No abstract

Leprosy reactions are responsible for incapacities in leprosy and represent the major cause of permanent neuropathy. The identification of biomarkers able to identify patients more prone to develop reaction could contribute to adequate clinical management and the prevention of disability. Reversal reaction may occur in unstable borderline patients and also in lepromatous patients. To identify biomarker signature profiles related with the reversal reaction onset, multibacillary patients were recruited and classified accordingly the occurrence or not of reversal reaction during or after multidrugtherapy. Analysis of skin lesion cells at diagnosis of multibacillary leprosy demonstrated that in the group that developed reaction (T1R) in the future there was a downregulation of autophagy associated with the overexpression of TLR2 and MLST8. The autophagy impairment in T1R group was associated with increased expression of NLRP3, caspase-1 (p10) and IL-1β production. In addition, analysis of IL-1β production in serum from multibacillary patients demonstrated that patients who developed reversal reaction have significantly increased concentrations of IL-1β at diagnosis, suggesting that the pattern of innate immune responses could predict the reactional episode outcome. In vitro analysis demonstrated that the blockade of autophagy with 3-methyladenine (3-MA) in Mycobacterium leprae-stimulated human primary monocytes increased the assembly of NLRP3 specks assembly, and it was associated with an increase of IL-1β and IL-6 production. Together, our data suggest an important role for autophagy in multibacillary leprosy patients to avoid exacerbated inflammasome activation and the onset of reversal reaction.

Chikungunya virus (CHIKV) infection causes intense cytokine/chemokine inflammatory responses and debilitating joint pain. Indoleamine2,3–dioxygenase 1 (IDO-1) is an enzyme that initiates the tryptophan degradation that is important in initial host innate immune defense against infectious pathogens. Besides that, IDO-1 activation acts as a regulatory mechanism to prevent overactive host immune responses. In this study, we evaluated IDO-1 activity and cytokine/chemokine patterns in CHIKV patients. Higher IDO-1 (Kyn/Trp ratio) activation was observed during the early acute phase of CHIKV infection and declined in the chronic phase. Importantly, increased concentrations of Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Interferon γ (IFN-γ), C-C motif chemokine ligand 2/Monocyte Chemoattractant Protein-1 (CCL2/MCP-1) and C-X-C motif chemokine ligand 10/Interferon Protein-10 (CXCL10/IP-10) were found in the acute phase of infection, while C-C motif chemokine ligand 4/Macrophage Inflammatory Protein 1 β (CCL4/MIP-1β) was found at increased concentrations in the chronic phase. Likewise, CHIKV patients with arthritis had significantly higher concentrations of CCL4/MIP-1β compared to patients without arthritis. Taken together, these data demonstrated increased IDO-1 activity, possibly exerting both antiviral effects and regulating exacerbated inflammatory responses. CCL4/MIP-1β may have an important role in the persistent inflammation and arthritic symptoms following chikungunya infection.

Leprosy is a chronic infectious disease caused by the intracellular pathogen Mycobacterium leprae. The disease may present different clinical forms depending on the immunological status of the host. M. leprae may infect macrophages and Schwann cells, and recent studies have demonstrated that macrophages are fundamental cells for determining the outcome of the disease. Skin lesions from patients with the paucibacillary form of the disease present a predominance of macrophages with a pro-inflammatory phenotype (M1), whereas skin lesions of multibacillary patients present a predominance of anti-inflammatory macrophages (M2). More recently, it was shown that autophagy is responsible for the control of bacillary load in paucibacillary macrophages and that the blockade of autophagy is involved in the onset of acute inflammatory reactional episodes in multibacillary cells. So, strategies that aim to induce autophagy in infected macrophages are promising not only to improve the efficacy of multidrug therapy (MDT) but also to avoid the occurrence of reactional episodes that are responsible for the disabilities observed in leprosy patients.2 production of nitric oxide, thus causing peripheral nerve damage characteristic of patients with leprosy [10]. Other studies have shown the ability of M. leprae to induce the production of oxidative mediators and their products, peroxynitrite and nitrotyrosine [11][12][13][14].Studies have demonstrated the ability of M. leprae to interact with a range of scavenger receptors of macrophages culminating in a tolerogenic response profile. The scavenger receptors are membrane receptors whose main function is the removal of molecules and cellular debris from the body, binding through a variety of polyanions, leading to phagocytosis of the target, being found in several cell types such as macrophages [15]. The ability of M. leprae to interact with the CD163 receptor, a scavenger receptor, which, during this interaction, can act as a co-receptor for M. leprae entry in macrophages, has been described [16]. It is known that activation of this receptor is related to the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), leading to the synthesis and increase of the activity of the enzyme heme oxygenase-1 (HO-1), which, through anti-inflammatory and antioxidant pathways, releases interleukin (IL)-10 and generates carbon monoxide, contributing to the polarization of these cells [17][18][19]. Bonilla and colleagues [20] demonstrated that autophagy, a mechanism of metabolic control, regulates the expression of scavenger receptors macrophage receptor with collagenous structure (MARCO) and scavenger receptor type A (SRA-I) that increase phagocytosis and NRF2 activity during Bacillus Calmette-Guérin (BCG) or M. tuberculosis (H37Rv) infection.M. leprae is able to induce macrophage SRA-I and CD36 expression [6] that contributes to the uptake of lipids, culminating in an increase in the uptake and accumulation of oxidized lipids within the macrophages, leading to a fo...

Inflammatory disorders are associated with the activation of tryptophan (TRYP) catabolism via the kynurenine pathway (KP). Several reports have demonstrated the role of KP in the immunopathophysiology of both leprosy and coronavirus disease 19 (COVID-19). The nervous system can be affected in infections caused by both Mycobacterium leprae and SARS-CoV-2, but the mechanisms involved in the peripheral neural damage induced by these infectious agents are not fully understood. In recent years KP has received greater attention due the importance of kynurenine metabolites in infectious diseases, immune dysfunction and nervous system disorders. In this review, we discuss how modulation of the KP may aid in controlling the damage to peripheral nerves and the effects of KP activation on neural damage during leprosy or COVID-19 individually and we speculate its role during co-infection.