CD157 Confers Host Resistance to Mycobacterium tuberculosis via TLR2-CD157-PKCzeta-Induced Reactive Oxygen Species Production

Abstract

Recruitment of monocytes to the infection site is critical for host resistance against Mycobacterium tuberculosis. CD157 has a crucial role in neutrophil and monocyte transendothelial migration and adhesion, but its role in tuberculosis (TB) is unclear. Here, we show that both mRNA and protein levels of Cd157 are significantly increased during M. tuberculosis infection. Deficiency of Cd157 impaired host response to M. tuberculosis infection by increasing bacterial burden and inflammation in the lung in the murine TB model. In vitro experiments show that the bactericidal ability was compromised in Cd157 knockout (KO) macrophages, which was due to impaired M. tuberculosis-induced reactive oxygen species (ROS) production. We further reveal that CD157 interacts with TLR2 and PKCzeta and facilitates M. tuberculosis-induced ROS production in Cd157 KO macrophages, which resulted in enhanced M. tuberculosis killing. For the clinic aspect, we observe that the expression of CD157 decreases after effective anti-TB chemotherapy. CD157 is specifically increased in pleural fluid in tuberculous pleurisy patients compared to pneumonia and lung cancer patients. Interestingly, the levels of soluble CD157 (sCD157) correlate with human peripheral monocyte-derived macrophage bactericidal activity. Exogenous application of sCD157 could compensate for macrophage bactericidal ability and restore ROS production. In conclusion, we have identified a novel protective immune function of CD157 during M. tuberculosis infection via TLR2-dependent ROS production. Application of sCD157 might be an effective strategy for host-directed therapy against TB in those with insufficient CD157 production. IMPORTANCE Tuberculosis, a chronic bacterial disease caused by Mycobacterium tuberculosis, remains a major global health problem. CD157, a dual-function receptor and β-NAD+-metabolizing ectoenzyme, promotes cell polarization, regulates chemotaxis induced through the high-affinity fMLP receptor, and controls transendothelial migration. The role of CD157 in TB pathogenesis remains unknown. In this study, we find that both mRNA and protein levels of CD157 are significantly increased in TB. Deficiency of CD157 impaired host defense against M. tuberculosis infection both in vivo and in vitro, which is mediated by an interaction among CD157, TLR2, and PKCzeta. This interaction facilitates M. tuberculosis-induced macrophagic ROS production, which enhances macrophage bactericidal activity. Interestingly, the sCD157 level in plasma is reversibly associated with MDM M. tuberculosis killing activity. By uncovering the role of CD157 in pathogenesis of TB for the first time, our work demonstrated that application of soluble CD157 might be an effective strategy for host-directed therapy against TB.

Host‐directed therapy to combat mycobacterial infections*

“…7,96 Recently, TLR2-dependent ROS production and bactericidal activity was found to be impaired in CD157-deficient murine macrophages which could be rescued by administration of soluble CD157. 95,97 Moreover, expression levels of CD157, an enzyme important for leukocyte migration and involved in nicotinamide-adenine-dinucleotide (NAD + ) metabolism, are elevated in patients with active TB compared to LTBI and lowered when patients are treated with TB chemotherapy, indicating an important role of CD157 in host immunity, biomarker profiling and also providing a potential HDT. 97 Although ROS production is important for host resistance against mycobacterial infection, modulating ROS as HDT strategy requires careful monitoring as excess ROS leads to oxidative stress and concomitant necrosis.…”

“…95,97 Moreover, expression levels of CD157, an enzyme important for leukocyte migration and involved in nicotinamide-adenine-dinucleotide (NAD + ) metabolism, are elevated in patients with active TB compared to LTBI and lowered when patients are treated with TB chemotherapy, indicating an important role of CD157 in host immunity, biomarker profiling and also providing a potential HDT. 97 Although ROS production is important for host resistance against mycobacterial infection, modulating ROS as HDT strategy requires careful monitoring as excess ROS leads to oxidative stress and concomitant necrosis. 98 Corroborating this view, reducing ROS accumulation in Mtb-infected macrophages with ROS scavenger N-acetyl-cysteine in fact restricted Mtb replication and restored macrophage cell viability, 99 and in a guinea pig Mtb infection model N-acetyl-cysteine administration was also shown to be efficacious.…”

“…Mycobacterium‐induced ROS production occurs via the TLR(2)‐MyD88 signaling axis and impairments in this pathway increase susceptibility to Mtb infection 7,96 . Recently, TLR2‐dependent ROS production and bactericidal activity was found to be impaired in CD157‐deficient murine macrophages which could be rescued by administration of soluble CD157 95,97 . Moreover, expression levels of CD157, an enzyme important for leukocyte migration and involved in nicotinamide‐adenine‐dinucleotide (NAD + ) metabolism, are elevated in patients with active TB compared to LTBI and lowered when patients are treated with TB chemotherapy, indicating an important role of CD157 in host immunity, biomarker profiling and also providing a potential HDT 97 …”

Roles of CD38 in the Immune Response to Infection

“…Although limited information is available on the role of CD157 in the host response to infection, recent studies indicated that CD157 is important for conferring host resistance to Mycobacterium tuberculosis (M. tuberculosis) [84]. The activity of macrophages at the infection site is indeed critical for the host defense against M. tuberculosis.…”

CD157: From Myeloid Cell Differentiation Marker to Therapeutic Target in Acute Myeloid Leukemia

“…Elevated soluble CD157 was also found in pleural effusions from patients with malignant pleural mesothelioma compared to patients with other cancer types or benign pathologies [22]. Recently, the concentration of soluble CD157 was found to be significantly increased in pleural fluid obtained from tuberculous pleurisy patients with respect to patients with pneumonia or lung cancer [23].…”