UN ESTUDIO INTEGRATIVO DE LOS EFECTOS DEL FITNESS MUTACIONAL Y SU RELEVANCIA PAR...
UN ESTUDIO INTEGRATIVO DE LOS EFECTOS DEL FITNESS MUTACIONAL Y SU RELEVANCIA PARA LA INMUNIDAD EN UN PICORNAVIRUS HUMANO
RNA VIRUSES CAUSE TREMENDOUS MORBIDITY AND MORTALITY, AND POSE A THREAT FOR CAUSING NEW PANDEMICS. THESE PATHOGENS ARE CHARACTERIZED BY EXTREME MUTATION RATES, WHICH PLAY KEY ROLES IN THEIR BIOLOGY AND PATHOGENESIS. HOWEVER, HOW R...
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El organismo AGENCIA ESTATAL DE INVESTIGACIÓN notifico la concesión del proyecto
el día 2021-01-01
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Descripción del proyecto
RNA VIRUSES CAUSE TREMENDOUS MORBIDITY AND MORTALITY, AND POSE A THREAT FOR CAUSING NEW PANDEMICS. THESE PATHOGENS ARE CHARACTERIZED BY EXTREME MUTATION RATES, WHICH PLAY KEY ROLES IN THEIR BIOLOGY AND PATHOGENESIS. HOWEVER, HOW RNA VIRUSES CONTEND WITH HIGH MUTATION RATES DESPITE MOST MUTATIONS BEING DELETERIOUS TO PROTEIN FUNCTION REMAINS UNKNOWN. MOREOVER, HOW MUTATIONS IN VIRAL PROTEINS HELP OVERCOME HOST INNATE AND ADAPTIVE IMMUNE RESPONSES REMAINS TO BE FULLY ELUCIDATED. IN A PREVIOUS PROJECT, WE UNDERTOOK THE FIRST DEEP MUTATIONAL SCANNING ANALYSIS OF A PICORNAVIRUS, GENERATING POPULATIONS OF THE HUMAN PATHOGEN COXSACKIEVIRUS B3 THAT ENCODE >90% OF ALL POSSIBLE SINGLE AMINO ACID MUTATIONS ACROSS THE CAPSID REGION AND DEFINING THEIR EFFECT ON VIRAL FITNESS. IN THE CURRENT PROJECT, WE WILL FIRST CAPITALIZE ON THESE DIVERSE CAPSID POPULATIONS TO UNDERSTAND HOW PICORNAVIRUSES INTERACT WITH ANTIBODY RESPONSES BY DEFINING ALL MUTATIONS THAT ALTER NEUTRALIZATION BY HUMAN AND MOUSE POLYCLONAL SERA AS WELL AS DEFINE THE DOMINANCE OF ANTIBODY EPITOPES IN A HUMAN POPULATION. NEXT, WE WILL EXTEND OUR DEEP MUTATIONAL SCANNING ANALYSIS TO THE REMAINDER OF THE VIRAL PROTEIN-CODING REGION TO PROVIDE THE FIRST COMPREHENSIVE ANALYSIS OF MUTATIONAL FITNESS EFFECTS ACROSS A COMPLETE PROTEOME, PROVIDING NOVEL INSIGHTS INTO VIRAL BIOLOGY AND EVOLUTION. FINALLY, WE WILL USE THE HIGHLY DIVERSE VIRAL POPULATIONS GENERATED IN THESE STUDIES TO DEFINE ALL MUTATIONS ACROSS THE VIRAL PROTEIN-CODING REGION THAT ALTER SENSITIVITY TO A KEY ANTIVIRAL MECHANISM, TYPE I INTERFERON. OVERALL, THE PROPOSED WORK WILL PROVIDE A DEEP UNDERSTANDING OF THE BIOLOGY, PATHOGENESIS, AND EVOLUTION OF A MEDICALLY RELEVANT, PROTOTYPICAL HUMAN PICORNAVIRUS. IN ADDITION, GENERAL INSIGHTS INTO VIRAL PROTEIN DESIGN AND HOST-PATHOGEN INTERACTIONS ARE ANTICIPATED. ICORNAVIRUS\EXPLORACION MUTACIONAL PROFUNDA\ANTICUERPOS\INMUNIDAD INNATA\EVOLUCION