Abstract
An early immune response to Zika virus (ZIKV) infection may determine its clinical manifestation and outcome, including neurological effects. However, low-grade and transient viremia limits the prompt diagnosis of acute ZIKV infection. We have investigated the plasma cytokine, chemokine, and growth factor profiles of 36 individuals from an endemic area displaying different symptoms such as exanthema, headache, myalgia, arthralgia, fever, hyperemia, swelling, itching, and nausea during early-phase infection. These profiles were then associated with symptoms, revealing important aspects of the immunopathophysiology of ZIKV infection. The levels of some cytokines/chemokines were significantly higher in acute ZIKV-infected individuals compared to healthy donors, including interferon (IFN) gamma-induced protein 10 (IP-10), regulated on activation, normal T cell expressed and secreted (RANTES), IFN-γ, interleukin (IL)-9, IL-7, IL-5, and IL-1ra, including some with predominantly immunoregulatory activity. Of note, we found that higher levels of IP-10 and IL-5 in ZIKV-infected individuals were strongly associated with exanthema and headache, respectively. Also, higher levels of IL-1ra were associated with subjects with arthralgia, whereas those with fever showed lower levels of granulocyte-colony stimulating factor (G-CSF). No correlation was observed between the number of symptoms and ZIKV viral load. Interestingly, only IP-10 showed significantly decreased levels in the recovery phase. In conclusion, our results indicate that acute ZIKV infection in a larger cohort resident to an endemic area displays a modest systemic immune activation profile, involving both proinflammatory and immunoregulatory cytokines and chemokines that could participate of virus control. In addition, we showed that differential cytokine/chemokine levels are related to specific clinical symptoms, suggesting their participation in underlying mechanisms.
Highlights
Zika virus (ZIKV) infection is an emerging endemic disease, with recent outbreaks in the Americas [1]
IP-10 (p < 0.0001) showed the highest levels in infected individuals compared to healthy subjects, followed by RANTES (p < 0.0001), IFN-γ (p = 0.02), IL-9 (p = 0.03), IL-7 (p = 0.005), IL-1 receptor antagonist (IL-1ra) (p < 0.0001), and IL-5 (p = 0.01; Figures 1A,B and 2A)
The levels of three cytokines were higher in patients with infection: IP-10 (p < 0.001), RANTES (p < 0.001), and IFN-γ (p < 0.03)
Summary
Zika virus (ZIKV) infection is an emerging endemic disease, with recent outbreaks in the Americas [1]. In the recent outbreaks, adult ZIKV infection was associated with Guillain–Barré syndrome [6], myelitis, meningoencephalitis [7, 8], and a fetal neuro- logical syndrome involving microcephaly [9,10,11]. Changes in pro- and anti-inflammatory cytokines have been reported in a small group of six individuals, who were infected with ZIKV while visiting endemic areas [21]. Considering the small number of patients in that study, an evaluation of immune mediators in the acute phase in a larger cohort of patients residing in an endemic area may shed some light on the immunopathophysiology of ZIKV infection
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