Replication in the Mononuclear Phagocyte System (MPS) as a Determinant of Hantavirus Pathogenicity.

Martin J Raftery,Thomas Giese,Rainer G Ulrich,Pritesh Lalwani,Lukas Radosa,Günther Schönrich,Nina Lütteke,Detlev H Krüger,Lidija Kobak

doi:10.3389/fcimb.2020.00281

Abstract

Members of different virus families including Hantaviridae cause viral hemorrhagic fevers (VHFs). The decisive determinants of hantavirus-associated pathogenicity are still enigmatic. Pathogenic hantavirus species, such as Puumala virus (PUUV), Hantaan virus (HTNV), Dobrava-Belgrade virus (DOBV), and Sin Nombre virus (SNV), are associated with significant case fatality rates. In contrast, Tula virus (TULV) only sporadically causes mild disease in immunocompetent humans and Prospect Hill virus (PHV) so far has not been associated with any symptoms. They are thus defined here as low pathogenic/apathogenic hantavirus species. We found that productive infection of cells of the mononuclear phagocyte system (MPS), such as monocytes and dendritic cells (DCs), correlated well with the pathogenicity of hantavirus species tested. HTNV (intermediate case fatality rates) replicated more efficiently than PUUV (low case fatality rates) in myeloid cells, whereas low pathogenic/apathogenic hantavirus species did not produce any detectable virus titers. Analysis of PHPUV, a reassortant hantavirus derived from a pathogenic (PUUV) and an apathogenic (PHV) hantavirus species, indicated that the viral glycoproteins are not decisive for replication in MPS cells. Moreover, blocking acidification of endosomes with chloroquine decreased the number of TULV genomes in myeloid cells suggesting a post-entry block for low pathogenic/apathogenic hantavirus species in myeloid cells. Intriguingly, pathogenic but not low pathogenic/apathogenic hantavirus species induced conversion of monocytes into inflammatory DCs. The proinflammatory programming of MPS cells by pathogenic hantavirus species required integrin signaling and viral replication. Our findings indicate that the capacity to replicate in MPS cells is a prominent feature of hantaviral pathogenicity.

Highlights

Hantaviruses are globally emerging zoonotic pathogens that cause different types of viral hemorrhagic fever (VHF) (Kruger et al, 2015; Papa et al, 2016)
We comparatively studied the ability of pathogenic (HTNV) and low pathogenic (TULV) hantavirus species to infect monocyte-derived immature dendritic cells (DCs) or Immature DCs (iDCs) isolated from peripheral blood
At 5 days post-infection (p.i.), hantavirus N protein was detected in all Hantaan virus (HTNV)-infected cells but neither in iDCs nor in bDCs infected with Tula virus (TULV) (Figure 1A)

Summary

Introduction

Hantaviruses (order Bunyavirales, family Hantaviridae) are globally emerging zoonotic pathogens that cause different types of viral hemorrhagic fever (VHF) (Kruger et al, 2015; Papa et al, 2016). The severity and case fatality rate of hantavirus-associated VHF depends on the hantavirus species involved (Jonsson et al, 2010; Kruger et al, 2011). Hantavirus species circulating in Europe and Asia, such as Puumala virus (PUUV), Hantaan virus (HTNV), and DobravaBelgrade virus (DOBV) are associated with hemorrhagic fever with renal syndrome (HFRS) with case fatality rates of

Methods

Results

Conclusion