Modulating macrophage function to reinforce host innate resistance against Mycobacterium avium complex infection

Abstract

Mycobacterium avium complex (MAC) is the main causative agent of infectious diseases in humans among nontuberculous mycobacteria (NTM) that are ubiquitous organisms found in environmental media such as soil as well as in domestic and natural waters. MAC is a primary causative agent of NTM-lung disease that threaten immunocompromised or structural lung disease patients. The incidence and the prevalence of M. tuberculosis infection have been reduced, while MAC infections and mortality rates have increased, making it a cause of global health concern. The emergence of drug resistance and the side effects of long-term drug use have led to a poor outcome of treatment regimens against MAC infections. Therefore, the development of host-directed therapy (HDT) has recently gained interest, aiming to accelerate mycobacterial clearance and reversing lung damage by employing the immune system using a novel adjuvant strategy to improve the clinical outcome of MAC infection. Therefore, in this review, we discuss the innate immune responses that contribute to MAC infection focusing on macrophages, chief innate immune cells, and host susceptibility factors in patients. We also discuss potential HDTs that can act on the signaling pathway of macrophages, thereby contributing to antimycobacterial activity as a part of the innate immune response during MAC infection. Furthermore, this review provides new insights into MAC infection control that modulates and enhances macrophage function, promoting host antimicrobial activity in response to potential HDTs and thus presenting a deeper understanding of the interactions between macrophages and MACs during infection.

Keywords: Mycobacterium avium complex; host-directed therapy; innate immunity; macrophage; nontuberculous mycobacteria.

Figure 1

Overview of representative host innate genetic defects increasing the susceptibility to MAC infection. Host susceptibility factors to MAC infection can infer important innate immunological functions against the infection in the host. Several innate or acquired host factors can increase the susceptibility to MAC infection by suppressing the host defense, and these factors are shown in the corresponding signaling pathways (yellow box). Dendritic cells endocytose mycobacteria, which induces the presentation of antigens to naïve T cells. Antigen presentation induces the differentiation of naïve T cells into Th1 cells causing macrophage activation, which produces reactive oxygen and nitrogen species and leads to intracellular bacterial death. In addition, IFN-γ and TLR2 signaling induces the production of pro-inflammatory cytokines, such as IL-12, IL-23, and TNF-α. Secreted IL-12 and IL-23 bind to their receptors on Th1 cells and enhance IFN-γ production. TNF-α production promotes macrophage apoptosis and granuloma formation. MAC, Mycobacterium avium complex; MSMD, Mendelian susceptibility to mycobacterial disease; AATD, alpha-1 antitrypsin deficiency; CGD, chronic granulomatous disease; BMI, body mass index; IFN, interferon; TLR, Toll-like receptor; IL, interleukin; TNF, tumor necrosis factor.

Figure 2

Representative host protective innate immune mechanisms of macrophages against MAC infection. Macrophages are immune cells that play a key role in host innate defense mechanisms against MAC infection. TLR2 signaling is activated by the binding of mycobacterial PAMP, such as ssGPL and ManLAM, to TLR heterodimers, which induces MyD88-dependent cascade that activates the kinase activity of the IRAK complex. TLR9 recognizes MAC DNA and promotes a MyD88-dependent response. The IRAK complex activates TRAF6, which, in turn, activates TAK-1. Activation of TAK-1 leads to the translocation of AP-1 and NF-κβ into the nucleus to produce pro-inflammatory cytokines, such as IL-1β, IL-12, and TNF-α. These cytokines augment the antimycobacterial response, including granuloma formation, phagocyte activation, and apoptosis. MAC-containing phagosomes undergo maturation and fusion events to eliminate the phagocytosed bacteria. M. avium proteins such as MAV_2941 and MMPL4 inhibit phagosome maturation, which subsequently promotes intracellular survival. The recognition of bacterial RNA plays a critical role in the innate immune response during MAC infection. The released MAC RNA binds to RIG-I, which induces a MAVS-dependent response, thereby activating TBK-1. Activated TBK-1 and MAVS promote the nuclear translocation of IRF3/7 and ETV5, leading to type I interferon and ICAM-1 expression, respectively. Taken together, the innate immune response induced by TLR2/1, TLR2/6, and TLR9 signaling and host cytosolic RNA-sensing pathways contributes to bacterial clearance during MAC infection. MAC, Mycobacterium avium complex; TLR, Toll-like receptor; PAMP, pathogen-associated molecular pattern; ssGPL, species-specific glycopeptidolipid; ManLAM, mannose-capped lipoarabinomannan; IRAK, interleukin-1 receptor-associated kinase; TRAF6, tumor necrosis factor receptor (TNFR)-associated factor 6; TAK-1, transforming growth factor-β (TGF-β)-activated kinase 1; AP-1, activator protein 1; NF, nuclear factor; IL, interleukin; TNF, tumor necrosis factor; RIG-I, retinoic acid inducible gene-I; MAVS, mitochondrial antiviral signaling protein; TBK-1, TANK-binding kinase-1; IRF, interferon regulatory factor; ETV, Ets variant; ICAM, intracellular adhesion molecule.

Figure 3

Proposed host-directed therapeutic agents enhance the host innate antimycobacterial activities against MAC infection. Several inflammatory signaling pathways are activated to eliminate intracellular mycobacteria. Host-directed therapeutic drugs may improve the clinical outcome of MAC infection by modulating the antimycobacterial response of macrophages, including phagocytosis, phagosome maturation, reactive oxygen and nitrogen species production, pro-inflammatory cytokine production, and granuloma formation. Metformin and UA promote the phagocytosis of extracellular mycobacteria. After phagocytosis, mycobacteria-containing phagosomes mature through a series of fusion and fission events with endosomes before fusing with lysosomes. Several drugs, including statins and metformin, promote phagosome maturation. Additionally, statins induce phagosome–lysosome fusion and cholesterol depletion to promote the intracellular killing of MAC. Citrulline and arginine promote nitric oxide (NO) production following the conversion of arginine to citrulline in macrophages via iNOS. Furthermore, UA and VA promoted the production of NO by upregulating iNOS. VA inhibits the expression of HDAC1, which suppresses the production of pro-inflammatory cytokines. Mycobacterial infection induces ROS production through the activation of TLR2 and TLR4 signaling which initiates the dissociation of KEAP1 from NRF2. Several drugs, such as resveratrol, curcumin, and betulinic acid, promote the dissociation of NRF2 from KEAP1, leading to the nuclear translocation of NRF2 which activates NRAMP1 and HO-1. The activation of NRAMP1 promotes phagosome–lysosome fusion, leading to the intracellular killing of mycobacteria in macrophages. In addition, HO-1 activation promotes granuloma formation, which restricts mycobacterial infection. HO-1 catalyzes heme into biliverdin, Fe²⁺, and CO. Fe²⁺ promotes NO production from arginine via iNOS. HO-1 also promotes the production of pro-inflammatory cytokines and granuloma formation through MCP1 and CCR2 signaling. In summary, the induction of phagocytosis, phagosome maturation, ROS/NO production, NF-κβ signaling, NRF2–KEAP1, and HO-1 pathways by numerous drugs facilitates the restriction and clearance of MAC and subsequently improves the clinical outcomes. MAC, Mycobacterium avium complex; UA, ursolic acid; iNOS, inducible nitric oxide synthase; VA, valproic acid; HDAC1, histone deacetylase 1; ROS, reactive oxygen species; TLR, Toll-like receptor; KEAP1, Kelch-like ECH-associated protein 1; NRF2, nuclear factor-erythroid factor 2-related factor 2; NRAMP1, natural resistance-associated macrophage protein 1; HO-1, heme oxygenase-1; MCP1, monocyte chemoattractant protein 1; CCR2, C-C chemokine receptor type 2; NF, nuclear factor.