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Obtaining Leucine Rich Repeats (LRR) protein mutants in Leptospira interrogans and phenotypic evaluation of Host-pathogen interactions

Grant number: 22/16481-7
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): June 01, 2023
Effective date (End): December 31, 2027
Field of knowledge:Biological Sciences - Microbiology - Applied Microbiology
Principal Investigator:Ana Lucia Tabet Oller do Nascimento
Grantee:Bruno Botega Foltran
Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated research grant:19/17488-2 - Advancing the understanding of pathogenesis and virulence of Leptospira interrogans through proteomics, structural, mutagenesis and immunological analyses, AP.TEM

Abstract

Leptospirosis is a zoonosis of worldwide importance and considered a neglected tropical disease. The disease is caused by pathogenic bacteria of the genus Leptospira and affects several mammals, including humans as accidental and terminal hosts. To date, there is no effective vaccine against the disease, which has great socioeconomic importance, especially in tropical developing countries, and estimates made by the WHO occur annually about 873,000 severe cases and 49,000 deaths of people from leptospirosis worldwide. . Combating leptospirosis is made more difficult by the lack of basic sanitation in regions of extreme poverty, the increase in cases of floods and the lack of understanding of the biology of the pathogen. Several research groups seek to better understand the mechanisms of pathogenicity and development of an effective vaccine by evaluating potential candidates, which in general are outer membrane proteins conserved in different species of pathogenic leptospires. A class of proteins of interest are those containing domain LRRs (Leucine Rich Repeats) which are normally membrane or secreted proteins, being in direct contact with host components; the role of LRR proteins in the pathogenesis of leptospirosis is still poorly explored. Characterization is usually done through the expression and purification of recombinant proteins, which often may not mirror what occurs in vivo. Thus, developing mutant strains has been an interesting approach. In this sense, the present project will focus on elucidating the role of 2 LRR proteins from L. interrogans, through in vitro assays with the respective recombinant proteins, and validation of the findings through the construction of recombinant L. biflexa (saprophytic) strains expressing these proteins, aiming at a phenotype gain through the functional validation of these as possible ligands to host components. Then, using CRISPR-interference mutagenesis techniques developed by our group, knockdown mutants of the proteins of interest will be obtained for studies of loss of phenotype in the pathogenic strain L. interrogans. The virulence of the mutants will also be evaluated in an animal model. The set of results obtained with this Research Project will contribute to a better understanding of host-pathogen interactions and virulence mechanisms of leptospires. (AU)

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