Differential cell line susceptibility to the emerging Zika virus: implications for disease pathogenesis, non-vector-borne human transmission and animal reservoirs

Abstract

Zika virus (ZIKV) is unique among human-pathogenic flaviviruses by its association with congenital anomalies and trans-placental and sexual human-to-human transmission. Although the pathogenesis of ZIKV-associated neurological complications has been reported in recent studies, key questions on the pathogenesis of the other clinical manifestations, non-vector-borne transmission and potential animal reservoirs of ZIKV remain unanswered. We systematically characterized the differential cell line susceptibility of 18 human and 15 nonhuman cell lines to two ZIKV isolates (human and primate) and dengue virus type 2 (DENV-2). Productive ZIKV replication (⩾2 log increase in viral load, ZIKV nonstructural protein-1 (NS1) protein expression and cytopathic effects (CPE)) was found in the placental (JEG-3), neuronal (SF268), muscle (RD), retinal (ARPE19), pulmonary (Hep-2 and HFL), colonic (Caco-2),and hepatic (Huh-7) cell lines. These findings helped to explain the trans-placental transmission and other clinical manifestations of ZIKV. Notably, the prostatic (LNCaP), testicular (833KE) and renal (HEK) cell lines showed increased ZIKV load and/or NS1 protein expression without inducing CPE, suggesting their potential roles in sexual transmission with persistent viral replication at these anatomical sites. Comparatively, none of the placental and genital tract cell lines allowed efficient DENV-2 replication. Among the nonhuman cell lines, nonhuman primate (Vero and LLC-MK2), pig (PK-15), rabbit (RK-13), hamster (BHK21) and chicken (DF-1) cell lines supported productive ZIKV replication. These animal species may be important reservoirs and/or potential animal models for ZIKV. The findings in our study help to explain the viral shedding pattern, transmission and pathogenesis of the rapidly disseminating ZIKV, and are useful for optimizing laboratory diagnostics and studies on the pathogenesis and counter-measures of ZIKV.

Advances in Zika Virus Research: Stem Cell Models, Challenges, and Opportunities

“…ZIKV preferentially infects spermatogonia, primary spermatocytes, and Sertoli cells in the testis, resulting in cell death and destruction of the seminiferous tubules. In vitro studies have further shown that many cells lines derived from humans, primates, rodents, pigs, rabbit hamsters, chickens and mosquitoes, support productive ZIKV replication in vitro (Chan et al, 2016). These studies paved the way to use genetically tractable human cell types derived from iPSCs to investigate the underlying pathophysiology and molecular mechanisms of ZIKV infection.…”

Características de la estructura molecular de las proteínas E del virus Zika y E1 del virus de la rubeola. Posibles implicaciones en el neurotropismo y en las alteraciones del sistema nervioso

“…Aunque la caracterización de la expresión de Axl en las células del sistema nervioso central puede explicar la entrada del ZIKV, es necesario adelantar más estudios para confirmar si dicho receptor determina el tropismo celular del virus en células neuronales cultivadas y en vivo, así como su capacidad para infectar fibroblastos de piel (43) y células epiteliales de cordón umbilical (44). Debe señalarse, además, que todavía no se han determinado completamente los receptores celulares del ZIKV.…”

“…Dicho neurotropismo diferencial durante el desarrollo se ha observado en estudios recientes en ratones, los cuales evidenciaron altos grados de infección por el ZIKV en el cerebro, la médula espinal (6,46) y las células epiteliales (44,46). Aunque no se sabe por qué algunas células epiteliales y neuronales son más propensas a la infección por el ZIKV que otras (por ejemplo, las neuronas progenitoras lo son más que las corticales maduras) (5,8,47), se podrían presentar diferentes mecanismos de entrada mediados por distintos tipos de receptores (por ejemplo, Axl o TAR), así como tasas de infección diferentes debido a cambios en el grado de expresión de factores del huésped requeridos para la entrada (por ejemplo, TLR3), la replicación o el ensamblaje del ZIKV (42).…”

Global Alert: Zika Virus-an Emerging Arbovirus

“…Thus, they suggested that this provides evidence for the association between the virus and microcephaly. In contrast, Chan et al [37] found both viral replication and cytopathic effects in neuronal, placental, hepatic, colonic, retinal, pulmonary, and muscular cell lines. They found viral replication but not cytopathic effects in renal, testicular, and prostate cells.…”