Abstract
Severe neurological complications following arbovirus infections have been a major concern in seasonal outbreaks, as reported in the Northeast region of Brazil, where the same mosquito transmitted Zika (ZIKV), Dengue (DENV), and Chikungunya (CHIKV) viruses. In this study, we evaluated the levels of 36 soluble markers, including cytokines, chemokines, growth factors, and soluble HLA-G (Luminex and ELISA) in: i) serum and cerebrospinal fluid (CSF), during the acute phase and two years after the infection (recovery phase, only serum), ii) the relationship among all soluble molecules in serum and CSF, and iii) serum of infected patients without neurological complications, during the acute infection. Ten markers (sHLA-G, IL-10, IL-22, IL-8, MIP-1α, MIP-1β, MCP-1, HGF, VEGF, and IL-1RA) exhibited differential levels between the acute and recovery phases, with pronounced increases in MIP-1α (P<0.0001), MCP-1 (P<0.0001), HGF (P= 0.0001), and VEGF (P<0.0001) in the acute phase. Fourteen molecules (IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-13, IL-15, IL-17A, IFN-α, TNF, and G-CSF) exhibited distinct levels between arbovirus patients presenting or not neurological complications. IL-8, EGF, IL-6, and MCP-1 levels were increased in CSF, while RANTES and Eotaxin levels were higher in serum. Soluble serum (IL-22, RANTES, Eotaxin) and CSF (IL-8, EGF, IL-3) mediators may discriminate putative risks for neurological complications following arbovirus infections. Neurological complications were associated with the presence of a predominant inflammatory profile, whereas in non-complicated patients an anti-inflammatory profile may predominate. Mediators associated with neuroregeneration (EGF and IL-3) may be induced in response to neurological damage. Broad spectrum immune checkpoint molecules (sHLA-G) interact with cytokines, chemokines, and growth factors. The identification of soluble markers may be useful to monitor neurological complications and may aid in the development of novel therapies against neuroinflammation.
Highlights
In the 2015 outbreak, Brazil registered a significant increase in the number of hospitalizations and reported cases of microcephaly in babies, and Guillain Barré Syndrome (GBS), encephalitis and other neurological diseases in adults and children, with subsequent confirmation of their association with the Flaviviridae Zika virus (ZIKV) [1,2,3,4,5,6,7]
The levels of nine mediators were increased in the acute phase when compared to the recovery phase, including the cytokines IL-10 and IL-22, the chemokines IL-8, MIP-1a, MIP-1b, and MCP-1, the growth factors HGF and VEGF, and the cytokine receptor IL-1RA
We evaluated the role of the immune checkpoint HLA-G molecule on arbovirus infections and its relationship with cytokines, chemokines, and growth factors
Summary
In the 2015 outbreak, Brazil registered a significant increase in the number of hospitalizations and reported cases of microcephaly in babies, and Guillain Barré Syndrome (GBS), encephalitis and other neurological diseases in adults and children, with subsequent confirmation of their association with the Flaviviridae Zika virus (ZIKV) [1,2,3,4,5,6,7]. An overlap of cases with articular manifestations was observed in the same epidemics, attributed to a new arbovirus (Chikungunya virus – CHIKV; Togavirividae family) [11, 12], which causes a broad spectrum of clinical manifestations, including temporary or chronic joint diseases and different types of neurological involvement [5, 13,14,15]. A single mosquito (Aedes aegypti) was responsible for the transmission of the three arboviruses (ZIKV, DENV, and CHIKV) at different combinations, and the highest concentration of Brazilian cases exhibiting severe neurological disorders was observed in Recife, capital of Pernambuco State [16]. Arbovirus-associated neurological diseases may be caused by the direct action of viruses, inflammatory reaction in nervous tissue or systemic metabolic alterations (encephalopathies), induced or not by the exacerbated systemic immune response [17]. A fraction of infected patients develops neurological manifestations, exhibiting incubation time that vary according to the arbovirus [16]
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