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.

Keywords: autophagy; host-directed therapy; innate immunity; leprosy; metabolism; tuberculosis; type I interferon.

Figure 1

Antimicrobial activity and NOD2-induced autophagy mediate the link between innate and adaptive immunity in mycobacterial infection. The recognition of mycobacterial lipoproteins by the TLR-2/1 heterodimer is a critical way to initiate a pro-inflammatory response and activation of a vitamin-D antimicrobial program against intracellular pathogens such as Mycobacterium leprae. Mycobacterial muramyl dipeptide sensing by NOD2 receptors enhances the inflammatory response in a leucine-rich repeat kinase 2 (LRRK2)-dependent manner and activates autophagic mechanisms. All of these processes lead to mycobacterial killing and are essential for bacterial handling, antigen presentation, and consequent generation of an effective CD4 T cell response.

Figure 2

Antimicrobial autophagy is inhibited in Mycobacterium leprae infections through the activation of the type I interferon (IFN) pathway. After being inside the host cell, M. leprae is able to disrupt the phagosomal membrane by a mechanism that is dependent on the mycobacterial ESX-1 secretion system. Then, bacterial DNA activates the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1) pathway and promotes interferon regulatory factor 3 (IRF3) translocation, which induces IFN-β production. In response to an autocrine and/or paracrine IFN-β stimulus, macrophages increase OASL expression. OASL production inhibits bacterial clearance, blocking LC3-dependent autophagy, and promotes mycobacterial survival by creating a permissive microenvironment for sustainable growth and disease progression.

Figure 3

Schwann cell central metabolism is subverted by Mycobacterium leprae. After infection, Schwann cells increase their insulin-like growth factor (IGF) expression, upregulating glucose transporter 1 (GLUT-1) and glucose uptake by Akt signaling. Glycolysis is downregulated, feeding the pentose phosphate pathway (PPP) with carbons used to synthesize building blocks to promote Schwann cell dedifferentiation and proliferation, generating during this process the reducing power [nicotinamide adenine dinucleotide phosphate (NADPH)] responsible for pumping up lipid biosynthesis. Pyruvate generated by the PPP is rapidly converted to citrate and subsequently converted to lipids, virtually stopping the tricarboxylic acid cycle, respiration and mitochondrial energy potential of the Schwann cells. All of these modulations are crucial for subverting the host immunity against the mycobacteria and, consequently, to the success of the M. leprae infection, representing potential for new host-target therapy strategies to halt leprosy progression. The gray arrows represent downregulated pathways.