NK Cell Responses in Zika Virus Infection Are Biased towards Cytokine-Mediated Effector Functions

Abstract

Zika virus (ZIKV) is a mosquito-borne flavivirus that has emerged as a global concern because of its impact on human health. ZIKV infection during pregnancy can cause microcephaly and other severe brain defects in the developing fetus and there have been reports of the occurrence of Guillain-Barré syndrome in areas affected by ZIKV. NK cells are activated during acute viral infections and their activity contributes to a first line of defense because of their ability to rapidly recognize and kill virus-infected cells. To provide insight into NK cell function during ZIKV infection, we have profiled, using mass cytometry, the NK cell receptor-ligand repertoire in a cohort of acute ZIKV-infected female patients. Freshly isolated NK cells from these patients contained distinct, activated, and terminally differentiated, subsets expressing higher levels of CD57, NKG2C, and KIR3DL1 as compared with those from healthy donors. Moreover, KIR3DL1+ NK cells from these patients produced high levels of IFN-γ and TNF-α, in the absence of direct cytotoxicity, in response to in vitro stimulation with autologous, ZIKV-infected, monocyte-derived dendritic cells. In ZIKV-infected patients, overproduction of IFN-γ correlated with STAT-5 activation (r = 0.6643; p = 0.0085) and was mediated following the recognition of MHC class 1–related chain A and chain B molecules expressed by ZIKV-infected monocyte-derived dendritic cells, in synergy with IL-12 production by the latter cells. Together, these findings suggest that NK cells contribute to the generation of an efficacious adaptive anti-ZIKV immune response that could potentially affect the outcome of the disease and/or the development of persistent symptoms.

Aedes aegypti salivary extracts exert immunomodulatory effects onmacrophages, dendritic cells, and T lymphocytes and increase Zikavirus production in vitro.

“…On the other hand the reduction in IL-12 production, an essential cytokine for Th1 antiviral response, further indicates a nuanced dysregulation of APC antiviral signaling by mosquito saliva (36). The IL-12 reduction can downregulate the function of NK and CD8 + T cells, both extremely relevant to controlling ZIKV infection (40).…”

Comprehensive analysis of early T cell responses to acute Zika Virus infection during the first epidemic in Bahia, Brazil

“…A panel of 40 mAbs-transition metal conjugates was used to stain PBMCs ( S1 Table ). Cells were stained and prepared, as described elsewhere [ 16 ]. Cell events were acquired on the CyTOF-2 mass cytometer (Fluidigm) using CyTOF software version 6.7.1014 (Fluidigm) at the Plateforme de Cytométrie de la Pitié-Salpêtrière (CyPS) in Paris, France.…”

“…Accordingly, our group previously reported in a sub-group of 16 Brazilian patients with acute ZIKV-infection, a massive activation of NK cells, some of which exhibited intracellular markers of immune activation, including a spontaneous ex vivo expression of phospho-STAT5. In addition, a proportion of these NK cells also spontaneously produced IFN-γ ex vivo in correlation with the STAT5 activation [ 16 ]. These results suggested the STAT5 pathway had been activated in vivo and might have lead to IFN-γ production into NK cells.…”

“…In order to address the question of the early involvement of T cells in the early phases of acute ZIKV infection, and to evaluate whether T cells show similar co-expression of phospho-STAT5 and IFN-γ, we investigated in the present study the T cell activation and functional status and the T cell specificities for ZIKV in the same cohort of Brazilian patients [ 11 ] in which we had previously conducted our NK cell analysis [ 16 ]. First, we conducted a comprehensive mass cytometry analysis to explore the early STAT5 activation and IFN-γ production in parallel to other functional and phenotypic characteristics of early circulating activated T cells during the initial days of ZIKV infection.…”

Costimulatory CD226 Signaling Regulates Proliferation of Memory-like NK Cells in Healthy Individuals with Latent Mycobacterium tuberculosis Infection

“…Initially recognized as part of a stereotyped innate immune mechanism, several reports have clearly shown that NK cells can acquire memory characteristics [ 6 , 7 , 8 , 9 ]. A role of memory-like NK cells (mlNKs) has been shown for cytomegalovirus [ 7 , 10 ], Zika virus [ 11 , 12 ], simian-human immunodeficiency virus (SHIV) [ 13 ], HIV [ 14 ], flu virus [ 15 , 16 ] as well as tuberculosis (TB) [ 17 , 18 ]. NK memory has also been reported against haptens [ 6 ] as well as a combination of IL12, IL15 and IL18 cytokines [ 8 , 9 ].…”