PGL I expression in live bacteria allows activation of a CD206/PPARγ cross-talk that may contribute to successful Mycobacterium leprae colonization of peripheral nerves.

Chyntia Carolina Díaz Acosta,Patrícia Torres Bozza,André Alves Dias,Euzenir Nunes Sarno,Luciana Silva Rodrigues,Maria Cristina Vidal Pessolani,Fabrício Da Mota Ramalho Costa,Flávio Alves Lara,Thiago Gomes Toledo-Pinto,Christophe Guilhot,Leonardo Ribeiro Batista-Silva,Katherine Antunes Mattos,Márcia De Berrêdo-Pinho,Patricia Sammarco Rosa,Thabatta Leal Silveira Andrezo Rosa,Marcel A Behr

doi:10.1371/journal.ppat.1007151

Abstract

Mycobacterium leprae, an obligate intracellular bacillus, infects Schwann cells (SCs), leading to peripheral nerve damage, the most severe leprosy symptom. In the present study, we revisited the involvement of phenolic glycolipid I (PGL I), an abundant, private, surface M. leprae molecule, in M. leprae-SC interaction by using a recombinant strain of M. bovis BCG engineered to express this glycolipid. We demonstrate that PGL I is essential for bacterial adhesion and SC internalization. We also show that live mycobacterium-producing PGL I induces the expression of the endocytic mannose receptor (MR/CD206) in infected cells in a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent manner. Of note, blocking mannose recognition decreased bacterial entry and survival, pointing to a role for this alternative recognition pathway in bacterial pathogenesis in the nerve. Moreover, an active crosstalk between CD206 and the nuclear receptor PPARγ was detected that led to the induction of lipid droplets (LDs) formation and prostaglandin E2 (PGE2), previously described as fundamental players in bacterial pathogenesis. Finally, this pathway was shown to induce IL-8 secretion. Altogether, our study provides evidence that the entry of live M. leprae through PGL I recognition modulates the SC phenotype, favoring intracellular bacterial persistence with the concomitant secretion of inflammatory mediators that may ultimately be involved in neuroinflammation.

Highlights

The most serious consequence of leprosy is the peripheral nerve damage that occurs in all clinical forms of the disease
Nerve damage is due to the ability of Mycobacterium leprae, the etiologic agent, to invade SCs, the glial cells of the peripheral nervous system
This study demonstrates the critical role of phenolic glycolipid I (PGL I), an M. leprae-abundant specific cell wall lipid, in establishing infection

Summary

Introduction

The most serious consequence of leprosy is the peripheral nerve damage that occurs in all clinical forms of the disease. Nerve damage results from the capacity of M. leprae, an obligate intracellular bacillus, to infect SCs, the glial cells of the peripheral nervous system (PNS). M. leprae-nerve fiber colonization results in loss of sensation, an early symptom of the disease. M. leprae is seen inside vacuoles in the non-myelinating and myelinating SC cytoplasm in nerve specimens of leprosy patients [3,4] and, as a consequence, the three physiological functions of nerves–sensory, motor and autonomic–are affected. The first symptoms of leprosy are related to loss of temperature sensation and decreased touch sensation, functions provided by nonmyelinating fibers, indicating their early invasion by the leprosy bacillus during the natural course of the disease [5]. The use of non-myelinating SCs as an in vitro model of infection is physiologically relevant and may reveal early fundamental aspects of M. leprae neuropathogenesis

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