Hantavirus-infection Confers Resistance to Cytotoxic Lymphocyte-Mediated Apoptosis

Shawon Gupta,Jonas Klingström,Nicole D Tischler,Malin Stoltz,Hans-Gustaf Ljunggren,Karin B Sundström,Niklas K Björkström,Monika Braun,Mark T Heise

doi:10.1371/journal.ppat.1003272

Abstract

Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardio-pulmonary syndrome (HCPS; also called hantavirus pulmonary syndrome (HPS)), both human diseases with high case-fatality rates. Endothelial cells are the main targets for hantaviruses. An intriguing observation in patients with HFRS and HCPS is that on one hand the virus infection leads to strong activation of CD8 T cells and NK cells, on the other hand no obvious destruction of infected endothelial cells is observed. Here, we provide an explanation for this dichotomy by showing that hantavirus-infected endothelial cells are protected from cytotoxic lymphocyte-mediated induction of apoptosis. When dissecting potential mechanisms behind this phenomenon, we discovered that the hantavirus nucleocapsid protein inhibits the enzymatic activity of both granzyme B and caspase 3. This provides a tentative explanation for the hantavirus-mediated block of cytotoxic granule-mediated apoptosis-induction, and hence the protection of infected cells from cytotoxic lymphocytes. These findings may explain why infected endothelial cells in hantavirus-infected patients are not destroyed by the strong cytotoxic lymphocyte response.

Highlights

Hantaviruses are emerging zoonotic viruses that cause two severe diseases: hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardio-pulmonary syndrome (HCPS; called hantavirus pulmonary syndrome (HPS)) in the Americas, with case-fatality rates of up to 10% for HFRS and up to 40% for HCPS [1,2]
While endothelial cells are the main targets for hantaviruses, infection per se is not lytic
It has been suggested that cytotoxic lymphocyte-mediated killing of hantavirus-infected endothelial cells might contribute to HFRS/HCPS-pathogenesis

Summary

Introduction

Hantaviruses are emerging zoonotic viruses that cause two severe diseases: hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardio-pulmonary syndrome (HCPS; called hantavirus pulmonary syndrome (HPS)) in the Americas, with case-fatality rates of up to 10% for HFRS and up to 40% for HCPS [1,2]. Several different hantaviruses cause HFRS and HCPS. Hantaan virus (HTNV) and Andes virus (ANDV) are the most common HFRS- and HCPS-causing hantaviruses, respectively [1,2]. Endothelial cells are the main targets for hantaviruses and increased vascular permeability is, as in other hemorrhagic fevers [3], a hallmark of HFRS and HCPS. The underlying mechanisms of the increased vascular permeability observed in HFRS and HCPS are, not completely understood. It is unclear whether hantaviruses themselves or, alternatively, the related immune responses, are responsible for causing pathology [1,4,5,6]

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Discussion

Conclusion