Grover et al, 2018). PE/PPE proteins are characterized by the conserved PE and PPE domains at Ntermini, including 99 PE genes and 69 PPE genes in MTB H37Rv.…”