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

Abstract

BackgroundDengue 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.MethodologyWe 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 FindingsWe 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/SignificanceAlthough 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.

Glycogen synthetase kinase 3 inhibition drives MIC‐A/B to promote cytokine production by human natural killer cells in Dengue virus type 2 infection

“…Activated NK cells can inhibit viral infection by killing virus‐infected cells and the secretion of gamma interferon (IFN‐γ). In DENV‐2, a high level of IFN‐γ production was observed, without stimulation of cytotoxicity , in accordance with the up‐regulation of major histocompatibility (MHC) class‐1 molecules that occur during DENV and other flavivirus infections . However, it is important to note that CD16 on NK cells has been shown to mediate ADCC activity of antibodies induced by DENV infection .…”

Upregulation of HLA‐E by dengue and not Zika viruses

“…Using our coculture conditions, the cytolytic activity and cytokine expression in NK92 cells expressing the inhibitory receptor NKG2a was not affected by HLA‐E upregulation on HMEC‐1 cells. NK cells expressing the inhibitory (NKG2a) and activating (NKG2c) ligands for HLA‐E have recently been shown to be upregulated on NK cells during acute DENV infection . Additional studies are required to determine whether NKG2c+ NK cells are impacted by HLA‐E expression on ECs.…”

“…NK cells expressing the inhibitory (NKG2a) and activating (NKG2c) ligands for HLA-E have recently been shown to be upregulated on NK cells during acute DENV infection. 25 Additional studies are required to determine whether NKG2c+ NK cells are impacted by HLA-E expression on ECs. Furthermore, how NK cells respond to ligands including HLA-E following DENV infection of other target cells such as primary dendritic cells and monocytes may differ from responses to ECs and are worthy of future study.…”

Control of the HIV-1 DNA Reservoir Is AssociatedIn VivoandIn Vitrowith NKp46/NKp30 (CD335 CD337) Inducibility and Interferon Gamma Production by Transcriptionally Unique NK Cells

“…Accordingly, the in vitro effect of HLA:KIR carriage on NK cell control of HIV replication (HIV p24 ) in patients with delayed disease progression remains controversial (36,37). During infections with different viruses, including human cytomegalovirus (HCMV) (38,39), murine CMV (MCMV) (40), and possibly chikungunya virus, dengue virus, and hantavirus (41,42), persistent or transient expansions of a specific NK cell subset bearing NKG2C in humans and its homolog in mice have been described. These cell expansions are interpreted as possible memory-like features of NK cells with resemblance to adaptive immune T cell responses (11,12).…”