Abstract
Zika virus (ZIKV) infection can cause fetal developmental abnormalities and Guillain–Barré syndrome in adults. Although progress has been made in understanding the link between ZIKV infection and microcephaly, the pathology of ZIKV, particularly the viral reservoirs in human, remains poorly understood. Several studies have shown that compared to serum samples, patients’ urine samples often have a longer duration of ZIKV persistency and higher viral load. This finding suggests that an independent viral reservoir may exist in the human urinary system. Despite the clinical observations, the host cells of ZIKV in the human urinary system are poorly characterized. In this study, we demonstrate that ZIKV can infect renal proximal tubular epithelial cells (RPTEpiCs) in immunodeficient mice in vivo and in both immortalized and primary human renal proximal tubular epithelial cells (hRPTEpiCs) in vitro. Importantly, ZIKV infection in mouse kidneys caused caspase-3-mediated apoptosis of renal cells. Similarly, in vitro infection of immortalized and primary hRPTEpiCs resulted in notable cytopathic effects. Consistent with the clinical observations, we found that ZIKV infection can persist with prolonged duration in hRPTEpiCs. RNA-Seq analyses of infected hRPTEpiCs revealed a large number of transcriptional changes in response to ZIKV infection, including type I interferon signaling genes and anti-viral response genes. Our results suggest that hRPTEpiCs are a potential reservoir of ZIKV in the human urinary system, providing a possible explanation for the prolonged persistency of ZIKV in patients’ urine.Emerging Microbes & Infections (2017) 6, e77; doi:10.1038/emi.2017.67; published online 23 August 2017
Highlights
A Zika virus (ZIKV) infection is typically accompanied by mild symptoms that are present in 20% infected individuals.[1]
Our results suggest that hRPTEpiCs are a potential reservoir of ZIKV in the human urinary system, providing a possible explanation for the prolonged persistency of ZIKV in patients’ urine
Buffered saline or 1 × 105 plaque-forming unit (PFU) of SZ01 ZIKV was inoculated into AG6 mice via i.p. injection
Summary
A Zika virus (ZIKV) infection is typically accompanied by mild symptoms that are present in 20% infected individuals.[1]. It has been reported that sexual transmission of ZIKV can occur from males to females,[14,15,16] males to males[17] and, in one suspected case, a female to a male.[18] ZIKV may be transmitted from sexual partners without ZIKV-related symptoms.[16] ZIKV can exist in human semen[19,20] and in the genital tract.[21,22,23] In support of these clinical findings, studies using mouse models have shown that ZIKV can infect and replicate in the vagina[24,25] and that infection of testes led to testis damage and male infertility.[26,27] These studies uncovered a ZIKV reservoir in the reproductive system apart from that in the nervous system. ZIKV has been reported to exist in the urine of adults[28,29,30,31,32] and in neonates[29] as well as in the amniotic fluids (composed primarily of fetal urine) of ZIKV-infected fetuses.[33,34] Interestingly, in most patients ZIKV RNA cannot be detected in the sera after the first week of illness,[35,36] their urine samples have detectable levels of ZIKV RNA until at least 2 weeks after the onset of symptoms.[30,36,37,38] The United
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