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The PPE18 of Mycobacterium tuberculosis Interacts with TLR2 and Activates IL-10 Induction in Macrophage¹

Shiny Nair,^* Poongothai A. Ramaswamy,^* Sudip Ghosh, Dhananjay C. Joshi,^* Niteen Pathak,^* Imran Siddiqui, Pawan Sharma, Seyed E. Hasnain,^*¶|| Shekhar C. Mande,^* and Sangita Mukhopadhyay^2*

*Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad, India; National Institute of Nutrition (ICMR), Jamai-Osmania PO, Hyderabad, India; International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India; Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India; ^¶University of Hyderabad, P.O. Central University, Hyderabad, India; and ^||Institute of Life Sciences, Hyderabad Central University Campus, Hyderabad, India

The pathophysiological functions of proline-glutamic acid (PE)/proline-proline-glutamic acid (PPE) family of proteins of Mycobacterium tuberculosis are not well understood. In this study, we demonstrate that one of the PPE proteins, PPE18 can stimulate macrophages to secrete IL-10, known to favor a Th2 type response. The recombinant PPE18 was found to specifically interact with the TLR2 leading to an early and sustained activation of p38 MAPK, which is critical for IL-10 induction. In silico docking analyses and mutation experiments indicate that PPE18 specifically interacts with the leucine rich repeat 1115 domain of TLR2 and the site of interaction is different from that of a synthetic lipopeptide Pam₃CSK₄ known to activate predominantly ERK 1/2. When PMA-differentiated THP-1 macrophages were infected with a mutant Mycobacterium tuberculosis strain lacking the PPE18, produced poorer levels of IL-10 as compared with those infected with the wild-type strain. In contrast, an M. smegmatis strain overexpressing the PPE18 induced higher levels of IL-10 in infected macrophages. Our data indicate that the PPE18 protein may trigger an anti-inflammatory response by inducing IL-10 production.

² Address correspondence and reprint requests to Sangita Mukhopadhyay, Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics (CDFD), Gruhakalpa Building, Nampally, Hyderabad, India. E-mail address: sangita{at}cdfd.org.in or kashbon{at}yahoo.com

¹ This work was supported by grants from Department of Biotechnology (DBT), Government of India and Indian Council of Medical Research (ICMR), Government of India, and also a core grant to CDFD from DBT, India. Part of this work was carried out at BSL-3 laboratory at the DBT-funded National Facility for Tuberculosis Research at ICGEB, New Delhi. This work was also supported by research fellowship to SN from the Council of Scientific and Industrial Research (CSIR), India.