No abstract

The continual emergence of SARS-CoV-2 variants threatens to compromise the effectiveness of worldwide vaccination programs, and highlights the need for complementary strategies for a sustainable containment plan. An effective approach is to mobilize the body′s own antimicrobial peptides (AMPs), to combat SARS-CoV-2 infection and propagation. We have found that human cathelicidin (LL37), an AMP found at epithelial barriers as well as in various bodily fluids, has the capacity to neutralise multiple strains of SARS-CoV-2. Biophysical and computational studies indicate that LL37′s mechanism of action is through the disruption of the viral membrane. This antiviral activity of LL37 is enhanced by the hydrotropic action of niacinamide, which may increase the bioavailability of the AMP. Interestingly, we observed inverse correlation between LL37 levels and disease severity of COVID-19 positive patients, suggesting enhancement of AMP response as an interesting therapeutic avenue to mitigate disease severity. The combination of niacinamide and LL37 is a potent antiviral formulation that targets viral membranes of various variants and can potentially overcome vaccine escape.

Fibrosis is the result of excessive deposition of extracellular matrix (ECM) proteins leading to tissue hardening and loss of organ function. A central player driving fibrosis is the activated fibroblast, which exhibits enhanced migration, proliferation, contraction, and ECM production. However, this raises an interesting puzzle of whether the same fibroblast performs all of the processes that fall under the umbrella term of activation. Given the heterogeneity of fibroblasts in connective tissues, there are subpopulations of fibroblasts that perform specific functions that are under different regulatory controls. Using a transgenic mouse model of skin fibrosis, we find that the secretion of Mindin from Snail transgenic keratinocytes differentially alters the characteristic of distinct fibroblast subpopulations. Mindin induces migration and inflammatory gene expression of the Sca1+ subpopulation of dermal fibroblasts in a Fyn kinase dependent manner. On the other hand, Mindin increases the contractile behaviour and collagen production in the papillary CD26+ dermal fibroblasts via cSrc. Moreover, in the context of the fibrotic microenvironment of the tumour stroma, we found that differential responses of resident fibroblasts subpopulations to Mindin extends to the generation of functionally heterogeneous cancer associated fibroblasts (CAFs). Overall, this work highlights the importance of Mindin in mediating the cellular and signalling heterogeneity of dermal fibroblasts in skin fibrosis and cancer.