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Mycobacterium tuberculosis PPE18 protein inhibits MHC class II antigen presentation and B cell response in mice
Komal Dolasia1,2, Faiza Nazar1, Sangita Mukhopadhyay1
1Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India.
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.
Insights
Mycobacterium tuberculosis PPE18 protein hinders macrophage antigen presentation by disrupting phagolysosomal acidification. This impairs CD4 T cell activation and adaptive immunity, aiding pathogen survival.
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- The PE/PPE protein family is crucial for Mycobacterium tuberculosis pathogenesis.
- Previous studies indicated PPE18 protein enhances M. tuberculosis survival during infection.
Purpose of the Study:
- To investigate the mechanism by which PPE18 protein influences host immune response.
- To elucidate PPE18's role in modulating antigen presentation by macrophages.
Main Methods:
- Assessed PPE18's effect on MHC class II-mediated antigen presentation in macrophages.
- Analyzed antigen uptake, peptide presentation, and phagolysosomal acidification.
- Evaluated CD4 T cell activation and B cell responses in infected mice.
Main Results:
- PPE18 inhibited MHC class II antigen presentation without altering MHC class II or co-stimulatory molecule levels.
- Antigen degradation was inhibited by PPE18 due to disrupted phagolysosomal acidification.
- Impaired antigen presentation led to reduced CD4 T cell activation and poorer B cell maturation and antibody production in vivo.
Conclusions:
- Mycobacterium tuberculosis utilizes PPE18 to evade adaptive immunity by inhibiting MHC class II antigen presentation.
- PPE18 perturbs phagolysosomal acidification, hindering antigen processing and presentation.
- Targeting PPE18 could offer a novel therapeutic strategy against tuberculosis.
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