Zika virus causes acute oophoritis mediated by T lymphocytes in a mouse model

D.E. Broughton, S. Schaeffer, J. Halabi,Elizabeth A. Caine,Jennifer Govero,Michael S. Diamond,Kelle H. Moley

Fertility and Sterility(2018)

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摘要
An adapted strain of Zika virus (ZIKV) has been shown to negatively impact male reproductive tissues in a mouse model, specifically the epididymis and testes.1 Studies in our laboratory have confirmed that ZIKV also exhibits tropism to the female reproductive tract and causes acute inflammation and follicular apoptosis. However, the immune response in the ovary has not been fully characterized. The objective of this study was to characterize the immune response in the ovary following ZIKV infection in a murine model. Female mice (C57BL/6, 7 weeks) were inoculated via a subcutaneous route with 106 focus forming units (FFU) of a mouse-adapted ZIKV strain (Dakar 41519). Ovaries from infected and control mice were collected at 7, 14, or 21 days post-infection. Viral titers were determined with quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Cell apoptosis in the ovary was detected by immunofluorescence TUNEL staining. Immunohistochemistry (IHC) was performed on ovarian tissue sections for inflammatory cell markers including CD45, CD4, and CD8α. Inflammatory cells counts were compared between infected and control mice, controlling for ovarian volume. The experiments above were also performed on mice with a knockout for recombination activating gene 1 (RAG-1), which lack mature functional B and T lymphocytes. ZIKV RNA was detected in the ovarian tissue of infected mice (N=26) at all time points (4-5 Log10 FFU equivalents/gram of tissue). Ovarian viral titers were higher than corresponding values in the serum. Cellular apoptosis was present in degenerating follicles in both infected (N=5) and uninfected (N=5) ovaries, but was significantly increased in the ZIKV exposed animals at the day 7 time point (p=0.04). IHC demonstrated increased CD45+ cells, a pan-lymphocyte marker, in infected ovaries at day 7 (N=5, p=0.02). IHC also demonstrated an increase in T cell infiltration (by both markers CD4 and CD8α) in infected ovaries at all time points (N=4, p<0.05). When these experiments were performed on RAG-1 knockout mice, IHC did not demonstrate any T-cell infiltration in infected or control ovaries, consistent with the expected phenotype. Viral titers in RAG-1 knockout mice were comparable to the mice with intact RAG-1, but ZIKV infected ovaries did not show a similar increase in follicular apoptosis. ZIKV exhibits tropism to the ovary and causes an acute oophoritis dominated by a T lymphocyte infiltrate. This immune response mediates follicular apoptosis in the acute stage of infection. Tissue destruction is not seen in a T cell deficient mouse model, highlighting the importance of cell-mediated immunity in the response to ZIKV.
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关键词
acute oophoritis,virus
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