Mycobacterium tuberculosis PPE18 protein inhibits MHC class II antigen presentation and B cell response in mice

Abstract

PPE18 protein belongs to PE/PPE family of Mycobacterium tuberculosis. We reported earlier that PPE18 protein provides survival advantage to M. tuberculosis during infection. In the current study, we found that PPE18 inhibits MHC class II‐mediated antigen presentation by macrophages in a dose‐dependent manner without affecting the surface level of MHC class II or co‐stimulatory molecules. PPE18 does not affect antigen uptake or presentation of preprocessed peptide by macrophages. Antigen degradation was found to be inhibited by PPE18 protein due to perturbation in phagolysosomal acidification. PPE18‐mediated inhibition of MHC class II antigen presentation caused poorer activation of CD4 T cells. Mice infected with M. smegmatis expressing PPE18 exhibited reduced maturation and activation of B cells and had decreased Mycobacteria‐specific antibody titers. Thus M. tuberculosis probably utilizes PPE18 to inhibit MHC class II antigen presentation causing poorer activation of adaptive immune responses. This study may be useful in understanding host–pathogen interaction and open up directions of designing novel therapeutics targeting PPE18 to tackle this nefarious pathogen.

Peptides-Based Vaccine MP3RT Induced Protective Immunity Against Mycobacterium Tuberculosis Infection in a Humanized Mouse Model

“…PPE18 is a crucial virulence factor for the intracellular survival of M. tuberculosis and one of the main components of the M72/AS01E vaccine (31,32). Recently, Komal Dolasia et al reported that PPE18 protein inhibited MHC class II antigen presentation (33). However, we found that two peptides (PPE18 115-129 and PPE18 149-163 ) of PPE18 protein could be recognized and presented by splenolymphocytes from humanized mice.…”

“…Recently, Komal Dolasia et al. reported that PPE18 protein inhibited MHC class II antigen presentation ( 33 ). However, we found that two peptides (PPE18 115-129 and PPE18 149-163 ) of PPE18 protein could be recognized and presented by splenolymphocytes from humanized mice.…”

“…Our further study found that immunodominant peptide MPT63 10-24 was a part of the signal peptide of MPT63 protein, indicating that these amino acid residues would be challenging to express Escherichia coli BL21 cells. We also observed that two immunodominant peptides TB10.4 21-35 and TB10.4 23-37 shared similar amino acid, and the SI value induced by peptide TB10.4 21-35 was significantly higher than that of TB10.4 [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] . Based on the reasons described above, both immunodominant peptides MPT63 10-24 and TB10.4 [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] were not included in our further study.…”

“…After that, the potential immunodominant Th1 peptides were screened by ELISPOT assay, and the results showed that the SI values of eight peptides (MPT63 10-24 , Mtb8. [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] ) were greater than 2 in at least two independent experiments (Figure 2). Our further study found that immunodominant peptide MPT63 10-24 was a part of the signal peptide of MPT63 protein, indicating that these amino acid residues would be challenging to express Escherichia coli BL21 cells.…”

Clinical manifestations and immune response to tuberculosis

“…Mycobacteria inhibit MHC-II synthesis which leads to reduced CD4 + TL-mediated immunity action due to a lack of antigen presentation (Noss et al 2001 ; Dolasia et al 2021 ). Mtb can avoid and/or tolerate phagolysosome formation; this directly affects phagocyte maturation, limits lysosome formation and inhibits phagosome acidification (Wong et al 2013 ; Chen et al 2015 ; Sajid et al 2015 ).…”