Zika Virus Causes Acute Infection and Inflammation in the Ovary of Mice Without Apparent Defects in Fertility

Abstract

Background Zika virus (ZIKV) has become a global concern because infection of pregnant mothers was linked to congenital birth defects. Zika virus is unique from other flaviviruses, because it is transmitted vertically and sexually in addition to by mosquito vectors. Prior studies in mice, nonhuman primates, and humans have shown that ZIKV targets the testis in males, resulting in persistent infection and oligospermia. However, its effects on the corresponding female gonads have not been evaluated. Methods In this study, we assessed the effects of ZIKV on the ovary in nonpregnant mice. Results During the acute phase, ZIKV productively infected the ovary causing accumulation of CD4+ and virus-specific CD8+ T cells. T cells protected against ZIKV infection in the ovary, as higher viral burden was measured in CD8−/− and TCRβδ−/− mice. Increased cell death and tissue inflammation in the ovary was observed during the acute phase of infection, but this normalized over time. Conclusions In contrast to that observed with males, minimal persistence and no long-term consequences of ZIKV infection on ovarian follicular reserve or fertility were demonstrated in this model. Thus, although ZIKV replicates in cells of the ovary and causes acute oophoritis, there is rapid resolution and no long-term effects on fertility, at least in mice.

Sexual Transmission of Arboviruses: A Systematic Review

“…ZIKV infects and damages the testes of infected mice and can cause infertility [ 92 , 93 , 98 , 99 , 100 , 101 , 102 , 103 , 104 ]. ZIKV also replicates in the female reproductive tract depending on the immunocompromised status of the females and timing of infection relative to the estrus cycle, having been detected in uterine tissue, ovaries and vaginal washes [ 95 , 105 , 106 , 107 ]. Mice challenged by the anorectal route are also susceptible to infection, with virus detected in multiple organs, including the testes, indicating that anal intercourse is a possible mode of ZIKV transmission [ 108 , 109 ].…”

Castanospermine reduces Zika virus infection-associated seizure by inhibiting both the viral load and inflammation in mouse models

“…Apart from systemic inflammation, ZIKV cause inflammation of brain ( Vieira et al, 2018 ) human retinal pigment epithelium ( Simonin et al, 2019 ), ovary ( Caine et al, 2019 ). Inflammation and seizure-like activities may not be specific to ZIKV, as it is also reported in immunocompromised mice infected with DENV too ( Getts et al, 2007 ; Tsai et al, 2016 ).…”

Zika virus infection in the genital tract of non-pregnant females: a systematic review

“…Several animal studies 28,41,[50][51][52][53][54][55][56][57][58][59][60][61][62] tried to elucidate ZIKV viral dynamics aiming at observing the distribution of the virus in tissues and the triggered immune response, as well as the damage to tissues, including FGT ( Table 2). The majority of animal studies were performed in small animals, such as mice 28,50,53,55,56,58,[60][61][62] , but there are studies in non-human primates (NHPs) 41,52,57,59 .…”

“…Therefore, researchers have used immune compromised animals to study ZIKV infection and dissemination. In this way, some researchers have used isogenic mice strains such as C57BL/6 mice 28,53,55,56,61,62 ; Axl-/-, Mertk-/-, Axl-/-Mertk-/-, and Axl-/-Tyro3-/-mice 58 ; Rag-/-and Ifnar1-/-mice 60 or the immunodeficient AG129 (deficiency in the type-I IFNAR and type-II IFNGR interferon receptors) and the A129 (deficiency in the type-I interferon receptor) mice 38,40,55 to facilitate ZIKV infection, dissemination and study the presence of ZIKV in FGT and other tissues/fluids.…”

“…Ovarian titers were higher than the ones found in serum samples. Caine et al 62 characterized ZIKV infection and the ensuing immune response in the ovary using a murine model (WT and congenic CD8−/− and TCRβδ−/− C57BL/6) and found that animals can be acutely infected. On 7 dpi, CD4+ and CD8+ T cells had infiltrated the ovary causing oophoritis, with detectable ZIKV-specific CD8+ T cells.…”