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- Title
Diverse susceptibilities and responses of human and rodent cells to orthohantavirus infection reveal different levels of cellular restriction.
- Authors
Gallo, Giulia; Kotlik, Petr; Roingeard, Philippe; Monot, Marc; Chevreux, Guillaume; Ulrich, Rainer G.; Tordo, Noël; Ermonval, Myriam
- Abstract
Orthohantaviruses are rodent-borne emerging viruses that may cause severe diseases in humans but no apparent pathology in their small mammal reservoirs. However, the mechanisms leading to tolerance or pathogenicity in humans and persistence in rodent reservoirs are poorly understood, as is the manner in which they spread within and between organisms. Here, we used a range of cellular and molecular approaches to investigate the interactions of three different orthohantaviruses–Puumala virus (PUUV), responsible for a mild to moderate form of hemorrhagic fever with renal syndrome in humans, Tula virus (TULV) with low pathogenicity, and non-pathogenic Prospect Hill virus (PHV)–with human and rodent host cell lines. Besides the fact that cell susceptibility to virus infection was shown to depend on the cell type and virus strain, the three orthohantaviruses were able to infect Vero E6 and HuH7 human cells, but only the former secreted infectious particles. In cells derived from PUUV reservoir, the bank vole (Myodes glareolus), PUUV achieved a complete viral cycle, while TULV did not enter the cells and PHV infected them but did not produce infectious particles, reflecting differences in host specificity. A search for mature virions by electron microscopy (EM) revealed that TULV assembly occurred in part at the plasma membrane, whereas PHV particles were trapped in autophagic vacuoles in cells of the heterologous rodent host. We described differential interactions of orthohantaviruses with cellular factors, as supported by the cellular distribution of viral nucleocapsid protein with cell compartments, and proteomics identification of cellular partners. Our results also showed that interferon (IFN) dependent gene expression was regulated in a cell and virus species dependent manner. Overall, our study highlighted the complexity of the host-virus relationship and demonstrated that orthohantaviruses are restricted at different levels of the viral cycle. In addition, the study opens new avenues to further investigate how these viruses differ in their interactions with cells to evade innate immunity and how it depends on tissue type and host species. Author summary: Orthohantaviruses are zoonotic RNA viruses found all over the world in association with small mammal reservoirs. When occasionally transmitted to humans by aerosol they can cause two main types of diseases: hemorrhagic fever with renal syndrome (HFRS) mainly in Europe and Asia and hantavirus cardiopulmonary syndrome (HCPS) in North and South America with a case fatality rate of up to 15% and 40% respectively. An increasing number of outbreaks are recorded in endemic areas and, with disturbance of rodent habitats, climate change and the risk of virus genome reassortment, the emergence of new orthohantaviruses is of concern. With no treatment, no vaccines and few molecular tools, little is known about the pathophysiology of these viruses. Our comparative study of the viral cycle and interaction of different pathogenic and low or non-pathogenic orthohantaviruses in cells derived from human or rodent hosts reveals differences in entry, RNA replication or release of infectious particles, concurrently to regulation of host genes. This study illustrates how the development of a rodent host cell model together with the availability of an annotated bank vole genome may contribute to a better understanding of mechanisms of the interactions between orthohantaviruses and their hosts.
- Subjects
HEMORRHAGIC fever with renal syndrome; HOST specificity (Biology); RODENTS; HOST-virus relationships; HEMORRHAGIC fever; BEGOMOVIRUSES; AUTOPHAGY; PESTE des petits ruminants
- Publication
PLoS Neglected Tropical Diseases, 2022, Vol 16, Issue 10, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0010844