Evaluation of Natterina-like XP_017212453.1 molecular mechanisms that facilitate inflammasome activation in zebrafish larvae

• Grant number: 23/10147-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2023
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Biology
• Principal Investigator: Carla Lima da Silva
• Grantee: Darlan Gusso
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling, AP.CEPID

Abstract

The Natterin family was identified in the venom of Thalassophryne nattereri, which was expanded by the inclusion of 331 species that have 859 natterin or natterin-like genes. These do not have orthologs in mammals, but in fish. Among the 109 species of fish that have one or more genes, the zebrafish (Danio rerio) has 10 that encode 11 proteins. Although the many biological functions for Natterin-like remain uncharacterized, studies demonstrate its role as effector molecules of innate immunity against microbes. We have recently shown that the Natterin-like encoded by loc795232 gene acts as a defense molecule against bacterial pathogens, triggering the activation of the inflammasome complex. We demonstrate that CRISPR/Cas9-depleted larvae of the loc795232 are more susceptible to death by S. aureus and by S. typhimurium while surviving larvae show altered patterns of locomotor activity in response to infection. The greater susceptibility to infection in depleted larvae is associated with deficient expression of mature caspase-a and caspase-b. Given its evolutionary conservation, its wide expression in tissues involved in immunity and its role in development, we considered the hypothesis that members of this family, specifically the Natterin-like encoded by gene loc795232, may be involved in the co-regulation of a pathway that affects the ability of inflammasome sensors to respond to or relay signals to the ASC adapter and consequently activate pro-caspases. In this project, our objective is to evaluate the specific role of Natterina-like XP_017212453.1 encoded by loc795232 as a molecule capable of interacting with critical cytosolic sensors for inflammasome activation.