NK Cell Activation in Human Hantavirus Infection Explained by Virus-Induced IL-15/IL15Rα Expression

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.

IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction

“…However, the host has evolved mechanisms to counteract pathogen immune evasion and ensure protective immunity that involve upregulation of the expression of IL-15 and non-classical MHC molecules. Intracellular pathogens such as mycobacteria 128 , listeria 129 , Cryptosporidium parvum 130 and a wide range of viruses 89,131–133 have been reported to induce IL-15 expression, probably downstream of the activation of various innate immune receptors such as TLR4 (REFS 81,133). Furthermore, intracellular pathogens have been reported to upregulate the expression of non-classical MHC class I ligands for activating NK receptors on host cells.…”

Biology and Diseases of Mice

“…Each hantavirus is antigenically distinct and maintained within single or at most a few rodent or insectivore hosts, but are infectious for other hosts. The main research complication from natural infection is the zoonotic risk and potentially subclinical effects on the immune response associated with viral defenses such as CD8 + T cell (Taruishi et al, 2007) and NK function as demonstrated in human studies (Braun et al, 2014). Several hantaviruses are zoonotic and may cause severe disease in humans.…”

Current strategies exploiting NK‐cell therapy to treat haematologic malignancies

“…We believe that these adaptive NK cells are induced by CMV specifically and are not induced by other pathogens. Although others have suggested that NKG2C + NK cells are associated with the hantavirus in Sweden and the chikungunya virus in Africa, all of the patients participating in these studies were also co‐exposed to CMV, suggesting that the NKG2C + NK cells were caused by CMV infection rather than infection with other viruses (Braun et al, ; Petitdemange et al, ). To further highlight the specificity of CMV‐induced adaptive NK cells, recent studies have shown that CD57 + NKG2C + NK cells are not expanded in response to Epstein–Barr Virus (EBV) and that human HSV‐2 infection did not induce adaptive NK cells (Björkström, Svensson, Malmberg, Eriksson, & Ljunggren, ; Hendricks et al, ).…”