NK cell activation in human hantavirus infection explained by virus-induced IL-15/IL15Rα expression.

Monika Braun,Clas Ahlm,Jonas Klingström,Karin Sundström,Shawon Gupta,Hans-Gustaf Ljunggren,Niklas K Björkström,Christopher F Basler

doi:10.1371/journal.ppat.1004521

Monika Braun, Clas Ahlm + Show 6 more

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https://doi.org/10.1371/journal.ppat.1004521

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Abstract

Clinical infection with hantaviruses cause two severe acute diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). These diseases are characterized by strong immune activation, increased vascular permeability, and up to 50% case-fatality rates. One prominent feature observed in clinical hantavirus infection is rapid expansion of natural killer (NK) cells in peripheral blood of affected individuals. We here describe an unusually high state of activation of such expanding NK cells in the acute phase of clinical Puumala hantavirus infection. Expanding NK cells expressed markedly increased levels of activating NK cell receptors and cytotoxic effector molecules. In search for possible mechanisms behind this NK cell activation, we observed virus-induced IL-15 and IL-15Rα on infected endothelial and epithelial cells. Hantavirus-infected cells were shown to strongly activate NK cells in a cell-cell contact-dependent way, and this response was blocked with anti-IL-15 antibodies. Surprisingly, the strength of the IL-15-dependent NK cell response was such that it led to killing of uninfected endothelial cells despite expression of normal levels of HLA class I. In contrast, hantavirus-infected cells were resistant to NK cell lysis, due to a combination of virus-induced increase in HLA class I expression levels and hantavirus-mediated inhibition of apoptosis induction. In summary, we here describe a possible mechanism explaining the massive NK cell activation and proliferation observed in HFRS patients caused by Puumala hantavirus infection. The results add further insights into mechanisms behind the immunopathogenesis of hantavirus infections in humans and identify new possible targets for intervention.

Highlights

Pathogenic hantaviruses are zoonotic, rodent-borne, viruses that belong to the Bunyaviridae family
High natural killer (NK) cell activation was observed during the acute phase of clinical infection
We demonstrate hantavirus-induced IL-15/IL-15 receptor a chain (IL-15Ra) on infected endothelial cells, and show that this results in NK cell activation, similar to the profile found in hantavirus-infected patients

Summary

Introduction

Pathogenic hantaviruses are zoonotic, rodent-borne, viruses that belong to the Bunyaviridae family. When infecting humans, they cause hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS; called hantavirus cardio-pulmonary syndrome), two severe acute diseases with casefatality rates of up to 10% for HFRS and 50% for HPS [1]. Hantaviruses can infect several different types of cells, but endothelial and epithelial cells are the primary target cells for hantaviruses in humans [1]. In the context of immune activation, HFRS and HPS patients have recently been shown to display strong cytotoxic lymphocyte expansions including both NK and CD8 T cells [3,4,5,6]. Providing some insights into these findings, we recently found hantavirus-infected endothelial cells to be protected from cytotoxic lymphocyte-mediated killing, at least partly, through inhibition of granzyme B and caspase 3 mediated by the hantavirus nucleocapsid protein [12]

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