Suppression of major histocompatibility complex (MHC) class II antigen presentation is believed to be among the major mechanisms used by Mycobacterium tuberculosis to escape protective host immune responses. Through a genome-wide screen for the genetic loci of M. tuberculosis that inhibit MHC class II-restricted antigen presentation by mycobacteria-infected dendritic cells, we identified the PE_PGRS47 protein as one of the responsible factors. Targeted disruption of the PE_PGRS47 (Rv2741) gene led to attenuated growth of M. tuberculosis in vitro and in vivo, and a PE_PGRS47 mutant showed enhanced MHC class II-restricted antigen presentation during in vivo infection of mice. Analysis of the effects of deletion or over-expression of PE_PGRS47 implicated this protein in the inhibition of autophagy in infected host phagocytes. Our findings identify PE_PGRS47 as a functionally relevant, non-redundant bacterial factor in the modulation of innate and adaptive immunity by M. tuberculosis, suggesting strategies for improving antigen presentation and the generation of protective immunity during vaccination or infection.
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The authors thank the staff of the Flow Cytometry Core Facility of the Albert Einstein College of Medicine (supported by the Einstein Cancer Center grant NIH/NCI CA13330). The authors acknowledge the NIH Tetramer Core Facility (contract no. HHSN272201300006C) for provision of the I-Ab/TB9.8 tetramers. This work was supported by NIH grants AI093649 to S.A.P. and AI063537 to S.A.P., W.R.J. and J.C. The authors thank N. Mizushima, Tokyo Medical and Dental University, for providing the GFP-LC3 lentivirus construct and A.Y. Rudensky for providing the Y-Ae hybridoma. The authors also thank P. Jain and P. A. Gonzalez for their suggestions on the construction of the ΔPE_PGRS47 mutant strain and R. Sellers for assistance in analysis of histopathology. A.B. acknowledges support from ‘Estrategia de Sostenibilidad Universidad de Antioquia’. The authors thank R. Prados-Rosales for assistance with EM studies and E. Bejarano for advice on autophagy analysis.
The authors declare no competing financial interests.
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Saini, N., Baena, A., Ng, T. et al. Suppression of autophagy and antigen presentation by Mycobacterium tuberculosis PE_PGRS47. Nat Microbiol 1, 16133 (2016). https://doi.org/10.1038/nmicrobiol.2016.133
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