Transcriptional analysis of primary human monocyte-derived dendritic cells (moDCs) infected with different Zika virus strains and YF17D virus
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Swee Sen Kwek
PROVIDER: E-MTAB-6192 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Zika virus (ZIKV) is a mosquito-transmitted positive-sense RNA virus in the family Flaviviridae. ZIKV infections are associated with neurodevelopmental deficiencies termed Congenital Zika Syndrome. ZIKV strains are grouped into three phylogenetic lineages: East African, West African, and Asian, which contains the American lineage. RNA virus genomes exist as genetically-related sequences. The heterogeneity of these viral populations is implicated in viral fitness, and genome diversity is correlated to virulence. This study examines genetic diversity of representative ZIKV strains from all lineages utilizing next generation sequencing (NGS). Inter-lineage diversity results indicate that ZIKV lineages differ broadly from each other; however, intra-lineage comparisons of American ZIKV strains isolated from human serum or placenta show differences in diversity when compared to ZIKVs from Asia and West Africa. This study describes the first comprehensive NGS analysis of all ZIKV lineages and posits that sub-consensus-level diversity may provide a framework for understanding ZIKV fitness during infection.
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Project description:Zika virus (ZIKV) is a mosquito-borne flavivirus that caused an epidemic in the Americas in 2016 and is linked to severe neonatal birth defects, including microcephaly and spontaneous abortion. To better understand the host response to ZIKV infection, we adapted the 10x Genomics Chromium single cell RNA sequencing (scRNA-seq) assay to simultaneously capture viral RNA and host mRNA. Using this assay, we profiled the antiviral landscape in a population of human moDCs infected with ZIKV at the single cell level. The bystander cells, which lacked detectable viral RNA, expressed an antiviral state that was enriched for genes coinciding predominantly with a type I interferon (IFN) response. Within the infected cells, viral RNA negatively correlated with type I IFN dependent and independent genes (antiviral module). We modeled the ZIKV specific antiviral state at the protein level leveraging experimentally derived protein-interaction data. We identified a highly interconnected network between the antiviral module and other host proteins. In this work, we propose a new paradigm for the antiviral response to a specific virus, combining an unbiased list of genes that highly correlate with viral RNA on a per cell basis with experimental protein interaction data. Our ZIKV-inclusive scRNA-seq assay will serve as a useful tool to gaining greater insight into the host response to ZIKV and can be applied more broadly to the flavivirus field.
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Project description:Evidence of male-to-female sexual transmission of Zika virus (ZIKV) and viral RNA in semen and sperm months after infection support a potential role for testicular cells in ZIKV propagation. Here, we demonstrate that germ cells (GC) are most susceptible to ZIKV. We find that only GC infected by ZIKV, but not those infected by dengue fever (DENV) and yellow fever virus (YFV), produce high levels of infectious virus. This observation coincides with decreased expression of interferon-stimulated gene Ifi44l in ZIKV-infected GC and over-expression of Ifi44l results in reduced ZIKV production. Using primary human testicular tissue, we demonstrate that human GC are also permissive for ZIKV infection and production. Finally, we identify berberine chloride as a potent inhibitor of ZIKV infection in both murine and human testes. Together, these studies identify a potential cellular source for propagation of ZIKV in testes and a candidate drug for preventing sexual transmission of ZIKV.
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Project description:Blood CD14+ monocytes are the frontline immunomodulators categorized into classical, intermediate or non-classical subsets, subsequently differentiating into M1 pro- or M2 anti-inflammatory macrophages upon stimulation. While Zika virus (ZIKV) rapidly establishes viremia, the target cells and immune responses, particularly during pregnancy, remain elusive. Furthermore, it is unknown whether African- and Asian-lineage ZIKV have different phenotypic impacts on host immune responses. Using human blood infection, we identified CD14+ monocytes as the primary target for African- or Asian-lineage ZIKV infection. When immunoprofiles of human blood infected with ZIKV were compared, a classical/intermediate monocyte-mediated M1-skewed inflammation by African-lineage ZIKV infection was observed, in contrast to a non-classical monocyte-mediated M2-skewed immunosuppression by Asian-lineage ZIKV infection. Importantly, infection of pregnant women’s blood revealed enhanced susceptibility to ZIKV infection. Specifically, Asian-lineage ZIKV infection of pregnant women’s blood led to an exacerbated M2-skewed immunosuppression of non-classical monocytes in conjunction with global suppression of type I interferon-signaling pathway and an aberrant expression of host genes associated with pregnancy complications. 30 ZIKV+ sera from symptomatic pregnant patients also showed elevated levels of M2-skewed immunosuppressive cytokines and pregnancy complication-associated fibronectin-1. This study demonstrates the differential immunomodulatory responses of blood monocytes, particularly during pregnancy, upon infection with different lineages of ZIKV.
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Project description:Zika virus (ZIKV) is responsible for a major current outbreak in the Americas and has been causally associated with fetal microcephaly as well as Guillain-Barre syndrome in adults. However, the immune responses associated with controlling ZIKV replication remain poorly characterized. Here we report a detailed analysis of innate and adaptive immune responses following ZIKV infection in 16 rhesus monkeys. A robust proinflammatory innate immune response was observed within the first few days of infection, including upregulation of type 1 interferon, which correlated directly with viral loads. Immunomodulatory pathways, including IL-10 and TGF-β, were also upregulated. ZIKV-specific neutralizing antibodies emerged rapidly by day 7 and correlated inversely with viral loads, which were undetectable in peripheral blood by day 6-10. In contrast, virus replication persisted in cerebrospinal fluid (CSF) for at least 21-42 days in 75% (3 of 4) of the monkeys that received the lowest dose of ZIKV tested, and ZIKV-specific antibodies were essentially undetectable in CSF. These data suggest that antibodies play a critical role in the rapid control of acute viremia in the periphery but were largely excluded from the central nervous system, allowing viral persistence at this immuonoprivileged site. 16 outbred, Indian-origin, adult male and female rhesus monkeys (Macaca mulatta) were included in this study. All monkeys were housed at Bioqual, Rockville, MD. Animals were infected with 103-106 pfu (106-109 vp) of our ZIKV-BR or ZIKV-PR challenge stocks by the s.q. route (N=2/group). All animal studies were approved by the appropriate Institutional Animal Care and Use Committee (IACUC).
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Project description:The recent outbreaks of Zika virus (ZIKV) and its association with birth defects known as Congenital Zika Syndrome warrant investigation on the molecular processes related to its infection and pathogenesis. Among the flavivirus family, only ZIKV is linked to microcephaly as announced by World Health Organization, suggesting uniqueness of ZIKV infection compared to other members. By analyzing the ZIKV-host interactome, we found that the key microRNA (miRNA) processing enzyme Dicer was a leading target of ZIKV capsid protein in neural stem cells (NSCs), and its deficiency facilitated ZIKV infection. Mechanistically, ZIKV capsid can directly interact with Dicer and block its ribonuclease activity, dampening the production of host miRNAs that are essential for neurogenesis. Interestingly, this capsid-mediated immune evasion is specific to ZIKV because capsid proteins from other close flaviviruses, e.g., dengue, yellow fever and West Nile viruses, cannot bind to Dicer or inhibit its function. By molecular mapping, we defined a ZIKV capsid H41R mutant with loss of interaction to Dicer and no longer affecting its activity. More importantly, ZIKV H41R mutant exerted almost no impact on neurogenesis in vitro when expressed in NSCs compared to wild type capsid, and in utero infection of recombinant ZIKV-H41R mutant virus resulted in less inhibition on corticogenesis than wild-type ZIKV in mouse embryos. Interestingly, the epidemic ZIKV strain reinforces the capsid-Dicer interaction by two amino acid substitution compared to ancient Africa strain. Thus, our study demonstrated that capsid-dependent suppression of Dicer function is a unique determinant of ZIKV immune evasion and pathogenesis, which may unveil a new mechanism for ZIKV-mediated microcephaly.
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Project description:Zika virus (ZIKV), a flavivirus transmitted primarily by Aedes mosquitoes, has spread to 59 countries and territories throughout the world. ZIKV-infected patients can have several symptoms and there is scientific consensus that ZIKV is a cause of microcephaly. Most studies are focusing on the central nervous system (CNS), and it is largely unknown whether ZIKV also affects the developing peripheral nervous system. Here, using a human pluripotent stem cell-based model, we demonstrated that Puerto Rican ZIKV strain, PRVABC59, efficiently infects human neural crest cells (hNCCs). In contrast to little infection of CNS neurons, ZIKV readily infects human peripheral neurons (hPNs), leading to cell death. Global gene expression analyses of infected hNCCs and hPNs reveal transcriptional dysregulation, notably of cell-death- and cell-cycle-related pathways. Our results identify hNCCs and hPNs as a direct ZIKV target and provide a framework to investigate the ZIKV pathology on the peripheral neurons.
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Project description:Human infection with the flavivirus ZIKA (ZIKV) causes severe neurological, immunological, and developmental defects. Despite recent progress, the mechanisms by which ZIKV infection alters host transcriptional and translational programs remains unclear. Here, we report that ZIKV infection has profound effects on the topology and function of N6-adenosine methylation (m6A) of both viral and human RNAs. m6A and 2′-O-methylated nucleosides are abundant in ZIKV genomic RNA, and m6A-seq identified 12 m6A peaks spanning the full length of ZIKV RNA. m6A abundance in ZIKV RNA is controlled by the host methyltransferases METTL3 and METTL14 and the demethylase ALKBH5. Profiling of the m6A methylome of host mRNAs revealed that ZIKV infection alters the location of m6A in mRNAs, the methylation motifs, and the target genes modified by the methyltransferases. Our results identify a new mechanism by which ZIKV interacts with and alters the function of the host cell.
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