In contrast to the clinically similar DF, acute ZIKV infections are less severe and secondary infections are not described owing to the fact that only one serotype of ZIKV exists. After an acute ZIKV infection immunity to re-infection is established for an unknown time span, based on epidemiological evidence from past outbreaks [
1,
2]. In the patients studied here, elevation of chemokines was more pronounced than elevation of cytokines. In the recovery phase, cytokine levels generally decreased. A polyfunctional immune activation was seen during the acute phase of ZF, as reflected by elevated cytokine profiles associated with Th1 (IL-2, and non-significantly IFN-γ), Th2 (IL-4, IL-13), Th17 (IL-17), and also Th9 (IL-9) responses. Data on IL-9 functions during human viral infection is scarce, but studies have shown an association of elevated IL-9 levels and severe acute respiratory syncytial virus infections [
10] and non-response to treatment of chronic hepatitis C [
11], suggesting a modulator role of antiviral immunity. In our study, IL-2, IFN-γ and TNF-α levels were surprisingly lower than expected, contrasting with findings in other arboviral infections [
12,
13]. Of note, in our study RANTES is already increased in the acute phase, whereas IP-10 is particularly elevated in the recovery phase. Effective T cell recruitment to infection sites and formation of effector T cells was suggested by both increased RANTES and IP-10 concentrations [
14,
15]. Since CCR5 and CxCR3 are chemokine ligands receptors for RANTES and IP-10, respectively, immunophenotyping of peripheral blood T cells of ZIKV-infected patients as well as functional T cell assays should help to further explore the role of RANTES and IP-10 during ZF. Similar to descriptions of patients infected with dengue virus (DENV) [
16], a related flavivirus, sera of patients with ZF analyzed in our study also showed increased IL-4, IL-6, IL-8, IL-10, and IP-10 levels. IL-10 levels were also highest in the later (recovery) phase of ZIKV infection, as seen in DF [
14]. In contrast to DF, however, concentrations of IL-1ß, IL-2, MCP-1, and VEGF were not decreased in ZF patients. In DF, elevated IL-8 and IL-10 levels were shown to be associated with severe infection [
14], a clinical state which has so far not been seen in ZF. No “cytokine storm effects”, as known from DENV infections [
17] were demonstrated in the ZF patients in our study. Of note, significantly increased IFN-γ and TNF-α levels were absent in ZF in contrast to DF, pointing toward a Th2 bias in ZIKV infections. In DENV infections, thrombocytopenia correlated strongly with RANTES and VEGF levels [
16]. Both RANTES, a chemokine stored in a-granules of platelets, secreted upon platelet activation, and VEGF, a growth factor released by platelets, would be expected to decrease upon thrombocytopenia. In contrast, severe thrombocytopenia is rarely observed in ZF patients and RANTES and VEGF did not show decreased levels when compared with the control group. It remains to be elucidated whether ZIKV-induced GBS [
5] might be associated with different cytokine responses than changes in non-GBS ZIKV-infected patients.
Due to the small number of ZF patients examined, this study and the strength of the observations are limited. We have analyzed cytokine levels over time in returning travelers to Europe, and it is unknown whether different human ethnic groups might show different cytokine responses as described for DF [
18]. Recent ZF epidemics were only caused by the Asian genotype of ZIKV, which is the same genotype also seen in travel-related infections from outbreak areas. Thus, the cytokine data presented here are linked to an infection with the Asian genotype. As a restriction of the study, functional T cell tests (i.e., stimulation with ZIKV antigen followed by intracellular cytokine staining) have not been performed. Future studies will address lymphocyte and cytokine responses in more detail, allowing proper conclusions of Th1- and Th2-biased cell responses. Despite showing rather preliminary data, to our knowledge, this is the first study investigating immune parameters in acute ZF.