Jul 11, 2019 zika virus is a mosquitoborne viral disease that emerged as a significant health problem in the americas after an epidemic in 2015. Route of infection influences zika virus shedding in a. Pathophysiology and mechanisms of zika virus infection in. Mar 01, 2018 zika virus zikv is a mosquitoborne flavivirus associated with severe neonatal birth defects, but the causative mechanism is incompletely understood. Pdf zika virus reveals broad tissue and cell tropism during. Zika virus zikv has emerged as a global health threat due to its neuro teratogenic. Since zika virus was first isolated in 1947, the disease has spread outside of africa, mainly into southeast asia. The major host tissues of viral persistence and propagation are neural tissue, ocular tissue. Zika virus rna replication and persistence in brain and. Zika virus entry mechanisms in human cells request pdf. May 11, 2016 the ongoing zika virus zikv epidemic and unexpected clinical outcomes, including guillainbarre syndrome and birth defects, has brought an urgent need for animal models. Severe zika virus pathogenesis and reduces apoptosis in microglia andrew k.
Cell death and zika virus patua repositorio digital do instituto. Zika virus genome biology and molecular pathogenesis. May 16, 2019 the in vivo models of mouse, pig, chicken, and nonhuman primates are primarily used to investigate the teratogenicity of the virus, to study effects of the virus on specific tissues, and to study the systemic effects of a proposed antiviral agent. Zika virus transplacental transmission hofbauer cells neurotropism. Pathophysiology and mechanisms of zika virus infection in the. Zika virus zikv is a mosquitotransmitted flavivirus in the flavi viridae family of positivestranded rna viruses and is closely. Zika virus isolation, purification, and titration springerlink. Although we have discovered a great deal about the genome and pathogenesis of this reemergent flavivirus since this recent outbreak.
Spondweni virus spov, a member of the same serogroup as zika virus zikv, is a mosquitotransmitted flavivirus that historically has circulated in subsaharan africa. Zika virus zikv was first isolated from a sentinel rhesus macaque from the zika forest of uganda in 1947. Hughes bw, addanki kc, sriskanda an, mclean e, bagasra o 2016 infectivity of immature neurons to zika virus. Infection via mosquito bite alters zika virus tissue tropism and replication kinetics in rhesus macaques. Zika virus is an rna virus of the family flaviviridae, and is closely related to other members of this family, including dengue, yellow fever, west nile, and japanese encephalitis viruses. Congenital zikv infection produces a range of mild to severe pathologies, including microcephaly. Infection via mosquito bite alters zika virus tissue tropism. Here we show that the envelope protein e of zikv is polyubiquitinated by the e3 ubiquitin ligase trim7 through lys63 k63linked.
Complementary mechanisms potentially involved in the. Referral to maternalfetal medicine specialist is recommended. The virus exhibits wide tissue tropism in the mammalian host. Zika virus zikv is an important pathogen transmitted to humans by the mosquito vector aedes aegypti. Although zika virus zikv was isolated approximately 70 years ago, few experimental studies had been published prior to 2016. Zika virus tropism during early infection of the testicular interstitium. A natural polymorphism in zika virus ns2a protein responsible of. The rapid spread of zika virus zikv and its association with abnormal brain development constitute a global health emergency. Miner jj, diamond ms 2017 zika virus pathogenesis and tissue tropism. Molecular responses and tissue tropism in the mammalian host. Zika virus pathogenesis and tissue tropism cell host microbe.
Zika virus tissue and blood compartmentalization in acute. Resource a mouse model of zika virus pathogenesis graphical abstract highlights d development of a mouse model of zikv pathogenesis including multiple viral strains d ifnar1 mice sustain high viral burden in brain, spinal cord, and testes d zikv can establish viremia in the absence of clinical signs in mice d zikv mouse model may be useful for vaccine and antiviral. Denv tropismcell and tissue tropism of denv may have a major impact on th. Especially concerning are cases where zika is linked to the development of brain abnormalities in newborns. In 2015, public awareness of zika virus zikv rose in response to alarming statistics of infants with microcephaly being born to women who were infected with the virus during pregnancy, triggering global concern over these potentially devastating consequences. The emergence of zika virus zikv as a major public health threat has focused research on understanding virus biology and. Zika virus infection was clinically and epidemiologically. Zika, dengue and yellow fever viruses induce differential. Zika virus cell tropism in the developing human brain and.
Zika virus infection in human placental tissue explants is. Numerous small animal models have been used in various zikv pathogenicity studies, however, they are often performed using immunodeficient or. Flavivirus ns1 triggers tissuespecific vascular endothelial. The immunological and virological events that contribute to the establishment of zika virus zikv infection in humans are unclear. In 1952, the chuku strain of spov was isolated from a patient in nigeria, but crossreactivity in neutralization tests led to its initial misclassification as a zikv strain. Infection via mosquito bite alters zika virus tissue.
Dec, 2016 zika virus zikv is a mosquitoborne flavivirus that has rapidly spread through the americas and has been associated with fetal abnormalities, including microcephaly. Request pdf zika virus pathogenesis and tissue tropism although zika virus zikv was isolated approximately 70 years ago, few experimental studies had been published prior to 2016. The tissue tropism and pathogenesis of spov in mice has not been extensively explored, although historical studies. Zikv is able to infect several tissues and organs and, importantly, has been associated with microcephaly and central nervous system abnormalities in fetuses and newborn babies of mothers exposed to zikv during pregnancy, as well as neurological diseases such as guillainbarre.
Zika virus pathogenesis and current therapeutic advances request. The virus has emerged in the recent years and spread in the pacific area and the americas, where it has caused large human. Zika virus crosses placenta, reaching the fetus to target the neuronal tissue adibi et al. This has resulted in zikv being declared a public health emergency and has greatly accelerated the pace of zikv research and discovery. Request pdf zika virus pathogenesis and tissue tropism although zika virus zikv was isolated approximately 70 years ago, few. Authors jonathan j miner 1, michael s diamond 2 affiliations 1 department of medicine, washington university. The recent outbreak of zika virus zikv in the western hemisphere has prompted accelerated research and discovery in this area. Zika virus zikv is an emerging rna virus in the widespread flavivirus genus. Zika virus zikv belongs to the family flaviviridae, and is related to other viruses that cause human diseases. Zika virus tropism during early infection of the testicular interstitium and its role in viral pathogenesis in the testes plos pathog.
Ab zika virus zikv belongs to the family flaviviridae, and is related to other viruses that cause human diseases. Zika virus structure, maturation, and receptors oxford academic. Most recently, zikv infection has been linked with both autoimmune disorders in. Zika virus zikv is a mosquitoborne virus member of the flavivirus. We use primary human tissue to show that radial glia and astrocytes are more susceptible. Zika virus zikv outbreaks have raised alarm because of reports of congenital zika virus syndrome in infants. Pdf zika virus reveals broad tissue and cell tropism. Dec 11, 2018 the prevalence of zika virus infection was 7. Infection with any of the denv serotypes may be asymptomatic in the majority of. Jun, 2016 positive or inconclusive zika virus testing results antepartum consider serial ultrasounds every 3 4 weeks. Envelope protein ubiquitination drives entry and pathogenesis. The zika virus epidemic has brought an urgent need for animal models. Zika virus zikv is a mosquito borne flavivirus that has rapidly spread through the americas and has been associated with fetal abnormalities, including microcephaly. Our results demonstrate that the ubiquitination of zikv e is an important determinant of virus entry, tropism and pathogenesis.
Pathogenesis and molecular mechanisms of zika virus. Loss of the tam receptor axl ameliorates severe zika virus. Department of pathology triaging zika virus in pathology. Jan 31, 2017 animal models of zika virus zikv are needed to better understand tropism and pathogenesis and to test candidate vaccines and therapies to curtail the pandemic. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Markert, 3 sandra junglen, 1, 2 and christian drosten 1, 5.
Testing of frozen placental tissue and cord tissue for zika virus rna. Unlike other flaviviruses, zikv infection can cause congenital neurological disorders and replicates efficiently in reproductive tissues. Jun 15, 2016 zika virus in the human placenta and developing brain. Hastings, 1katherine hastings,2 ryuta uraki, 1jesse hwang, hallie gaitsch, khushwant dhaliwal, eric williamson, 1and erol fikrig,3 4 summary the tam receptor, axl, has been implicated as a candidate entry receptor for zika virus zikv infec. Infection via mosquito bite alters zika virus tissue tropism and replication kinetics in rhesus macaques nat commun. Aug 22, 2018 the immunological and virological events that contribute to the establishment of zika virus zikv infection in humans are unclear. Flaviviridae, flavivirus is primarily transmitted by aedes aegypti mosquitoes, but animal models of zikv pathogenesis have relied on needle inoculation 1,2,3,4,5,6,7. Mice lacking interferon ab signaling develop neurological disease and succumb to infection with high viral loadsinthebrain,spinalcord,andtestes, consistent with severe manifestations of zika virus in humans. To understand how microcephaly develops, it is important to identify which cell types of the developing brain are susceptible to infection.
Zika virus tropism during early infection of the testicular. Unlike other flaviviruses, zika can be transmitted sexually, increasing the potential for intraspecies infection. Humoral immune responses against zika virus infection and. Zika virus damages the human placental barrier and. Vectormediated transmission from aedes africanus was assumed to be the likeliest means of acquisition dick et al. Dengue and zika virus crossreactive human monoclonal antibodies protect against spondweni virus infection and pathogenesis in mice. To understand the pathophysiology of zikv infection, we used models of the developing brain that faithfully recapitulate the tissue architecture in early to midgestation. Frontiers zika virus transmission through blood tissue. Zika virus pathogenesis and tissue tropism sciencedirect.
It has been postulated that zikv genome changes may have evolved to modify tissue tropism, becoming more neurotrophic, andor more. A mouse model of zika virus pathogenesis sciencedirect. This can cause destruction of the periventricular white matter, calcifications, and loss of the cortex in the brain, resulting in microencephaly, or a. Author summary zika virus zikv has recently gained global media attention as a major emerging pathogen. Immense scientific efforts have been directed toward zika virus zikv over the last 2 years, leading to deeper insights into zikv parthenogenesis and innate and adaptive immune responses to zikv infection, the identification of host factors involved in transplacental zikv transmission, the establishment of novel mouse and primate disease models, and the development and early evaluation of. Zika virus in the human placenta and developing brain.
Role of autophagy in zika virus infection and pathogenesis. Zika virus zikv infection is associated with microcephaly in fetuses, but the pathogenesis of zikvrelated microcephaly is not well understood. Therefore, identification of cells that support zikv replication in the placenta is especially important to understand the mechanisms utilized by the virus to cross the placenta and to further design antizikv drugs. Zika virus infects intermediate progenitor cells and post. Dengue and zika virus crossreactive human monoclonal. Zika virus reveals broad tissue and cell tropism during the first trimester of pregnancy. Here, we show that robust cellular innate immune responses arising early in the blood and tissues in response to zikv infection are significantly stronger in males and correlate with increased viral persistence. Zika virus infection in human placental tissue explants is enhanced in the presence of dengue virus antibodies invitro kyra hermanns, 1, 2 claudia gohner, 2, 3 anne kopp, 1, 2 andre schmidt, 3 waltraut m. Zika virus zikv is an arbovirus belonging to the flaviviridae family. Until 2007, sporadic cases of zika virus illness in humans were reported. Humans and rhesus macaques possess similar fetal development and placental biology that is not shared between humans and rodents. Therefore, identification of cells that support zikv replication in the placenta is especially important to understand the mechanisms utilized by the virus to cross the. Route of infection influences zika virus shedding in a guinea. Autophagy is an evolutionarily conserved cellular pathway that culminates in lysosomal degradation of selected substrates.
Zika virus rna in brain and placental tissue performed a quantitative realtime rt. To understand the pathophysiology of zikv infection, we used models of the developing brain that faithfully. The recent spread of zikv to countries in the western hemisphere is associated with reports of microcephaly, congenital malformations, and guillainbarre syndrome. Recent studies have suggested a role for autophagy in zika virus zikv replication by demonstrating the accumulation of autophagic vesicles following zikv infection in both in vitro and. Request pdf zika virus pathogenesis and current therapeutic advances zika virus zikv is an emerging arthropodborne flavivirus that, upon infection. Mouse and nonhuman primate models now serve as useful platforms to study zika virus zikv pathogenesis, candidate therapies, and vaccines, but they rely on needle inoculation of virus. Zika virus pathogenesis and tissue tropism request pdf. Here we show that zikv infects the subventricular zone in human fetal brain tissues and that the tissue tropism broadens with the progression of gestation.
Zikv shares sequence homology and early clinical manifestations with yellow fever virus yfv and dengue virus denv and are all transmitted in urban cycles by the same species of mosquitoes. This tissue specific tropism is partially determined by the capacity of ns1 to bind endothelial cells and is characterized by disruption of endothelial glycocalyx components. Autophagy can serve dual roles in virus infection with either pro or antiviral functions depending on the virus and the stage of the viral replication cycle. We evaluated infection and pathogenesis with contemporary and historical zikv strains in immunocompetent mice and mice lacking components of the antiviral response. Postpartum histopathologic examination of the placenta and umbilical cord.
Feb 19, 2018 pdf zika virus zikv was initially thought to cause only mild, selflimiting symptoms. We identify the brain cell populations that are most susceptible to zikv. Early cellular innate immune responses drive zika viral. We assessed the tissue tropism of spov by measuring the viral burden at 7, 14, and 21 dpi. Humoral immune responses against zika virus infection and the. Due to the recent epidemic of zika virus zikv infection and resulting sequelae, as well as concerns about both the sexual and vertical transmission of the virus, renewed attention has been paid to the pathogenesis of this unique arbovirus. Zika virus isolation, purification, and titration springer nature. Aug 21, 2016 zika virus is a mosquitoborne flavivirus discovered in uganda in 1947.
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