The extraordinary success of Mycobacterium tuberculosis ( M. tb ) has been attributed to its ability to modulate host immune responses, and its genome encodes multiple immunomodulatory factors, including several proteins of the multigenic PE_PPE family. To understand its role in M. tb pathophysiology we have characterised the PPE50 (Rv3135) - PPE51 (Rv3136) gene cluster, one of nine PPE -PPE clusters in the genome. We demonstrate here that this cluster is operonic, and that PPE50 and PPE51 interact - the first demonstration of PPE - PPE interaction. THP-1 macrophages infected with recombinant Mycobacterium smegmatis strains expressing PPE50 and PPE51 showed lower intracellular viability than the control, which correlated with an increase in transcript levels of iNOS2 . Infected macrophages also exhibited an upregulation in levels of IL -10 , indicating an immunomodulatory role for these proteins. Using pull -downs and signalling assays, we identi fied TLR1 to be the cognate receptor for PPE50 - all the phenotypes observed on infection of THP-1 macrophages were reversed on pre-treatment with an antiTLR1 antibody, validating the functional outcome of PPE50-TLR1 interaction. Our data reveals a TLR1 dependent role for the PPE50-PPE51 cluster in promoting bacillary persistence, via CFU reduction and concomitant upregulation of the anti-in flammatory response - a two -pronged strategy to circumvent host immune surveillance. (c) 2023 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.
[1]CSIR Ctr Cellular & Mol Biol, Uppal Rd, Hyderabad 500007, India.
[2]Acad Sci & Innovat Res AcSIR, Ghaziabad 201002, India.
[3]Univ Colorado, Anschutz Med Campus,13001 E17th Pl, Aurora, CO 80045 USA.
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