title: TLR6-driven lipid droplets in Mycobacterium leprae-infected Schwann cells: immunoinflammatory platforms associated with bacterial persistence.
abstract: The mechanisms responsible for nerve injury in leprosy need further elucidation. We recently demonstrated that the foamy phenotype of Mycobacterium leprae-infected Schwann cells (SCs) observed in nerves of multibacillary patients results from the capacity of M. leprae to induce and recruit lipid droplets (LDs; also known as lipid bodies) to bacterial-containing phagosomes. In this study, we analyzed the parameters that govern LD biogenesis by M. leprae in SCs and how this contributes to the innate immune response elicited by M. leprae. Our observations indicated that LD formation requires the uptake of live bacteria and depends on host cell cytoskeleton rearrangement and vesicular trafficking. TLR6 deletion, but not TLR2, completely abolished the induction of LDs by M. leprae, as well as inhibited the bacterial uptake in SCs. M. leprae-induced LD biogenesis correlated with increased PGE(2) and IL-10 secretion, as well as reduced IL-12 and NO production in M. leprae-infected SCs. Analysis of nerves from lepromatous leprosy patients showed colocalization of M. leprae, LDs, and cyclooxygenase-2 in SCs, indicating that LDs are sites for PGE(2) synthesis in vivo. LD biogenesis Inhibition by the fatty acid synthase inhibitor C-75 abolished the effect of M. leprae on SC production of immunoinflammatory mediators and enhanced the mycobacterial-killing ability of SCs. Altogether, our data indicated a critical role for TLR6-dependent signaling in M. leprae-SC interactions, favoring phagocytosis and subsequent signaling for induction of LD biogenesis in infected cells. Moreover, our observations reinforced the role of LDs favoring mycobacterial survival and persistence in the nerve. These findings give further support to a critical role for LDs in M. leprae pathogenesis in the nerve.
authors.affiliation: Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ 21045-900, Brazil.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Mattos
authors.forename: Viviane G C
authors.initials: VG
authors.lastname: Oliveira
authors.forename: Heloisa
authors.initials: H
authors.lastname: D'Avila
authors.forename: Luciana S
authors.initials: LS
authors.lastname: Rodrigues
authors.forename: Roberta O
authors.initials: RO
authors.lastname: Pinheiro
authors.forename: Euzenir N
authors.initials: EN
authors.lastname: Sarno
authors.forename: Maria Cristina V
authors.initials: MC
authors.lastname: Pessolani
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Bozza
mesh_terms: D000818:Animals; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D007918:Leprosy / Q000276:immunology / Q000473:pathology*; D050356:Lipid Metabolism / Q000502:physiology; D008055:Lipids / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009166:Mycobacterium leprae / Q000276:immunology; D012583:Schwann Cells / Q000276:immunology / Q000382:microbiology* / Q000473:pathology*; D051216:Toll-Like Receptor 6 / Q000276:immunology* / Q000378:metabolism
chemical_list: D008055:Lipids; C495368:TLR6 protein, human; D051216:Toll-Like Receptor 6