RNA recombination at Chikungunya virus 3'UTR as an evolutionary mechanism that provides adaptability

MERWAISS, FERNANDO; ALVAREZ, DIEGO E.; FILOMATORI CLAUDIA V.; SUZUKI, YASUTSUGU; BARDOSSY, EUGENIA S.; SALEH, MARÍA CARLA

Mar del Plata

Congreso; Reunión anual de la Sociedad Argentina de Investigación Clínica (SAIC), la Sociedad de Farmacología Experimental (SAFE), la Sociedad Argentina de Biología (SAB), la Sociedad Argentina de Protozoología (SAP), la Asociación Argentina de Nanomedicinas (NANOM; 2019

RNA viruses contain dynamic genomes, which allow their rapid adaptation to new environments that has resulted in the expansion of re-emergent viruses. Chikungunya virus (CHIKV) is an important human pathogen transmitted by mosquitoes that has caused recent epidemics in the Indian Ocean and the Americas. Re-emerging lineages have fixed mutations in the coding sequence and large variations in the 3'UTR. As a result, these lineages feature 3'UTRs carrying different copy numbers ofc onserved sequence blocks referred to as direct repeats. To investigate how CHIKV overcomes the species barriers that are imposed during transmission, we have examined the evolution of viral populations adapted to host passaging. Combination of experimental adaptation together with fitness measurements revealed that CHIKV 3'UTR is under opposite selective pressures in mosquito and mammalian cells. We observed that during RNA synthesis, viral polymerase switches templates by a copy-choice recombination mechanism and generates variants carrying different numbers of sequence repeats at the 3' end of the viral genome. Deletion variants, which accumulate mainly in mammals, are disadvantageous for replication in mosquitoes and thus, pose a constraint to host switch. Indeed, blocks of duplicated sequences act as substrates for recombination giving rise to a viral population that displays a collection of 3'UTRs. Those viral variants with more fitness in mosquitoes are positively selected to rescue replication. Our work reported for the first time that RNA recombination through template switching acts concertedly with viral selection to assure transmission of infection between hosts.Importantly, we studied the relevance of recombination in laboratory mosquito colonies and demonstrated that this mechanism also occurs in vivo. We propose a model for CHIKV transmission where RNA recombination accounts for the ability of the virus to rapidly adapt after population bottlenecks imposed during host switch.