Type I Interferons, Autophagy and Host Metabolism in Leprosy

Abstract

For those with leprosy, the extent of host infection by Mycobacterium leprae and the progression of the disease depend on the ability of mycobacteria to shape a safe environment for its replication during early interaction with host cells. Thus, variations in key genes such as those in pattern recognition receptors (NOD2 and TLR1), autophagic flux (PARK2, LRRK2, and RIPK2), effector immune cytokines (TNF and IL12), and environmental factors, such as nutrition, have been described as critical determinants for infection and disease progression. While parkin-mediated autophagy is observed as being essential for mycobacterial clearance, leprosy patients present a prominent activation of the type I IFN pathway and its downstream genes, including OASL, CCL2, and IL10. Activation of this host response is related to a permissive phenotype through the suppression of IFN-γ response and negative regulation of autophagy. Finally, modulation of host metabolism was observed during mycobacterial infection. Both changes in lipid and glucose homeostasis contribute to the persistence of mycobacteria in the host. M. leprae-infected cells have an increased glucose uptake, nicotinamide adenine dinucleotide phosphate generation by pentose phosphate pathways, and downregulation of mitochondrial activity. In this review, we discussed new pathways involved in the early mycobacteria–host interaction that regulate innate immune pathways or metabolism and could be new targets to host therapy strategies.

GPR183 Regulates Interferons, Autophagy, and Bacterial Growth During Mycobacterium tuberculosis Infection and Is Associated With TB Disease Severity

“…Autophagy is a cellular process facilitating the elimination of intracellular pathogens including Mtb ( 39 ). Antimicrobial autophagy was shown to be inhibited by Mycobacterium leprae through upregulation of IFN-β and autocrine IFNAR activation which in turn increased expression of the autophagy blocker OASL (2′-5′-oligoadenylate synthetase like) ( 40 ). Whether there is a link between the 7 α ,25-OHC-induced reduction of IFN-β production and the increase in autophagy remains to be investigated in future studies.…”

The immunology of other mycobacteria: M. ulcerans, M. leprae

“…Another important PRR involved in innate immune activation is the cytosolic sensor NOD-2. The receptor recognizes M. leprae muramyl dipeptide (MDP) and preferentially induces dendritic cell differentiation through the secretion of the pro-inflammatory cytokine IL-32 [103]. In addition, NOD-2 activation initiates a leucine-rich repeat kinase 2 (LRRK2)-dependent pro-inflammatory response as well as autophagy.…”

“…Several studies have shown that M. leprae infection promotes modifications of host cell metabolism and results in conversion of the host immune response. One of the most important metabolic pathways in correlation with the spectrum of clinical forms is, among others, the regulation of lipid metabolism [101,103]. Enhancement of lipid metabolism is mainly observed in lepromatous lesions with the appearance of foamy macrophages (Virchow cells) composed of host-oxidized phospholipids.…”

“…Host-derived phospholipids can regulate the immune response by inhibition of the vitamin D receptor (VDR)/cathelicidin antimicrobial pathway and induction of IL-10. Accumulation of these lipids is directly modulated by M. leprae through different mechanisms, including modulation of the host lipid synthesis and enhancement of lipid droplet formation [101,103]. Besides these regulatory effects, M. leprae survives and replicates inside the lipid droplets in the phagosome of immune cells.…”

“…It is also hypothesized that M. leprae can use host-derived lipids as a source of nutrients, and virulence factors as fatty acids are the main in vivo source of carbon for the mycobacteria through β-oxidation and are used in the production of surface-exposed lipid virulence factors in M. tuberculosis [108]. Moreover, Moraes and colleagues also suggested that M. leprae could use lipids to cover and hide its surface antigens from innate immune receptors in the cytosol [103]. All three mechanisms have not yet been validated in M. leprae infection.…”