Avaliação dos efeitos da infecção pelo Zika virus durante o período gestacional no desenvolvimento das proles de camundongos com ou sem infecção prévia pelo Dengue virus 1

Abstract

Zika virus (ZIKV) infection is pointed as a public health problem in Brazil. However, there is still a lack of studies that evaluate the effects of gestational ZIKV infection associated to a prior Dengue virus 1 (DENV-1) infection. Thus, the aim of the present study was to investigate the effects of previous DENV-1 infection in the development of mice infected with ZIKV during the gestational period. Female Swiss adult mice were inoculated with DENV-1 or saline (0,9% NaCl) and submitted to mating strategy after infection confirmation. During pregnancy, the females were infected with ZIKV or saline. ELISA assays were performed to confirm female infections. Furthermore, RT-qPCR assays in neonate mice brain were performed to investigate viral particles of ZIKV. The physical and reflexology development, locomotor activity, anxiety, visual acuity and spatial reference memory were evaluated by behavioral tests in the offspring during childhood (PN18, PN19 and PN20) and adolescence (PN40, PN41, PN42 and PN43). The levels of brain-derived neurotrophic factor (BDNF) were quantified in different brain structures of pups in PN18. Detection of anti-DENV-1 and anti-ZIKV IgG antibodies in females, at different times, showed that the infections were successful. Negative results were obtained for the RT-qPCR assay for ZIKV in neonate mice brain. Our results showed that offspring with gestational infection by ZIKV, associated with prior DENV-1 infection, displayed a decrease in weight gain and length, especially in females, at different ages. DENV/ZIKV group presented early detection of testis descent, early loss of palmar grip and late detection of visual orientation when compared to the other groups. Also, DENV/ZIKV offsprings exhibited hipolocomotion, reduction of anxiety, decrease of visual acuity, when compared to the animals of control group SALINE/SALINE, and improvement in the acquisition of spatial memory when compared to the animals of SALINE/ZIKV group. There were observed a decrease in the BDNF levels in the striatum of DENV/ZIKV group compared to the SALINE/SALINE and DENV/SALINE groups during childhood. Still, SALINE/ZIKV pups showed a reduction in BDNF levels in the cerebellum and striatum when compared to SALINE/SALINE animals. DENV/SALINE pups presented a decrease in BDNF levels in the cerebellum compared to control animals and, also showed a BDNF increase in the striatum when compared to the DENV/ZIKV animals. Our results suggest that mice with prior DENV-1 infection associated to gestacional ZIKV infection, present impairment in the physical and reflexological development, as well as behavioral and biochemical changes depending on the age, even with ZIKV absence in brain tissue.