Control of Acute Arboviral Infection by Natural Killer Cells

Abstract

The recent explosive pandemic of chikungunya virus (CHIKV) followed by Zika (ZIKV) virus infections occurring throughout many countries represents the most unexpected arrival of arthropod-borne viral diseases in the past 20 years. Transmitted through the bite of Aedes mosquitoes, the clinical picture associated with these acute arbovirus infections, including Dengue (DENV), CHIKV and ZIKV, ranges from classical febrile illness to life-threatening disease. Whereas ZIKV and CHIKV-mediated infections have previously been recognized as relatively benign diseases, in contrast to Dengue fever, recent epidemic events have brought waves of increased morbidity and mortality leading to a serious public health problem. Although the host immune response plays a crucial role in controlling infections, it may also promote viral spread and immunopathology. Here, we review recent developments in our understanding of the immune response, with an emphasis on the early antiviral immune response mediated by natural killer cells and emphasize their Janus-faced effects in the control of arbovirus infection and pathogenesis. Improving our understanding knowledge on of the mechanisms that control viral infection is crucial in the current race against the globalization of arbovirus epidemics.

Keywords: arboviruses; cytotoxicity; interferon-γ; natural killer cells.

Figure 1

Non-exhaustive alphabetic list of flaviviruses (in red) and alphaviruses (in blue) and their geographical localization. Flaviviruses: Bagaza virus (BAGV), Bamaga virus (BGV), Banzi virus (BANV), Bouboui virus (BOUV), Dengue virus (DENV), Israel Turkey meningoencephalomyelitis (ITV), Japanese encephalitis virus (JEV), Jugra virus (JUGV), Kokobera virus (KOKV), Lamni virus (LAMV), Murray Valley encephalitis virus (MVEV), Nouanamé virus (NOUV), Rabensburg virus (RABV), Saint Louis encephalitis virus (SLEV), Spondweni virus (SPOV), Tembusu virus (TMUV), T’Ho virus (THOV), Usutu virus (USUV), Wesselsbron virus (WESSV), West Nile virus (WNV), yellow fever virus (YFV) and Zika virus (ZIKV). Alphaviruses: Barmah forest virus (BFV), Chikungunya virus (CHIKV), Mayaro virus (MAYV), O’nyong-nyong virus (ONNV), Ross River virus (RRV), Semliki forest virus (SFV) and Sindbis virus (SINV).

Figure 2

Virus dissemination, immune activation and clinical manifestations in patients infected by alphavirus or flavivirus. These viruses are transmitted through the bite of a female mosquito. The virus infects susceptible cells of the dermis, such as endothelial cells, fibroblasts and macrophages. Locally produced viral particles are then transported through the circulation to secondary lymphoid organs. This acute phase of infection is associated with the upregulation of the production of proinflammatory cytokines, such as IL-1β and IFN-α, that induce innate immune responses, including those exerted by NK cells. Through the circulation alphavirus or flavivirus disseminated also to different organs, including the brain, spleen, liver, joints and muscles. Peripheral and tissue-resident NK cells can directly fight infected cells by triggering cytotoxicity (alphaviruses) or massive production of IFN-γ (flaviviruses), which contributes to the control of infection and the generation of adaptive T cell immunity, as well as the production of protective antibodies and the induction of antibody-dependent cellular cytotoxicity. For other flaviviruses, such as DENV, antibody complexes are also associated with the triggering of antibody-dependent enhancement which has been linked to the development of more severe forms of disease.