Innate lymphoid cells are activated in HFRS, and their function can be modulated by hantavirus-induced type I interferons

by Marina García, Anna Carrasco García, Whitney Weigel, Wanda Christ, Ronaldo Lira-Junior, Lorenz Wirth, Johanna Tauriainen, Kimia Maleki, Giulia Vanoni, Antti Vaheri, Satu Mäkelä, Jukka Mustonen, Johan Nordgren, Anna Smed-Sörensen, Tomas Strandin, Jenny Mjösberg, Jonas Klingström

Hantaviruses cause the acute zoonotic diseases hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Infected patients show strong systemic inflammation and immune cell activation. NK cells are highly activated in HFRS, suggesting that also other innate lymphoid cells (ILCs) might be responding to infection. Here, we characterized peripheral ILC responses, and measured plasma levels of soluble factors and plasma viral load, in 17 Puumala virus (PUUV)-infected HFRS patients. This revealed an increased frequency of ILC2 in patients, in particular the ILC2 lineage-committed c-Kit^lo ILC2 subset. Patients’ ILCs showed an activated profile with increased proliferation and displayed altered expression of several homing markers. How ILCs are activated during viral infection is largely unknown. When analyzing PUUV-mediated activation of ILCs in vitro we observed that this was dependent on type I interferons, suggesting a role for type I interferons—produced in response to virus infection–in the activation of ILCs. Further, stimulation of naïve ILC2s with IFN-β affected ILC2 cytokine responses in vitro, causing decreased IL-5 and IL-13, and increased IL-10, CXCL10, and GM-CSF secretion. These results show that ILCs are activated in HFRS patients and suggest that the classical antiviral type I IFNs are involved in shaping ILC functions.