Wnt ligands interact with the transmembrane cell surface receptors Frizzled and ROR/RYK to initiate complex signaling cascades that are crucial for cell physiology and the proper functioning of the immune system. Wnt signaling is instrumental in maintaining immune surveillance and during infections by pathogenic microbes helps mount host resistance to infection. Some pathogens, however, utilize Wnt signaling to build a niche for their survival. The goal of this review is to summarize current and developing concepts about the tug of war between Wnt signaling and pathogens for deployment of host resources, focusing mostly on macrophages and cytoskeletal actin dynamics. An additional objective is to outline the interrelation between Wnt signaling and the host microbiota, which is vital for immune defense, discussing in the same perspective, how Wnt signaling could be differentiating pathogen from non-pathogen.
In India, Corona Virus-2 Disease-2019 (COVID-19) continues to this day, although with subdued intensity, following two major waves of viral infection. Despite ongoing vaccination drives to curb the spread of COVID-19, the potential of the administered vaccines to render immune protection to the general population, and how this compares with the immune potential of natural infection remain unclear. In this study we examined correlates of immune protection (humoral and cell mediated) induced by the two vaccines Covishield and Covaxin, in individuals living in and around Kolkata, India. Additionally, we compared the vaccination induced immune response profile with that of natural infection, evaluating thereby if individuals infected during the first wave retained virus specific immunity. Our results indicate that while Covaxin generates better cell-mediated immunity toward the Delta variant of SARS-CoV-2 than Covishield, Covishield is more effective than Covaxin in inducing humoral immunity. Both Covishield and Covaxin, however, are more effective toward the wild type virus than the Delta variant. Moreover, the overall immune response resulting from natural infection in and around Kolkata is not only to a certain degree better than that generated by vaccination, especially in the case of the Delta variant, but cell mediated immunity to SARS-CoV-2 also lasts for at least ten months after the viral infection.
Antigen processing and antigen-specific CD8 T cell activation form part and parcel of cell-mediated immunity to infections. Yet, several lacunae remain in our understanding of how antigen processing and CD8 T cell response are coordinated. In this study, using mouse bone marrow-derived dendritic cells (BMDC) as antigen-presenting cells and Ovalbumin (OVA)/DQ-Ovalbumin (DQ-OVA) as model antigen we demonstrated that Wnt5A signaling in BMDC supports antigen processing/presentation and concomitant CD8 T cell activation through regulation of actin and proteasome dynamics. Recombinant Wnt5A conditioning of BMDC and associated actin assembly facilitated DQ-OVA processing, which was inhibited by the proteasome inhibitor MG132. Moreover, Wnt5A depletion led to a significant reduction in OVA processing and presentation. Impaired DQ-OVA processing in Wnt5A depleted BMDC correlated with altered dynamics of both actin and the proteasome regulator PA28α-PA28β, and reduced association of DQ-OVA with actin and proteasome subunits. Inhibited OVA processing/presentation in the Wnt5A depleted BMDC also resulted in subdued activation of OVA-sensitized CD8 T cells in co-culture with the BMDC. In concurrence with these findings, we demonstrated reduced OVA processing and impaired CD8 T cell response to OVA immunization in Wnt5A heterozygous mice lacking a copy of the Wnt5A gene in comparison to the wild-type cohorts. Taken together, our results reveal a crucial requirement of Wnt5A signaling in antigen processing/presentation and CD8 T cell activation, thus unveiling a vital regulatory node of cell-mediated immunity, unidentified thus far.
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