Longitudinal Analysis of Natural Killer Cells in Dengue Virus-Infected Patients in Comparison to Chikungunya and Chikungunya/Dengue Virus-Infected Patients

Background: Dengue virus (DENV) is the most prominent arbovirus worldwide, causing major epidemics in South-East Asia, South America and Africa. In 2010, a major DENV-2 outbreak occurred in Gabon with cases of patients co-infected with chikungunya virus (CHIKV). Although the innate immune response is thought to be of primordial importance in the development and outcome of arbovirus-associated pathologies, our knowledge of the role of natural killer (NK) cells during DENV-2 infection is in its infancy. Methodology: We performed the first extensive comparative longitudinal characterization of NK cells in patients infected by DENV-2, CHIKV or both viruses. Hierarchical clustering and principal component analyses were performed to discriminate between CHIKV and DENV-2 infected patients. Principal Findings: We observed that both activation and differentiation of NK cells are induced during the acute phase of infection by DENV-2 and CHIKV. Combinatorial analysis however, revealed that both arboviruses induced two different signatures of NK-cell responses, with CHIKV more associated with terminal differentiation, and DENV-2 with inhibitory KIRs. We show also that intracellular production of interferon-γ (IFN-γ) by NK cells is strongly stimulated in acute DENV-2 infection, compared to CHIKV. Conclusions/Significance: Although specific differences were observed between CHIKV and DENV-2 infections, the significant remodeling of NK cell populations observed here suggests their potential roles in the control of both infections. Author Summary: Dengue fever is the most important arthropod-borne viral disease worldwide, affecting 50 to 100 million individuals annually. The clinical picture associated with acute dengue virus (DENV) infections ranges from classical febrile illness to life-threatening disease. The innate immunity is the first line of defense in the control of viral replication. In this article, we examine the particular role of natural killer (NK) cells in DENV infection at different time points after the onset of symptoms. This extensive study was performed in comparison with patients infected by Chikungunya virus (CHIKV), another major arbovirus transmitted by the same mosquito vectors, and co-infected CHIKV/DENV-2 patients. We observed that DENV2 and CHIKV induced different signatures of NK-cell responses suggesting specific roles in the control of both infections.