Genome-based solutions for managing mucormycosis.

An uncommon opportunistic fungal infection known as mucormycosis is caused by a class of molds called mucoromycetes. Currently, antifungal therapy and surgical debridement are the primary treatment options for mucormycosis. Despite the importance of comprehensive knowledge on mucormycosis, there is a lack of well-annotated databases that provide all relevant information. In this study, we have gathered and organized all available information related to mucormycosis that include disease's genome, proteins, diagnostic methods. Furthermore, using the AlphaFold2.0 prediction tool, we have predicted the tertiary structures of potential drug targets. We have categorized the information into three major sections: "genomics/proteomics," "immunotherapy," and "drugs." The genomics/proteomics module contains information on different strains responsible for mucormycosis. The immunotherapy module includes putative sequence-based therapeutics predicted using established tools. Drugs module provides information on available drugs for treating the disease. Additionally, the drugs module also offers prerequisite information for designing computationally aided drugs, such as putative targets and predicted structures. In order to provide comprehensive information over internet, we developed a web-based platform MucormyDB (https://webs.iiitd.edu.in/raghava/mucormydb/).

TF-FVIIa PAR2-ß-Arrestin Signaling Sustains Organ Dysfunction in Coxsackievirus B3 Infection of Mice.

BACKGROUND: Accumulating evidence implicates the activation of G-protein-coupled PARs (protease-activated receptors) by coagulation proteases in the regulation of innate immune responses. METHODS: Using mouse models with genetic alterations of the PAR2 signaling platform, we have explored contributions of PAR2 signaling to infection with coxsackievirus B3, a single-stranded RNA virus provoking multiorgan tissue damage, including the heart. RESULTS: We show that PAR2 activation sustains correlates of severe morbidity-hemodynamic compromise, aggravated hypothermia, and hypoglycemia-despite intact control of the virus. Following acute viral liver injury, canonical PAR2 signaling impairs the restoration process associated with exaggerated type I IFN (interferon) signatures in response to viral RNA recognition. Metabolic profiling in combination with proteomics of liver tissue shows PAR2-dependent reprogramming of liver metabolism, increased lipid droplet storage, and gluconeogenesis. PAR2-sustained hypodynamic compromise, reprograming of liver metabolism, as well as imbalanced IFN responses are prevented in ß-arrestin coupling-deficient PAR2 C-terminal phosphorylation mutant mice. Thus, wiring between upstream proteases and immune-metabolic responses results from biased PAR2 signaling mediated by intracellular recruitment of ß-arrestin. Importantly, blockade of the TF (tissue factor)-FVIIa (coagulation factor VIIa) complex capable of PAR2 proteolysis with the NAPc2 (nematode anticoagulant protein c2) mitigated virus-triggered pathology, recapitulating effects seen in protease cleavage-resistant PAR2 mice. CONCLUSIONS: These data provide insights into a TF-FVIIa signaling axis through PAR2-ß-arrestin coupling that is a regulator of inflammation-triggered tissue repair and hemodynamic compromise in coxsackievirus B3 infection and can potentially be targeted with selective coagulation inhibitors.