title: 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.
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China.|Department of Microbiology, The University of Hong Kong, Hong Kong, China.|Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China.|Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China.
authors.forename: Jasper Fuk-Woo
authors.initials: JF
authors.lastname: Chan
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Cyril Chik-Yan
authors.initials: CC
authors.lastname: Yip
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Jessica Oi-Ling
authors.initials: JO
authors.lastname: Tsang
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Kah-Meng
authors.initials: KM
authors.lastname: Tee
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Jian-Piao
authors.initials: JP
authors.lastname: Cai
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Kenn Ka-Heng
authors.initials: KK
authors.lastname: Chik
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Chris Chung-Sing
authors.initials: CC
authors.lastname: Chan
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Garnet Kwan-Yue
authors.initials: GK
authors.lastname: Choi
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Sridhar
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Anna Jinxia
authors.initials: AJ
authors.lastname: Zhang
authors.affiliation: Department of Pathogen Biology, Hainan Medical University, Haikou, Hainan 571101, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Ophthalmology, The University of Hong Kong, Hong Kong, China.|Resarch Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong, China.|State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, China.
authors.forename: Kin
authors.initials: K
authors.lastname: Chiu
authors.affiliation: Department of Ophthalmology, The University of Hong Kong, Hong Kong, China.|Resarch Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong, China.
authors.forename: Amy Cheuk-Yin
authors.initials: AC
authors.lastname: Lo
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.
authors.forename: Sai-Wah
authors.initials: SW
authors.lastname: Tsao
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong, China.|Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China.
authors.forename: Kin-Hang
authors.initials: KH
authors.lastname: Kok
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.
authors.forename: Dong-Yan
authors.initials: DY
authors.lastname: Jin
authors.affiliation: Department of Microbiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Kwok-Hung
authors.initials: KH
authors.lastname: Chan
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China.|Department of Microbiology, The University of Hong Kong, Hong Kong, China.|Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China.|Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China.|The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong, China.
authors.forename: Kwok-Yung
authors.initials: KY
authors.lastname: Yuen
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003716:Dengue Virus / Q000254:growth & development / Q000502:physiology; D004197:Disease Reservoirs; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D000072138:Mosquito Vectors / Q000821:virology; D011247:Pregnancy; D011323:Primates; D011817:Rabbits; D013552:Swine; D014709:Vero Cells; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D056189:Viral Tropism; D014779:Virus Replication; D000071244:Zika Virus / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity / Q000502:physiology*; D000071243:Zika Virus Infection / Q000635:transmission / Q000821:virology*
chemical_list: D017361:Viral Nonstructural Proteins