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Desloire, S.

Publications and source records attributed to Desloire, S..

2 recordsLinked to original sources
bioRxiv2024

Two strains of Toscana virus show different virulence and replication capacity in mice and cell culture models

Toscana virus (TOSV), belonging to Phenuiviridae family, is circulating in most Mediterranean countries and is transmitted to humans by infected female sand flies. While most infections are asymptomatic, TOSV is considered as a leading cause of meningitis and encephalitis in humans during summer. Three TOSV genotypes (named A, B, and C) have been identified, although no virus strain belonging to lineage C has been isolated so far. To date, the relationship between TOSV genetic diversity and viral pathogenicity or replication capacity remains unknown. This study aimed to compare two TOSV strains from either lineage A (TOSV-A) or B (TOSV-B) in several cell culture and two mouse models. We showed that TOSV-A replicated more efficiently in BSR and A549 cells while TOSV-B had a replication advantage in human induced pluripotent stem cells differentiated in neural cells and LL-5 sand fly cells. In vivo, we were unable to detect any virus in the brains of immunocompetent C57BL/6JRj mice infected with either strain of TOSV. On the contrary, we showed that TOSV-A disseminated to the central nervous system of 129/Sv ifnar -/- mice unlike TOSV-B, despite higher viremia of TOSV-B and a greater dissemination of this strain in other organs. The reasons for these differences are not yet known, although we showed that the presence of TOSV neutralizing antibodies in serum was slightly delayed in TOSV-A-infected mice. Altogether, the data presented in this study provide new avenues to study TOSV-induced pathogenesis and ultimately unveil molecular viral determinants modulating TOSV replication capacity. Author SummaryToscana virus is a sand fly-borne phlebovirus with tropism for the human central nervous system (CNS) and the causal agent of aseptic meningitis and encephalitis during summer in countries surrounding the Mediterranean Sea. The pathogenesis induced by TOSV is still poorly understood as well as the correlation between TOSV genetic diversity and viral pathogenicity or replication capacity. In this study, we characterised two TOSV strains belonging to two different genetic lineages (named A and B) in several in vitro, ex vivo and in vivo models of infection. We showed that the biological properties of these two strains is strikingly different and, importantly, we identified 129/Sv ifnar -/- mice as a suitable model to study the mechanism of TOSV invasion of the CNS and viral pathogenesis. Our comparative study also highlights the importance of strengthening our efforts to identify molecular viral determinants modulating TOSV-induced pathogenesis and vector transmission, in order to better characterise the epidemiological risk posed by circulating strains.

microbiology↗
bioRxiv2024

Genetic diversity of Toscana virus glycoproteins affects the kinetics of virus entry and the infectivity of newly produced virions

Toscana virus (TOSV) is a pathogenic and transmissible Phlebovirus of the Bunyavirales order. Although TOSV is considered one of the leading causes of meningitis and encephalitis in humans during summer in the Mediterranean basin, its biology remains poorly characterized and neglected due to lack of tools to study the virus. To date, two principal genetic lineages (A and B) have been identified among TOSV-isolated strains based on phylogenetic analysis. The impact of TOSV genetic diversity on its biology is still unknown but highly relevant because it may influence the severity of the disease, viral tropism, and vaccine design. To address these questions, a reverse genetic approach based on two TOSV strains belonging to lineage A or B (i.e., TOSV-A and TOSV-B) and displaying different in vitro replicative fitness was used. Our results demonstrate that TOSV-A and TOSV-B have different Gn and Gc glycoproteins sequences which are responsible for the observed differences in terms of replicative fitness. Moreover, our data show that TOSV-A and TOSV-B display different entry kinetics and that newly-produced virions have different infectivity. This comparative approach allowed us to demonstrate that the genetic diversity of TOSV can significantly impact viral properties. This study highlights the need for a better molecular characterisation of the genome of circulating TOSV strains and, more specifically, of the viral Gn and Gc glycoproteins. Indeed, these proteins may strongly modulate viral pathogenicity and disease. Further work in this direction will provide important data to develop preventive strategies against this emerging pathogen taking into account TOSV glycoproteins genetic diversity. Authors SummaryToscana virus (TOSV) is a leading cause of aseptic brain infection in the Mediterranean basin during the summer. Despite the significant burden that TOSV represents to human health, the biology of this pathogen remains poorly understood and neglected. While distinct TOSV genetic lineages have been identified, the relationship between their genetic diversity and pathogenicity is still unclear. This point, however, is critical to understand the disease and design preventive strategies such as vaccines targeting circulating TOSV strains. Here, a reverse genetic approach was used to produce reassortant and chimeric viruses between two TOSV strains (referred to as TOSV-A and TOSV-B) belonging to the two main genetic lineages and displaying differential in vitro replication capacities. Our results show that the viral glycoproteins are key determinants in modulating TOSV replication. In addition, they demonstrate that viral entry and infectious viral particles production differ between TOSV-A and TOSV-B. This study provides the first evidence of differences in replication capacity between two genetically distinct TOSV viruses, and highlights the need for better molecular characterisation of circulating TOSV strains.

microbiology↗