Activation of the Wnt Pathway by Mycobacterium tuberculosis: A Wnt–Wnt Situation

Abstract

Mycobacterium tuberculosis (M. tuberculosis), an intracellular pathogenic Gram-positive bacterium, is the cause of tuberculosis (TB), a major worldwide human infectious disease. The innate immune system is the first host defense against M. tuberculosis. The recognition of this pathogen is mediated by several classes of pattern recognition receptors expressed on the host innate immune cells, including Toll-like receptors, Nod-like receptors, and C-type lectin receptors like Dectin-1, the Mannose receptor, and DC-SIGN. M. tuberculosis interaction with any of these receptors activates multiple signaling pathways among which the protein kinase C, the MAPK, and the NFκB pathways have been widely studied. These pathways have been implicated in macrophage invasion, M. tuberculosis survival, and impaired immune response, thus promoting a successful infection and disease. Interestingly, the Wnt signaling pathway, classically regarded as a pathway involved in the control of cell proliferation, migration, and differentiation in embryonic development, has recently been involved in immunoregulatory mechanisms in infectious and inflammatory diseases, such as TB, sepsis, psoriasis, rheumatoid arthritis, and atherosclerosis. In this review, we present the current knowledge supporting a role for the Wnt signaling pathway during macrophage infection by M. tuberculosis and the regulation of the immune response against M. tuberculosis. Understanding the cross talk between different signaling pathways activated by M. tuberculosis will impact on the search for new therapeutic targets to fuel the rational design of drugs aimed to restore the immunological response against M. tuberculosis.

IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling

“…The results also discard the possibility that the presence of IL-36g changes the signaling pathway mediated by WNT5A leading to bacterial killing. In addition, JNK and NF-kB are downstream pathways of noncanonical WNT signaling pathway (19,29,30). Ours results showed that both rhIL-36g and rhWNT5A induced increased p-JNK and p-p65 ( Fig.…”

“…In this study, we confirmed that IL-36g suppresses M. tuberculosis growth in macrophages by triggering WNT5A-induced noncanonical WNT signaling-mediated autophagy. Our study revealed that IL-36g or WNT5A can activated the noncanonical WNT pathway by inducing JNK and p65 phosphorylation (19,29,30), although the specific downstream mechanisms are worthy to be studied. Furthermore, we have filled in the pathway of WNT5A-induced autophagy, verifying it was mediated by COX-2, a key rate-limiting enzyme in the arachidonic acid pathway, and subsequent inactivation of AKT/mTOR signaling.…”

Immune correlates of postexposure vaccine protection against Marburg virus

“…Increasing evidence suggests a regulatory function of Wnt proteins in inflammation, cancers, and infectious diseases. Other pathogens such www.nature.com/scientificreports www.nature.com/scientificreports/ as Mycobacterium tuberculosis, influenza, Hepatitis B virus, and certain bunyaviruses are known to manipulate the host Wnt network to enhance immune evasion and replication [68][69][70][71][72] . Specifically, we observed high expression of genes encoding the Wnt proteins, Wnt6 and Wnt5a, in fatal subjects.…”

Wnt Signaling Regulates Macrophage Mediated Immune Response to Pathogens

“…Of special interest in this context is the interaction of the actin cytoskeleton with pathogenic mycobacteria, which thrive in self-generated niches within macrophages [60,73]. The interrelation between different modes of Wnt signaling and mycobacterial infection, although much studied [74,75], needs to be better understood with respect to actin dynamics. Now that Wnt5A signaling has been shown to play a major role in the regulation of actin cytoskeletal modulation and autophagy [11,12,76], future experiments addressing whether this can also facilitate the adaptive immune response through antigen processing and presentation may prove fruitful.…”