Biology subjects

Flamand, M.

Publications and source records attributed to Flamand, M..

3 recordsLinked to original sources

bioRxiv2021

The dengue virus NS1 protein conveys pro-inflammatory signals by docking onto human high-density lipoproteins

The nonstructural NS1 protein is a virulence factor secreted by dengue virus (DENV)-infected cells. NS1 is known to alter the complement system, activate immune cells and perturb endothelial barriers. Here we show that pro-inflammatory signals are triggered by a high affinity complex formed between NS1 and human high-density lipoproteins (HDL). Electron microscopy images of the NS1-HDL complexes show spherical HDL particles with rod-shaped NS1 protrusions on their surface. These complexes are readily detectable in the plasma of hospitalized dengue patients using anti-apolipoprotein A-I (ApoA-I) antibodies specific of the HDL moiety. The functional reprogramming of HDL particles by the NS1 protein as a means to exacerbate systemic inflammation during DENV infection provides a new paradigm linking the human lipoprotein network to dengue pathogenesis.

microbiology↗

bioRxiv2019

Genetic diversity of Collaborative Cross mice controls viral replication, clinical severity and brain pathology induced by Zika virus infection, independently of Oas1b

The explosive spread of Zika virus (ZIKV) has been associated with major variations in severe disease and congenital afflictions among infected populations, suggesting an influence of host genes. We investigated how genome-wide variants could impact susceptibility to ZIKV infection in mice. We first describe that the susceptibility of Ifnar1 knockout mice is largely influenced by their genetic background. We then show that the broad genetic diversity of Collaborative Cross mice, which receptor to type I interferon (IFNAR) was blocked by anti-IFNAR antibody, expressed phenotypes ranging from complete resistance to severe symptoms and death with large variations in the peak and rate of decrease of plasma viral load, in brain viral load, in brain histopathology and in viral replication rate in infected cells. Differences of susceptibility between CC strains were correlated between Zika, Dengue and West Nile viruses. We identified highly susceptible and resistant mouse strains as new models to investigate the mechanisms of human ZIKV disease and other flavivirus infections. Genetic analyses revealed that phenotypic variations are driven by multiple genes with small effects, reflecting the complexity of ZIKV disease susceptibility in human population. Notably, our results rule out a role of the Oas1b gene in the susceptibility to ZIKV. Altogether, this study emphasizes the role of host genes in the pathogeny of ZIKV infection and lays the foundation for further genetic and mechanistic studies.\n\nIMPORTANCEIn recent outbreaks, ZIKV has infected millions of people and induced rare but potentially severe complications, including Guillain-Barre syndrome and encephalitis in adults. While several viral sequence variants were proposed to enhance the pathogenicity of ZIKV, the influence of host genetic variants in the clinical heterogeneity remains mostly unexplored. We have addressed this question using a mouse panel which models the genetic diversity of human population and a ZIKV strain from a recent clinical isolate. Through a combination of in vitro and in vivo approaches, we demonstrate that multiple host genetic variants determine viral replication in infected cells, and clinical severity, kinetics of blood viral load and brain pathology in mice. We describe new mouse models expressing high susceptibility or resistance to ZIKV and to other flaviviruses. These models will facilitate the identification and mechanistic characterization of host genes that influence ZIKV pathogenesis.

genetics↗

bioRxiv2019

Genetic dissection of Rift Valley fever pathogenesis: Rfvs2 on mouse chromosome 11 enables survival to acute-onset hepatitis

The systemic inoculation of mice with Rift Valley fever virus (RVFV) reproduces major pathological features of severe human disease, notably the acute-onset hepatitis and delayed-onset encephalitis. We previously reported that a genomic interval (Rvfs2) derived from the susceptible MBT/Pas strain is associated with reduced survival time after RVFV infection. In this study, we investigated the pathophysiological mechanisms by which Rvfs2 confers increased susceptibility to BALB/c mice that are congenic for Rvfs2 (C.MBT-Rvfs2) after infection with virulent RVFV. Clinical traits, biochemical parameters, and histopathological features indicated similar liver damage in BALB/c and C.MBT-Rvfs2 mice between the third and fifth days after infection. However, C.MBT-Rvfs2 mice died at that point from acute liver injury while most BALB/c mice recovered from this condition but eventually died of encephalitis. We observed that hepatocytes proliferated actively within the infected liver of BALB/c mice on the sixth day after infection, promoting organ regeneration on the eighth day after infection and recovery from liver damage. We found that the production of infectious virions was up to 100-fold lower in the peripheral blood and liver of BALB/c compared to C.MBT-Rvfs2 mice. Likewise, RVFV protein amounts were much lower in BALB/c liver compared to C.MBT-Rvfs2 liver. Primary cultured hepatocytes showed higher viral replication rate in C.MBT-Rvfs2 which could contribute to the susceptibility conferred by Rvfs2. Using bone marrow chimera experiments, we uncovered that both hematopoietic and non-hematopoietic cells are required for the BALB/c allele of Rvfs2 to exert its protective effects against the RVFV-induced acute liver disease. Taken together, we have established that Rvfs2 acts as an important RVFV restriction factor by limiting virus multiplication in mice. Author SummaryRift Valley fever (RVF) is a mosquito-borne viral disease with potential to generate a public health emergency. The wide variation in RVF symptoms and severity observed within patient population suggests that natural host genetic determinants, among other factors, can influence the disease outcome. Infection of mice mimics several features of the pathology in humans, including acute-onset hepatitis and delayed-onset encephalitis. BALB/c inbred mice bearing the BALB/c haplotype at the Rvfs2 locus survive longer than those bearing the MBT haplotype. In this study, we investigated clinical traits, biochemical parameters, virological evidence, and histological features to characterize the pathogenesis of RVF in early and late susceptible mice. We show that animals of both groups develop acute liver disease shortly after infection. We demonstrate that, by comparison with early susceptible mice, BALB/c mice exhibit significantly reduced replication of RVF virus in vivo in the blood and liver and in vitro in primary cultured hepatocytes, and eventually self-recover from the liver damages. We use reciprocal transplantations of bone marrow cells between early and late susceptible mice to show that survival to severe liver disease requires both hematopoietic and non-hematopoietic cells. Taken together, we establish Rvfs2 as a single locus that enables mice to survive RVF virus-induced liver disease.

genetics↗