Viral Genome Segmentation Can Result from a Trade-Off between Genetic Content and Particle Stability

The evolutionary benefit of viral genome segmentation is a classical, yet unsolved question in evolutionary biology and RNA genetics. Theoretical studies anticipated that replication of shorter RNA segments could provide a replicative advantage over standard size genomes. However, this question has remained elusive to experimentalists because of the lack of a proper viral model system. Here we present a study with a stable segmented bipartite RNA virus and its ancestor non-segmented counterpart, in an identical genomic nucleotide sequence context. Results of RNA replication, protein expression, competition experiments, and inactivation of infectious particles point to a non-replicative trait, the particle stability, as the main driver of fitness gain of segmented genomes. Accordingly, measurements of the volume occupation of the genome inside viral capsids indicate that packaging shorter genomes involves a relaxation of the packaging density that is energetically favourable. The empirical observations are used to design a computational model that predicts the existence of a critical multiplicity of infection for domination of segmented over standard types. Our experiments suggest that viral segmented genomes may have arisen as a molecular solution for the trade-off between genome length and particle stability. Genome segmentation allows maximizing the genetic content without the detrimental effect in stability derived from incresing genome length

Biochemical and structural studies with neutralizing antibodies raised against foot-and-mouth disease virus

International audienceThe function of a loop exposed on the aphthovirus capsid (the G-H loop of protein VP1) has been explored by combining genetic and structural studies with viral mutants. The loop displays a dual function of receptor recognition and interaction with neutralizing antibodies. Remarkably, some amino acid residues play a critical role in both such disparate functions. Therefore residues subjected to antibody pressure for variation may nevertheless maintain a role in receptor recognition for which invariance is a requirement. Evolution of FMDV in cell culture may relax the requirements at this site and allow further increase of antigenic diversification. Essential residues at one stage of virus evolution may become dispensable at another not very distant point in the evolutionary landscape. Implications for FMDV evolution and vaccine design are discussed

TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization

While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.Fil: Caballero, Mauricio Tomás. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Serra, M. Elina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Acosta, Patricio Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Marzec, Jacqui. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Gibbons, Luz. Institute For Clinical Effectiveness And Health Policy, Ciudad Autonoma de Buenos Aires; ArgentinaFil: Salim, Maximiliano. Hospital Evita Pueblo; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Rodriguez, Andrea. Hospital Mi Pueblo; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Reynaldi, Andrea. Unidad Asistencial "Dr. César Milstein"; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Garcia, Alejandro. Fundación para la Investigación en Infectología Infantil; Argentina. Unidad Asistencial "Dr. César Milstein"; ArgentinaFil: Bado, Daniela. Unidad Asistencial "Dr. César Milstein"; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Buchholz, Ursula J.. National Institute Of Allergy And Infectious Diseases; Estados UnidosFil: Hijano, Diego Raúl. Fundación para la Investigación en Infectología Infantil; Argentina. Vanderbilt University; Estados UnidosFil: Coviello, Silvina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Newcomb, Dawn. Vanderbilt University; Estados UnidosFil: Bellabarba, Miguel. Unidad Asistencial "Dr. César Milstein"; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Ferolla, Fausto Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Libster, Romina Paula. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Vanderbilt University; Estados UnidosFil: Berenstein, Ada. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Siniawaski, Susana. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Blumetti, Valeria. Swiss Medical Center; ArgentinaFil: Echavarría, Marcela Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centro de Educación Medica E Invest.clinicas; ArgentinaFil: Pinto, Leonardo. Fundación para la Investigación en Infectología Infantil; Argentina. Pontificia Universidade Católica do Rio Grande do Sul; BrasilFil: Lawrence, Andrea. Vanderbilt University; Estados UnidosFil: Ossorio, Maria Fabiana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Grosman, Arnoldo. Hospital Espanol; ArgentinaFil: Mateu, Cecilia Gabriela. Fundación para la Investigación en Infectología Infantil; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bayle, Carola. Hospital Nacional Professor Dr. Alejandro Posadas; ArgentinaFil: Dericco, Alejandra. Hospital Nacional Professor Dr. Alejandro Posadas; ArgentinaFil: Pellegrini, Mariana. Hospital Nacional Professor Dr. Alejandro Posadas; ArgentinaFil: Igarza, Ignacio. Hospital Nacional Professor Dr. Alejandro Posadas; ArgentinaFil: Repetto, Horacio A.. Hospital Nacional Professor Dr. Alejandro Posadas; ArgentinaFil: Grimaldi, Luciano Alva. Hospital Zonal General de Agudos Lucio Meléndez; ArgentinaFil: Gudapati, Prathyusha. Vanderbilt University; Estados UnidosFil: Polack, Norberto R.. Unidad Asistencial "Dr. César Milstein"; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Althabe, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Shi, Min. National Institute of Environmental Health Sciences ; Estados UnidosFil: Ferrero, Fernando Claudio. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Bergel, Eduardo. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Stein, Renato T.. Pontificia Universidade Católica do Rio Grande do Sul; BrasilFil: Peebles, R. Stokes. Vanderbilt University; Estados UnidosFil: Boothby, Mark. Vanderbilt University; Estados UnidosFil: Kleeberger, Steven R.. National Institute Of Environmental Health Sciences; Estados UnidosFil: Polack, Fernando Pedro. Fundación para la Investigación en Infectología Infantil; Argentina. Vanderbilt University; Estados Unido