Biology subjects

Jouvion, G.

Publications and source records attributed to Jouvion, G..

5 recordsLinked to original sources

bioRxiv2025

Programmed in vivo excision of prophage {varphi}13 is an essential timing device for the Staphylococcus aureus infectious process

Mobile genetic elements play an essential part in the infectious process of major pathogens, yet the role of prophage dynamics in Staphylococcus aureus pathogenesis is still not well understood. Here we studied the impact of the {Phi}13 hlb- converting prophage, whose integration inactivates the hlb {beta}-toxin gene, on staphylococcal pathogenesis. We showed that prophage {Phi}13 is lost in approximately half the bacterial population during the course of infection. Inactivation of the {Phi}13 int recombinase gene, essential for insertion/excision, locked the prophage in the bacterial chromosome, leading to a significant loss of virulence in a murine systemic infection model. In contrast, the non-lysogen strain ({Delta}{Phi}13), where the hlb beta-hemolysin gene is reconstituted, displayed strongly increased virulence. Accordingly, histopathological analyses revealed more severe nephritis in mice infected with bacteria lacking prophage {Phi}13 ({Delta}{Phi}13), compared to infection with the parental strain. Infection with the {Delta}int mutant, where beta-hemolysin production is abolished, led to the least severe renal lesions. Cytokine induction in a human neutrophil model showed significantly increased IL-6 expression following infection with the beta-hemolysin producing strain ({Delta}{Phi}13). Our results indicate that timely in vivo excision of the {Phi}13 prophage is essential for progression of the Staphylococcus aureus infectious process: early excision leads to rapid host death whereas the inability to excise the prophage significantly reduces staphylococcal virulence. IMPORTANCEThis study highlights prophage {Phi}13 excision as a critical factor in S. aureus pathogenesis, influencing infection outcomes by balancing rapid host killing with reduced bacterial virulence. This mechanism may represent a bet-hedging strategy in genetic regulation, resulting in a mixed bacterial population capable of rapidly switching between two processes: bacterial colonization and host damage. Unraveling this dynamic opens new possibilities for developing targeted therapies to disrupt or modulate prophage activity, offering a novel approach to mitigating S. aureus infections.

microbiology↗

bioRxiv2021

A mouse-adapted SARS-CoV-2 strain replicating in standard laboratory mice.

SARS-CoV-2 has infected almost 200 million humans and caused over 4 million deaths worldwide. Evaluating countermeasures and improving our understanding of COVID-19 pathophysiology require access to animal models that replicate the hallmarks of human disease. Mouse infection with SARS-CoV-2 is limited by poor affinity between the virus spike protein and its cellular receptor ACE2. We have developed by serial passages the MACo3 virus strain which efficiently replicates in the lungs of standard mouse strains and induces age-dependent lung lesions. Compared to other mouse-adapted strains and severe mouse models, infection with MACo3 results in mild to moderate disease and will be useful to investigate the role of host genetics and other factors modulating COVID-19 severity.

microbiology↗

bioRxiv2021

The B1.351 and P.1 variants extend SARS-CoV-2 host range to mice

Receptor recognition is a major determinant of viral host range, infectivity and pathogenesis. Emergences have been associated with serendipitous events of adaptation upon encounters with novel hosts, and the high mutation rate of RNA viruses may explain their frequent host shifts. SARS-CoV-2 extensive circulation in humans results in the emergence of variants, including variants of concern (VOCs) with diverse mutations notably in the spike, and increased transmissibility or immune escape. Here we show that, unlike the initial and Delta variants, the three VOCs bearing the N501Y mutation can infect common laboratory mice. Contact transmission occurred from infected to naive mice through two passages. This host range expansion likely results from an increased binding of the spike to the mouse ACE2. Together with the observed contact transmission, it raises the possibility of wild rodent secondary reservoirs enabling the emergence of new variants.

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↗