Research Article: 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

Date Published: July 6, 2018

Publisher: Public Library of Science

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

http://doi.org/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.

Partial Text

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). SCs show remarkable plasticity and contribute to the regenerative capacity of the adult PNS even after severe injury has occurred. M. leprae-nerve fiber colonization results in loss of sensation, an early symptom of the disease. While multidrug therapy (MDT) treats the infection, it may be unsuccessful in either preventing or arresting the nerve damage responsible for disfigurement and disabilities [1, 2]. In-depth investigation of M. leprae-nerve interactions objectifying the development of new strategies for the prevention and treatment of leprosy-related nerve impairments is, therefore, of utmost importance. M. leprae is easily 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. However, the first symptoms of leprosy are related to loss of temperature sensation and decreased touch sensation, functions provided by non-myelinating fibers, indicating their early invasion by the leprosy bacillus during the natural course of the disease [5]. Thus, 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.

The most severe symptoms of leprosy are caused by nerve infection. Thus, deciphering the molecular basis of the early events of mycobacterial peripheral nerve infection is a crucial step towards acquiring a basic understanding of nerve pathogenesis with the potential to generate new tools for its prevention and treatment. The capacity of M. leprae to bind to laminin-2, a major component of the SC basal lamina, has been described as a fundamental feature of the bacterial predilection for the peripheral nervous system [6]. Moreover, the PGL I and Hlp/LBP-21 molecules produced by the leprosy bacillus located on the bacterial surface have been implicated as likely adhesins involved in this interaction [12].

 

Source:

http://doi.org/10.1371/journal.ppat.1007151