Zika virus infects renal proximal tubular epithelial cells with prolonged persistency and cytopathic effects

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.

Detection of a novel African-lineage-like Zika virus naturally infecting free-living neotropical primates in Southern Brazil

“…The most remarkable lesions observed were affecting kidney and liver. Inflamatory infiltrates and viral persistence in several tissues are described after ZIKV experimental infection 14,15 . ZIKV induces apoptosis in kidney cells and lymphocytic infiltration in infected mice, and African-lineage ZIKV is better adapted to human kidney cells than Asian-lineage ZIKV 14 .…”

“…Inflamatory infiltrates and viral persistence in several tissues are described after ZIKV experimental infection 14,15 . ZIKV induces apoptosis in kidney cells and lymphocytic infiltration in infected mice, and African-lineage ZIKV is better adapted to human kidney cells than Asian-lineage ZIKV 14 . NHP studied here did not present other causes for the infiltrates and necrosis observed in kidney tissue, nonetheless Mild inflammatory infiltrates without a defined cause can occur in kidney, specially in free ranging NHP, therefore it is difficult to draw conclusions regarding the histopathological findings in the kidneys.…”

“…Pathological findings in human fetuses infected with ZIKV include thickening of leptomeninges, subcortical calcifications with cortical displacement, ventricular derangement, astrocytosis, macrophagic infiltrate and microglial proliferation 10 . ZIKV infection in mice causes apoptosis, lymphocytic infiltrate and persistent infection in glomerular and tubular cells, moreover, ZIKV lineage MR 766 produces higher viremia and cytopathic effects in kidney cells than the Asian lineage 14 . Inoculation of Asian ZIKV in Rhesus monkey spread to several tissues including kidney, bladder, uterus, with persistence in central nervous tissue (CNS), joints and lymphnodes.…”

Neglected Tropical Diseases with an Impact on Kidney Function

“…In Brazil, the most recent outbreaks have affected millions of people [20,21]. In recent years, other arbovirosis has caused epidemics in the Caribbean region and Latin America: chikungunya fever and Zika virus infection, and renal involvement has already been reported [22][23][24][25][26][27].…”

Impact of Chronic Kidney Disease on Chikungunya Virus Infection Clinical Manifestations and Outcome: Highlights during an Outbreak in Northeastern Brazil

“…8 It is possible that a direct kidney damage can be caused by CHIKV (cytopathic effect of viral proteins on glomerular and tubular cells), associated with immune complex deposition on glomeruli, as has been described for other arbovirus infections such as dengue and Zika. [9][10][11][12] The aim of this study is to describe the impact of chronic kidney disease (CKD) on CHIKV infection clinical manifestations and outcome during a large outbreak in the state of Ceara in northeastern Brazil.…”