scholarly journals ADP-Ribosyltransferase PARP11 Suppresses Zika Virus in Synergy with PARP12

2021 ◽  
Author(s):  
Lili Li ◽  
Yueyue Shi ◽  
Sirui Li ◽  
Junxiao Liu ◽  
Shulong Zu ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neurological Complications ◽  
Host Cells ◽  
Interferon Response ◽  
Type I ◽  
Zikv Infection ◽  
Interferon Stimulated Genes ◽  
Ns3 Protein ◽  
Global Threat ◽  
Adp Ribosyltransferase

Abstract Zika virus (ZIKV) infection and ZIKV epidemic have been continuously spreading silently throughout the world and its associated microcephaly and other serious congenital neurological complications poses a significant global threat to public health. ZIKV infection stimulates type I interferon response in host cells which suppresses viral replication by inducing the expression of interferon-stimulated genes (ISGs). Here, we identified ADP-ribosyltransferase PARP11 as an anti-ZIKV ISG and found that PARP11 suppressed ZIKV independently on itself PARP enzyme activity. Furthermore, PARP11 interacted with PARP12 and promoted PARP12-mediating ZIKV NS1 and NS3 protein degradation. Homo family PARP11 and PARP12 cooperated with each other on ZIKV suppression and the anti-ZIKV function of PARP11 mostly dependent on the existence of PARP12. Our findings have broadened the understanding of the anti-viral function of PARP11, and more importantly suggest a potential therapeutics target against ZIKV infection.

scholarly journals ADP-ribosyltransferase PARP11 suppresses Zika virus in synergy with PARP12

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lili Li ◽  
Yueyue Shi ◽  
Sirui Li ◽  
Junxiao Liu ◽  
Shulong Zu ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Cell Lines ◽  
Zika Virus ◽  
Hek293t Cell ◽  
Host Cells ◽  
Interferon Response ◽  
Type I ◽  
Zikv Infection ◽  
Ns3 Protein ◽  
Adp Ribosyltransferase

Abstract Background Zika virus (ZIKV) infection and ZIKV epidemic have been continuously spreading silently throughout the world and its associated microcephaly and other serious congenital neurological complications poses a significant global threat to public health. Type I interferon response to ZIKV infection in host cells suppresses viral replication by inducing the expression of interferon-stimulated genes (ISGs). Methods The study aims to demonstrate the anti-ZIKV mechanism of PARP11. PARP11 knock out and overexpressing A549 cell lines were constructed to evaluate the anti-ZIKV function of PARP11. PARP11−/−, PARP12−/− and PARP11−/−PARP12−/− HEK293T cell lines were constructed to explain the synergistic effect of PARP11 and PARP12 on NS1 and NS3 protein degradation. Western blotting, immunofluorescence and immunoprecipitation assay were performed to illustrate the interaction between PARP11 and PARP12. Results Both mRNA and protein levels of PARP11 were induced in WT but not IFNAR1−/− cells in response to IFNα or IFNβ stimulation and ZIKV infection. ZIKV replication was suppressed in cells expressed PARP11 but was enhanced in PARP11−/− cells. PARP11 suppressed ZIKV independently on itself PARP enzyme activity. PARP11 interacted with PARP12 and promoted PARP12-mediated ZIKV NS1 and NS3 protein degradation. Conclusion We identified ADP-ribosyltransferase PARP11 as an anti-ZIKV ISG and found that it cooperated with PARP12 to enhance ZIKV NS1 and NS3 protein degradation. Our findings have broadened the understanding of the anti-viral function of ADP-ribosyltransferase family members, and provided potential therapeutic targets against viral ZIKV infection.

scholarly journals Adaptation to host cell environment during experimental evolution of Zika virus

2021 ◽  
Author(s):  
Vincent Grass ◽  
Emilie Hardy ◽  
Kassian Kobert ◽  
Soheil Rastgou Talemi ◽  
Elodie Décembre ◽  
...  
Keyword(s):  
Host Cell ◽  
Zika Virus ◽  
Immune Escape ◽  
Viral Evolution ◽  
Time Lag ◽  
Host Cells ◽  
Host Responses ◽  
Type I ◽  
Zikv Infection ◽  
Cellular Environment

Abstract Zika virus (ZIKV) infection can cause important developmental and neurological defects in Humans. Type I/III interferon responses control ZIKV infection and pathological processes, yet the virus has evolved various mechanisms to defeat these host responses. Here, we established a pipeline to delineate at high-resolution the genetic evolution of ZIKV in a controlled host cell environment. We uncovered that serially passaged ZIKV acquired increased infectivity and simultaneously developed a resistance to TLR3-induced restriction. We built a mathematical model that suggests that the increased infectivity is due to a reduced time-lag between infection and viral replication. We found that this adaptation is cell-type specific, suggesting that different cell environments may drive viral evolution along different routes. Deep-sequencing of ZIKV populations pinpointed mutations whose increased frequencies temporally coincide with the acquisition of the adapted phenotype. We functionally validated S455L, a substitution in ZIKV envelope (E) protein, recapitulating the adapted phenotype. Its positioning on the E structure suggests a putative function in protein refolding/stability. Taken together, our results uncovered ZIKV adaptations to the cellular environment leading to accelerated replication onset coupled with resistance to TLR3-induced antiviral response. Our work provides insights into Zika virus adaptation to host cells and immune escape mechanisms.

scholarly journals The Robust Restriction of Zika Virus by Type-I Interferon in A549 Cells Varies by Viral Lineage and Is Not Determined by IFITM3

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 503 ◽  
Author(s):  
Theodore A. Gobillot ◽  
Daryl Humes ◽  
Amit Sharma ◽  
Caroline Kikawa ◽  
Julie Overbaugh
Keyword(s):  
Cell Line ◽  
Zika Virus ◽  
Type I Interferon ◽  
A549 Cells ◽  
Antiviral Effect ◽  
Type I ◽  
Zikv Infection ◽  
Interferon Stimulated Genes ◽  
Fold Reduction ◽  
Viral Lineage

Type-I interferon (IFN-I) is a major antiviral host response but its impact on Zika virus (ZIKV) replication is not well defined, particularly as it relates to different circulating strains. Interferon stimulated genes (ISGs) that inhibit ZIKV, such as IFITM3, have been identified largely using overexpression studies. Here, we tested whether diverse ZIKV strains differed in their susceptibility to IFN-I-mediated restriction and the contribution of IFITM3 to this restriction. We identified a robust IFN-I-mediated antiviral effect on ZIKV replication (>100-fold reduction) in A549 cells, a commonly used cell line to study ZIKV replication. The extent of inhibition depended on the IFN-I type and the virus strain tested. Viruses from the American pathogenic outbreak were more sensitive to IFNα (p = 0.049) and IFNβ (p = 0.09) than African-lineage strains, which have not been linked to severe pathogenesis. Knocking out IFITM3 expression did not dampen the IFN-I antiviral effect and only high overexpression of IFITM3 led to ZIKV inhibition. Moreover, IFITM3 expression levels in different cells were not associated with IFN-mediated ZIKV inhibition. Taken together, our findings indicate that there is a robust IFN-I-mediated antiviral effect on ZIKV infection, particularly for American viruses, that is not due to IFITM3. A549 cells, which are a commonly used cell line to study ZIKV replication, present an opportunity for the discovery of novel antiviral ISGs against ZIKV.

scholarly journals Azithromycin Protects against Zika Virus Infection by Upregulating Virus-Induced Type I and III Interferon Responses

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Chunfeng Li ◽  
Shulong Zu ◽  
Yong-Qiang Deng ◽  
Dapei Li ◽  
Kislay Parvatiyar ◽  
...  
Keyword(s):  
Zika Virus ◽  
Antiviral Agent ◽  
Type I ◽  
Zikv Infection ◽  
Interferon Stimulated Genes ◽  
Pathogen Recognition Receptors ◽  
Congenital Microcephaly ◽  
Interferon Responses ◽  
Potential Use

ABSTRACT Azithromycin (AZM) is a widely used antibiotic, with additional antiviral and anti-inflammatory properties that remain poorly understood. Although Zika virus (ZIKV) poses a significant threat to global health, there are currently no vaccines or effective therapeutics against it. Here, we report that AZM effectively suppresses ZIKV infection in vitro by targeting a late stage in the viral life cycle. In addition, AZM upregulates the expression of host type I and III interferons and several of their downstream interferon-stimulated genes in response to ZIKV infection. In particular, we found that AZM upregulated the expression of MDA5 and RIG-I (pathogen recognition receptors induced by ZIKV infection) and increased the levels of phosphorylated TBK1 and IRF3. Interestingly, AZM treatment upregulated the phosphorylation of TBK1 without inducing the phosphorylation of IRF3 by itself. These findings highlight the potential use of AZM as a broad antiviral agent to combat viral infection and to prevent devastating ZIKV-associated clinical outcomes, such as congenital microcephaly.

scholarly journals Gas6 drives Zika virus-induced neurological complications in humans and congenital syndrome in immunocompetent mice

2021 ◽  
Author(s):  
Joao Luiz Silva-Filho ◽  
Lilian Gomes de Oliveira ◽  
Leticia Monteiro ◽  
Pierina L. Parise ◽  
Nagela G. Zanluqui ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neurological Disorders ◽  
Congenital Malformations ◽  
Neurological Complications ◽  
Adverse Outcomes ◽  
Type I ◽  
Zikv Infection ◽  
Immunocompetent Mice ◽  
Transplacental Infection ◽  
Brain Barriers

ABSTRACTZika virus (ZIKV) has the ability to cross placental and brain barriers, causing congenital malformations in neonates and neurological disorders in adults. However, the pathogenic mechanisms of ZIKV-induced neurological complications in adults and congenital malformations remain unknown. Gas6 is a soluble TAM receptor ligand able to promote flavivirus internalization and downregulation of immune responses. Here we demonstrate high Gas6 levels in the serum of patients with neurological complications which correlated with downregulation of genes associated with the type I IFN responses as consequence of Socs1 upregulation. Gas6 gamma-carboxylation is essential for ZIKV replication in monocytes, the main source of this protein. Gas6 also facilitates ZIKV replication in adult immunocompetent mice enabled susceptibility to transplacental infection and congenital malformations. Our data thus indicate that ZIKV promotes the upregulation of its ligand Gas6, which contributes to viral infectivity and drives the development of severe adverse outcomes during ZIKV infection.

scholarly journals Positive natural selection in primate genes of the type I interferon response

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Elena N. Judd ◽  
Alison R. Gilchrist ◽  
Nicholas R. Meyerson ◽  
Sara L. Sawyer
Keyword(s):  
Natural Selection ◽  
Positive Selection ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Sequence Alignments ◽  
Multiple Sequence ◽  
Multiple Sequence Alignments ◽  
Interferon Stimulated Genes ◽  
Interferon Induction

Abstract Background The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one. Results We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, “induction” genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid. Conclusion Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.

scholarly journals Pregnancy and Zika virus

2020 ◽  
Vol 14 (2) ◽  
pp. 229-238
Author(s):  
T. V. Startseva ◽  
N. N. Kanshina ◽  
M. V. Tretyakova ◽  
V. O. Bitsadze ◽  
J. Kh. Khizroeva ◽  
...  
Keyword(s):  
Nonhuman Primate ◽  
Zika Virus ◽  
Congenital Malformations ◽  
Asymptomatic Carrier ◽  
Clinical Signs ◽  
Neurological Complications ◽  
Zikv Infection ◽  
Coronavirus Infection ◽  
Novel Coronavirus ◽  
Urban Cycle

Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) in the genus Flavivirus and the Flaviviridae family. In 1947 and 1948 ZIKV was first isolated from a nonhuman primate as well as from mosquitoes in Africa, respectively. For half a century, ZIKV infections in human were sporadic prior to 2015–2016 pandemic spreading. Transmission of ZIKV from mother to fetus can occur in any trimester of pregnancy, even if mother was an asymptomatic carrier. The clinical signs of ZIKV infection are nonspecific and can be misdiagnosed as some other infectious diseases, especially those caused by arboviruses such as Dengue and Chikungunya. ZIKV infection was solely associated with mild illness prior to the large French Polynesian and Brazil outbreaks, when severe neurological complications, Guillain–Barre syndrome and dramatically increased rate of severe congenital malformations (including microcephaly) were reported. The adaptation of ZIKV to an urban cycle in endemic areas suggests that the incidence of ZIKV infections may be underestimated. The pandemic of novel coronavirus infection (COVID-19) demonstrates that lessons from ZIKV pandemic propagation has not been learned properly.

scholarly journals Adaptation to host cell environment during experimental evolution of Zika virus

2020 ◽  
Author(s):  
Vincent Grass ◽  
Emilie Hardy ◽  
Kassian Kobert ◽  
Soheil Rastgou Talemi ◽  
Elodie Décembre ◽  
...  
Keyword(s):  
Host Cell ◽  
Human Health ◽  
Zika Virus ◽  
Viral Evolution ◽  
Time Lag ◽  
Viral Escape ◽  
Host Responses ◽  
Type I ◽  
Zikv Infection ◽  
Antiviral Responses

AbstractZika virus (ZIKV) infection can cause developmental and neurological defects and represents a threat for human health. Type I/III interferon responses control ZIKV infection and pathological processes, yet the virus has evolved various mechanisms to defeat these host responses. Here, we established a pipeline to delineate at high-resolution the genetic evolution of ZIKV in a controlled host cell environment. We uncovered that serially passaged ZIKV acquired increased infectivity, defined as the probability for one virus to initiate infection, and simultaneously developed a resistance to TLR3-induced restriction. We built a mathematical model that suggests that the increased infectivity is due to a reduced time-lag between infection and viral replication. We found that this adaptation is cell-type specific, suggesting that different cell environments may drive viral evolution along different routes. Deep-sequencing of ZIKV quasi-species pinpointed mutations whose increased frequencies temporally coincide with the acquisition of the adapted phenotype. We functionally validated a point-mutation in ZIKV envelope (E) protein recapitulating the adapted phenotype. Its positioning on the E structure suggests a putative function in protein refolding/stability. Altogether, our results uncovered ZIKV adaptations to the cell environment leading to an accelerated replication onset coupled with resistance to TLR3-induced antiviral response. Our work provides insights into viral escape mechanisms and interactions with host cell and can serve as a framework to study other viruses.Significance StatementZika virus poses a major threat to Human health worldwide. To understand how Zika virus interacts with human cells, we studied its evolution in cell cultures. We found that the viruses adapted by initiating their replication sooner after cell entry. We sequenced the genomes of the viruses evolved over time and found mutations underlying the adaptation of the virus. One mutation in the envelope viral protein is sufficient to reproduce the faster initiation of replication. Our multidisciplinary approach based on analyzing viral evolution in a controlled environment and mathematical modeling revealed how Zika virus can escape antiviral responses, and can serve as framework to study other viruses.

scholarly journals A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP

2009 ◽  
Vol 206 (9) ◽  
pp. 1899-1911 ◽  
Author(s):  
Sarah M. McWhirter ◽  
Roman Barbalat ◽  
Kathryn M. Monroe ◽  
Mary F. Fontana ◽  
Mamoru Hyodo ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Map Kinases ◽  
Second Messenger ◽  
Innate Immune ◽  
Guanosine Monophosphate ◽  
Host Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I

The innate immune system responds to unique molecular signatures that are widely conserved among microbes but that are not normally present in host cells. Compounds that stimulate innate immune pathways may be valuable in the design of novel adjuvants, vaccines, and other immunotherapeutics. The cyclic dinucleotide cyclic-di–guanosine monophosphate (c-di-GMP) is a recently appreciated second messenger that plays critical regulatory roles in many species of bacteria but is not produced by eukaryotic cells. In vivo and in vitro studies have previously suggested that c-di-GMP is a potent immunostimulatory compound recognized by mouse and human cells. We provide evidence that c-di-GMP is sensed in the cytosol of mammalian cells via a novel immunosurveillance pathway. The potency of cytosolic signaling induced by c-di-GMP is comparable to that induced by cytosolic delivery of DNA, and both nucleic acids induce a similar transcriptional profile, including triggering of type I interferons and coregulated genes via induction of TBK1, IRF3, nuclear factor κB, and MAP kinases. However, the cytosolic pathway that senses c-di-GMP appears to be distinct from all known nucleic acid–sensing pathways. Our results suggest a novel mechanism by which host cells can induce an inflammatory response to a widely produced bacterial ligand.

scholarly journals Autophagy Contributes to Host Immunity and Protection against Zika Virus Infection via Type I IFN Signaling

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Yuyi Huang ◽  
Yujie Wang ◽  
Shuhui Meng ◽  
Zhuohang Chen ◽  
Haifan Kong ◽  
...  
Keyword(s):  
Virus Infection ◽  
Cell Line ◽  
Zika Virus ◽  
Fetal Brain ◽  
Host Immunity ◽  
Type I ◽  
Type I Ifn ◽  
Zikv Infection

Recent studies have indicated that the Zika virus (ZIKV) has a significant impact on the fetal brain, and autophagy is contributing to host immune response and defense against virus infection. Here, we demonstrate that ZIKV infection triggered increased LC3 punctuation in mouse monocyte-macrophage cell line (RAW264.7), mouse microglial cell line (BV2), and hindbrain tissues, proving the occurrence of autophagy both in vitro and in vivo. Interestingly, manual intervention of autophagy, like deficiency inhibited by 3-MA, can reduce viral clearance in RAW264.7 cells upon ZIKV infection. Besides, specific siRNA strategy confirmed that autophagy can be activated through Atg7-Atg5 and type I IFN signaling pathway upon ZIKV infection, while knocking down of Atg7 and Atg5 effectively decreased the ZIKV clearance in phagocytes. Furthermore, we analyzed that type I IFN signaling could contribute to autophagic clearance of invaded ZIKV in phagocytes. Taken together, our findings demonstrate that ZIKV-induced autophagy is favorable to activate host immunity, particularly through type I IFN signaling, which participates in host protection and defense against ZIKV infection.

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