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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.

Mycobacterium leprae (ML), the etiologic agent of leprosy, can subvert macrophage antimicrobial activity by mechanisms that remain only partially understood. In the present study, the participation of hormone insulin-like growth factor I (IGF-I) in this phenomenum was investigated. Macrophages from the dermal lesions of the disseminated multibacillary lepromatous form (LL) of leprosy expressed higher levels of IGF-I than those from the self-limited paucibacillary tuberculoid form (BT). Higher levels of IGF-I secretion by ML-infected macrophages were confirmed in ex vivo and in vitro studies. Of note, the dampening of IGF-I signaling reverted the capacity of ML-infected human and murine macrophages to produce antimicrobial molecules and promoted bacterial killing. Moreover, IGF-I was shown to inhibit the JAK/STAT1-dependent signaling pathways triggered by both mycobacteria and IFN-γ most probably through its capacity to induce the suppressor of cytokine signaling-3 (SOCS3). Finally, these in vitro findings were corroborated by in vivo observations in which higher SOCS3 expression and lower phosphorylation of STAT1 levels were found in LL versus BT dermal lesions. Altogether, our data strongly suggest that IGF-I contributes to the maintenance of a functional program in infected macrophages that suits ML persistence in the host, reinforcing a key role for IGF-I in leprosy pathogenesis.

Erythema Nodosum Leprosum (ENL) is an immune reaction in leprosy that aggravates the patient´s clinical condition. ENL presents systemic symptoms of an acute infectious syndrome with high leukocytosis and intense malaise clinically similar to sepsis. The treatment of ENL patients requires immunosuppression and thus needs to be early and efficient to prevent both disabilities and permanent nerve damage. Some patients experience multiple episodes of ENL and prolonged use of immunosuppressive drugs may lead to serious adverse effects. Thalidomide treatment is extremely effective at ameliorating ENL symptoms. Several mechanisms have been proposed to explain the efficacy of thalidomide in ENL, including the inhibition of TNF production. Given its teratogenicity, thalidomide is prohibitive for women of childbearing age. A rational search for molecular targets during ENL episodes is essential to better understand the disease mechanisms involved, which may also lead to the discovery of new drugs and diagnostic tests. Previous studies have demonstrated that IFN-γ and GM-CSF, involved in the induction of CD64 expression, increase during ENL. The aim of the present study was to investigate CD64 expression during ENL and whether thalidomide treatment modulated its expression. Leprosy patients were allocated to one of five groups: (1) Lepromatous leprosy, (2) Borderline leprosy, (3) Reversal reaction, (4) ENL, and (5) ENL 7 days after thalidomide treatment. The present study demonstrated that CD64 mRNA and protein were expressed in ENL lesions and that thalidomide treatment reduced CD64 expression and neutrophil infiltrates—a hallmark of ENL. We also showed that ENL blood neutrophils exclusively expressed CD64 on the cell surface and that thalidomide diminished overall expression. Patient classification based on clinical symptoms found that severe ENL presented high levels of neutrophil CD64. Collectively, these data revealed that ENL neutrophils express CD64, presumably contributing to the immunopathogenesis of the disease., Author Summary Leprosy reactions are an acute exacerbation of a patient´s clinical condition. Reactions are classified into type 1 (reversal reaction; RR) and type 2 (erythema nodosum leprosum; ENL) according to the etiopathogenesis. Early detection of both types of reactional states is fundamental to treatment management with the most adequate available drugs to ameliorate symptoms and avoid permanent disabilities. The current study investigated whether or not CD64 is expressed during ENL. Analyses of circulating neutrophils revealed that ENL patients expressed higher levels of surface CD64 in comparison to those with nonreactional leprosy and that the severity of ENL was coupled with high levels of CD64 expression. Despite the limited number of patients included in this study, it demonstrated that measurement of neutrophil CD64 expression could be used as a prognostic biomarker of ENL and that quantifying the CD64 response could also help indicate the severity of ENL. Indeed, the methodology adopted found that circulating neutrophil CD64 expression could provide a rapid and non-invasive ENL diagnosis capable of detecting reactions in outpatient clinics as well as leprosy reference centers, leading to more effective therapeutic decisions.