1. 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
- Author
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Leonardo Ribeiro Batista-Silva, Flávio Alves Lara, Christophe Guilhot, Euzenir Nunes Sarno, André Alves Dias, Maria Cristina Vidal Pessolani, Thabatta L. S. A. Rosa, Chyntia Carolina Diaz Acosta, Thiago Gomes de Toledo-Pinto, Patrícia T. Bozza, Katherine Antunes de Mattos, Marcia Berrêdo-Pinho, Patrícia Sammarco Rosa, Fabrício da Mota Ramalho Costa, and Luciana Silva Rodrigues
- Subjects
0301 basic medicine ,Bacterial Diseases ,Macroglial Cells ,Biochemistry ,0302 clinical medicine ,Fluorescence Microscopy ,Spectrum Analysis Techniques ,Animal Cells ,Lipid droplet ,Medicine and Health Sciences ,Small interfering RNAs ,Internalization ,Receptor ,Mycobacterium leprae ,lcsh:QH301-705.5 ,media_common ,Microscopy ,biology ,Organic Compounds ,Light Microscopy ,Flow Cytometry ,Mycobacterium Leprae ,Cell biology ,Actinobacteria ,Nucleic acids ,Chemistry ,Infectious Diseases ,Spectrophotometry ,Physical Sciences ,Cytophotometry ,Cellular Types ,Mannose receptor ,Intracellular ,Mannose Receptor ,Research Article ,Neglected Tropical Diseases ,lcsh:Immunologic diseases. Allergy ,media_common.quotation_subject ,Immunology ,Carbohydrates ,Glial Cells ,Receptors, Cell Surface ,Research and Analysis Methods ,Microbiology ,03 medical and health sciences ,Glycolipid ,Virology ,Leprosy ,Genetics ,Humans ,Secretion ,Lectins, C-Type ,Non-coding RNA ,Molecular Biology ,Antigens, Bacterial ,Bacteria ,Organic Chemistry ,Organisms ,Chemical Compounds ,Biology and Life Sciences ,Cell Biology ,Receptor Cross-Talk ,biology.organism_classification ,Tropical Diseases ,Gene regulation ,PPAR gamma ,030104 developmental biology ,Mannose-Binding Lectins ,lcsh:Biology (General) ,RNA ,Parasitology ,Schwann Cells ,Gene expression ,Glycolipids ,lcsh:RC581-607 ,Mannose ,030217 neurology & neurosurgery ,Mycobacterium Tuberculosis - 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., Author summary Nerve damage is the most severe symptom of leprosy, an ancient disease that continues to be a major health problem in several countries. Nerve damage is due to the ability of Mycobacterium leprae, the etiologic agent, to invade SCs, the glial cells of the peripheral nervous system. Understanding the molecular basis of M. leprae–SC interaction is essential for the creation of new tools aiming to treat and, above all, prevent leprosy neuropathy. This study demonstrates the critical role of PGL I, an M. leprae-abundant specific cell wall lipid, in establishing infection. PGL I is not only a prerequisite in initiating bacterial adhesion to and subsequent invasion of SCs, but also for changing the repertoire of cell surface proteins to allow for the entrance of bacteria via alternative pathways. These new invasive pathways induced by PGL I involve recognition of other bacterial cell surface glycolipids that, in turn, evoke functional changes in the infected cell, including the accumulation of host cell-derived lipids, which favor bacterial survival. These pathways also promote the secretion of inflammatory mediators that may contribute to nerve damage. In an era of translational-oriented research, exploring these receptors in depth could lead to the development of attractive strategies to ensure the targeted intracellular delivery of therapeutics aiming to prevent neuropathy.
- Published
- 2018