Publications by authors named "Genhong Cheng"

195 Publications

One year of SARS-CoV-2 evolution.

Cell Host Microbe 2021 Apr 24;29(4):503-507. Epub 2021 Feb 24.

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address:

Since the outbreak of SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, the viral genome has acquired numerous mutations with the potential to increase transmission. One year after its emergence, we now further analyze emergent SARS-CoV-2 genome sequences in an effort to understand the evolution of this virus.
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http://dx.doi.org/10.1016/j.chom.2021.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903908PMC
April 2021

Zika virus NS3 protease induces bone morphogenetic protein-dependent brain calcification in human fetuses.

Nat Microbiol 2021 Apr 28;6(4):455-466. Epub 2021 Jan 28.

Department of Cancer Biology and Global Center for Pathogens Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

The most frequent fetal birth defect associated with prenatal Zika virus (ZIKV) infection is brain calcification, which in turn may potentially affect neurological development in infants. Understanding the mechanism could inform the development of potential therapies against prenatal ZIKV brain calcification. In perivascular cells, bone morphogenetic protein (BMP) is an osteogenic factor that undergoes maturation to activate osteogenesis and calcification. Here, we show that ZIKV infection of cultivated primary human brain pericytes triggers BMP2 maturation, leading to osteogenic gene expression and calcification. We observed extensive calcification near ZIKV pericytes of fetal human brain specimens and in vertically transmitted ZIKV human signal transducer and activator of transcription 2-knockin mouse pup brains. ZIKV infection of primary pericytes stimulated BMP2 maturation, inducing osteogenic gene expression and calcification that were completely blocked by anti-BMP2/4 neutralizing antibody. Not only did ZIKV NS3 expression alone induce BMP2 maturation, osteogenic gene expression and calcification, but purified NS3 protease also effectively cleaved pro-BMP2 in vitro to generate biologically active mature BMP2. These findings highlight ZIKV-induced calcification where the NS3 protease subverts the BMP2-mediated osteogenic signalling pathway to trigger brain calcification.
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http://dx.doi.org/10.1038/s41564-020-00850-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012254PMC
April 2021

Interleukin-8 as a Biomarker for Disease Prognosis of Coronavirus Disease-2019 Patients.

Front Immunol 2020 8;11:602395. Epub 2021 Jan 8.

Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

The widespread prevalence of coronavirus disease-2019 (COVID-19) which is caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has resulted in a severe global public health emergency. However, there are no sensitive biomarkers to predict the disease prognosis of COVID-19 patients. Here, we have identified interleukin-8 (IL-8) as a biomarker candidate to predict different disease severity and prognosis of COVID-19 patients. While serum IL-6 become obviously elevated in severe COVID-19 patients, serum IL-8 was easily detectible in COVID-19 patients with mild syndromes. Furthermore, lL-8 levels correlated better than IL-6 levels with the overall clinical disease scores at different stages of the same COVID-19 patients. Thus, our studies suggest that IL-6 and IL-8 can be respectively used as biomarkers for severe COVID-19 patients and for COVID-19 disease prognosis.
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http://dx.doi.org/10.3389/fimmu.2020.602395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820901PMC
February 2021

Corrigendum to "Nrf2-mediated liver protection by esculento side A against acetaminophen toxicity through the AMPK/Akt/GSK3β pathway" [Free. Radic. Biol. Med. 101(2016)401-412].

Free Radic Biol Med 2021 Apr 19;166:360. Epub 2021 Jan 19.

Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, 130001, China. Electronic address:

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http://dx.doi.org/10.1016/j.freeradbiomed.2021.01.006DOI Listing
April 2021

Type-IInterferon-Inducible SERTAD3 Inhibits Influenza A Virus Replication by Blocking the Assembly of Viral RNA Polymerase Complex.

Cell Rep 2020 11;33(5):108342

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Influenza A virus (IAV) infection stimulates a type I interferon (IFN-I) response in host cells that exerts antiviral effects by inducing the expression of hundreds of IFN-stimulated genes (ISGs). However, most ISGs are poorly studied for their roles in the infection of IAV. Herein, we demonstrate that SERTA domain containing 3 (SERTAD3) has a significant inhibitory effect on IAV replication in vitro. More importantly, Sertad3 mice develop more severe symptoms upon IAV infection. Mechanistically, we find SERTAD3 reduces IAV replication through interacting with viral polymerase basic protein 2 (PB2), polymerase basic protein 1 (PB1), and polymerase acidic protein (PA) to disrupt the formation of the RNA-dependent RNA polymerase (RdRp) complex. We further identify an 8-amino-acid peptide of SERTAD3 as a minimum interacting motif that can disrupt RdRp complex formation and inhibit IAV replication. Thus, our studies not only identify SERTAD3 as an antiviral ISG, but also provide the mechanism of potential application of SERTAD3-derived peptide in suppressing influenza replication.
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http://dx.doi.org/10.1016/j.celrep.2020.108342DOI Listing
November 2020

Zika Virus Infection Leads to Variable Defects in Multiple Neurological Functions and Behaviors in Mice and Children.

Adv Sci (Weinh) 2020 Sep 2;7(18):1901996. Epub 2020 Aug 2.

State Key Laboratory of Molecular Developmental Biology CAS Center for Excellence in Brain Science and Intelligence Technology School of Future Technology Institute of Genetics and Developmental Biology Chinese Academy of Sciences Beijing 100101 China.

Zika virus (ZIKV) has evolved into a global health threat because of its causal link to congenital Zika syndrome. ZIKV infection of pregnant women may cause a spectrum of abnormalities in children. In the studies in Brazil, a large cohort of children with perinatal exposure to ZIKV is followed, and a spectrum of neurodevelopmental abnormalities is identified. In parallel, it is demonstrated that infection of the mouse neonatal brain by a contemporary ZIKV strain instead of an Asian ancestral strain can cause microcephaly and various abnormal neurological functions. These include defects in social interaction and depression, impaired learning and memory, in addition to severe motor defects, which are present in adult mice as well as in the prospective cohort of children. Importantly, although mouse brains infected later after birth do not have apparent abnormal brain structure, those mice still show significant impairments of visual cortical functions, circuit organization, and experience-dependent plasticity. Thus, the study suggests that special attention should be paid to all children born to ZIKV infected mothers for screening of abnormal behaviors and sensory function during childhood.
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http://dx.doi.org/10.1002/advs.201901996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509663PMC
September 2020

Will Hydroxychloroquine Still Be a Game-Changer for COVID-19 by Combining Azithromycin?

Front Immunol 2020 7;11:1969. Epub 2020 Aug 7.

Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, United States.

Recent small-scale clinical trials have shown promising results in the use of hydroxychloroquine, an FDA approved anti-malaria drug, for the treatment of COVID-19. However, large scale, randomized and double-blind clinical trials are needed to confirm the safety and efficacy of hydroxychloroquine in COVID-19 patients. Here, we review the progress of using hydroxychloroquine or chloroquine as anti-viral agents, failed clinical trials of chloroquine in treatment of dengue virus and influenza infection, and especially the mechanism of azithromycin in inhibiting viral replication, so as to shed light on the ongoing clinical trials and further researches of hydroxychloroquine on SARS-CoV-2 infected patients.
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http://dx.doi.org/10.3389/fimmu.2020.01969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426511PMC
September 2020

25-Hydroxycholesterol is a potent SARS-CoV-2 inhibitor.

Cell Res 2020 11 18;30(11):1043-1045. Epub 2020 Aug 18.

Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.

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http://dx.doi.org/10.1038/s41422-020-00398-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431750PMC
November 2020

Gravidity-dependent associations between interferon response and birth weight in placental malaria.

Malar J 2020 Aug 5;19(1):280. Epub 2020 Aug 5.

Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA.

Background: Maternal malarial infection leads to poor perinatal outcomes, including low birth weight from preterm delivery and/or fetal growth restriction, particularly in primigravidas. In placental malaria, Plasmodium falciparum-infected red blood cells cause an inflammatory response that can interfere with maternal-fetal exchange, leading to poor growth. The type I interferon (IFN-I) pathway plays an immunomodulatory role in viral and bacterial infections, usually by suppressing inflammatory responses. However, its role in placental malaria is unknown. This study examines the cytokine responses in placental tissue from subsets of malaria-infected and uninfected women, and attempts to correlate them with particular birth outcomes.

Methods: 40 whole placental biopsy samples were obtained from pregnant women at least 16 years of age recruited to a larger prospective chemoprevention trial against malaria. These were patients at Tororo District Hospital in Uganda, an area of high malaria endemicity where approximately 40% of women have evidence of malaria infection at delivery. They were regularly followed at a local clinic and monitored for fever, with blood smears performed then and at time of delivery to diagnose malaria infection. Placenta biopsies were taken for histological diagnosis of placental malaria, as well as quantitative PCR analysis of genes in the IFN-I pathway (IFN-β, IL-10 and MX-1). Parameters such as infant birth weight and gestational age were also recorded.

Results: Histological analysis revealed placental malaria in 18 samples, while 22 were found to be uninfected. RT-PCR analysis showed a four-fold increase in IFN-β and IL-10 expression in multigravidas with placental malaria when compared to gravidity-matched, uninfected controls. This effect was not observed in primigravidas. Interestingly, linear regression analysis showed a positive association between IFN-β levels and higher birth weights (β = 101.2 g per log2-fold increase in IFN-β expression, p = 0.042). This association was strongest in primigravidas with placental malaria (β = 339.0, p = 0.006).

Conclusions: These results demonstrate differential regulation of the IFN-I pathway in placental malaria according to gravidity, with the greatest anti-inflammatory response seen in multigravidas. The association between IFN-β levels and higher birth weight also suggests a protective role for IFN-I against fetal growth restriction in placental malaria.
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http://dx.doi.org/10.1186/s12936-020-03351-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409479PMC
August 2020

Zika virus vertical transmission in children with confirmed antenatal exposure.

Nat Commun 2020 07 14;11(1):3510. Epub 2020 Jul 14.

David Geffen UCLA School of Medicine, Los Angeles, CA, 90095, USA.

We report Zika virus (ZIKV) vertical transmission in 130 infants born to PCR+ mothers at the time of the Rio de Janeiro epidemic of 2015-2016. Serum and urine collected from birth through the first year of life were tested by quantitative reverse transcriptase polymerase chain reaction (PCR) and/or IgM Zika MAC-ELISA. Four hundred and seven specimens are evaluated; 161 sera tested by PCR and IgM assays, 85 urines by PCR. Sixty-five percent of children (N = 84) are positive in at least one assay. Of 94 children tested within 3 months of age, 70% are positive. Positivity declines to 33% after 3 months. Five children are PCR+ beyond 200 days of life. Concordance between IgM and PCR results is 52%, sensitivity 65%, specificity 40% (positive PCR results as gold standard). IgM and serum PCR are 61% concordant; serum and urine PCR 55%. Most children (65%) are clinically normal. Equal numbers of children with abnormal findings (29 of 45, 64%) and normal findings (55 of 85, 65%) have positive results, p = 0.98. Earlier maternal trimester of infection is associated with positive results (p = 0.04) but not clinical disease (p = 0.98). ZIKV vertical transmission is frequent but laboratory confirmed infection is not necessarily associated with infant abnormalities.
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http://dx.doi.org/10.1038/s41467-020-17331-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360785PMC
July 2020

Mutations, Recombination and Insertion in the Evolution of 2019-nCoV.

bioRxiv 2020 Mar 2. Epub 2020 Mar 2.

Background: The 2019 novel coronavirus (2019-nCoV or SARS-CoV-2) has spread more rapidly than any other betacoronavirus including SARS-CoV and MERS-CoV. However, the mechanisms responsible for infection and molecular evolution of this virus remained unclear.

Methods: We collected and analyzed 120 genomic sequences of 2019-nCoV including 11 novel genomes from patients in China. Through comprehensive analysis of the available genome sequences of 2019-nCoV strains, we have tracked multiple inheritable SNPs and determined the evolution of 2019-nCoV relative to other coronaviruses.

Results: Systematic analysis of 120 genomic sequences of 2019-nCoV revealed co-circulation of two genetic subgroups with distinct SNPs markers, which can be used to trace the 2019-nCoV spreading pathways to different regions and countries. Although 2019-nCoV, human and bat SARS-CoV share high homologous in overall genome structures, they evolved into two distinct groups with different receptor entry specificities through potential recombination in the receptor binding regions. In addition, 2019-nCoV has a unique four amino acid insertion between S1 and S2 domains of the spike protein, which created a potential furin or TMPRSS2 cleavage site.

Conclusions: Our studies provided comprehensive insights into the evolution and spread of the 2019-nCoV. Our results provided evidence suggesting that 2019-nCoV may increase its infectivity through the receptor binding domain recombination and a cleavage site insertion.

One Sentence Summary: Novel 2019-nCoV sequences revealed the evolution and specificity of betacoronavirus with possible mechanisms of enhanced infectivity.
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http://dx.doi.org/10.1101/2020.02.29.971101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217300PMC
March 2020

Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China.

Cell Host Microbe 2020 03 7;27(3):325-328. Epub 2020 Feb 7.

Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu 215123, China. Electronic address:

An in-depth annotation of the newly discovered coronavirus (2019-nCoV) genome has revealed differences between 2019-nCoV and severe acute respiratory syndrome (SARS) or SARS-like coronaviruses. A systematic comparison identified 380 amino acid substitutions between these coronaviruses, which may have caused functional and pathogenic divergence of 2019-nCoV.
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http://dx.doi.org/10.1016/j.chom.2020.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154514PMC
March 2020

Type-I-IFN-Stimulated Gene TRIM5γ Inhibits HBV Replication by Promoting HBx Degradation.

Cell Rep 2019 12;29(11):3551-3563.e3

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA. Electronic address:

To understand the molecular mechanisms that mediate the anti-hepatitis B virus (HBV) effect of interferon (IFN) therapy, we conduct high-throughput bimolecular fluorescence complementation screening to identify potential physical interactions between the HBx protein and 145 IFN-stimulated genes (ISGs). Seven HBx-interacting ISGs have consistent and significant inhibitory effects on HBV replication, among which TRIM5γ suppresses HBV replication by promoting K48-linked ubiquitination and degradation of the HBx protein on the K95 ubiquitin site. The B-Box domain of TRIM5γ under overexpression conditions is sufficient to trigger HBx degradation and is responsible both for interacting with HBx and recruiting TRIM31, which is an ubiquitin ligase that triggers HBx ubiquitination. High expression levels of TRIM5γ in IFN-α-treated HBV patients might indicate a better therapeutic effect. Thus, our studies identify a crucial role for TRIM5γ and TRIM31 in promoting HBx degradation, which may facilitate the development of therapeutic agents for the treatment of patients with IFN-resistant HBV infection.
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http://dx.doi.org/10.1016/j.celrep.2019.11.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996557PMC
December 2019

Combinatorial screening of a panel of FDA-approved drugs identifies several candidates with anti-Ebola activities.

Biochem Biophys Res Commun 2020 02 2;522(4):862-868. Epub 2019 Dec 2.

Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, 215123, China. Electronic address:

Ebola virus (EBOV), pathogen of Ebola hemorrhagic fever (EHF), is an enveloped filamental RNA virus. Recently, the EHF crisis occurred in the Democratic Republic of the Congo again highlights the urgency for its clinical treatments. However, no Food and Drug Administration (FDA)-approved therapeutics are currently available. Drug repurposing screening is a time- and cost-effective approach for identifying anti-EBOV therapeutics. Here, by combinatorial screening using pseudovirion and minigenome replicon systems we have identified several FDA-approved drugs with significant anti-EBOV activities. These potential candidates include azithromycin, clomiphene, chloroquine, digitoxin, epigallocatechin-gallate, fluvastatin, tetrandrine and tamoxifen. Mechanistic studies revealed that fluvastatin inhibited EBOV pseudovirion entry by blocking the pathway of mevalonate biosynthesis, while the inhibitory effect of azithromycin on EBOV maybe due to its intrinsic cationic amphiphilic structure altering the homeostasis of later endosomal vesicle similar as tamoxifen. Moreover, based on structure and pathway analyses, the anti-EBOV activity has been extended to other family members of statins, such as simvastatin, and multiple other cardiac glycoside drugs, some of which exhibited even stronger activities. More importantly, in searching for drug interaction, we found various synergy between several anti-EBOV drug combinations, showing substantial and powerful synergistic against EBOV infection. In conclusion, our work illustrates a successful and productive approach to identify new mechanisms and targets for treating EBOV infection by combinatorial screening of FDA-approved drugs.
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http://dx.doi.org/10.1016/j.bbrc.2019.11.065DOI Listing
February 2020

Cytokine signatures associate with disease severity in children with Mycoplasma pneumoniae pneumonia.

Sci Rep 2019 11 28;9(1):17853. Epub 2019 Nov 28.

Department of Translational Medicine, The First Hospital of Jilin University, Changchun, China.

Host immune response may be involved in the pathogenesis of children Mycoplasma pneumoniae pneumonia (MPP). In the current study, we investigated the alterations of cytokines levels among control, mild MPP and severe MPP children to determine whether cytokine signatures associate with MPP and correlate with disease severity. We measured 13 cytokines in bronchoalveolar lavage fluid (BALF) of 88 children with MPP and 26 children with foreign body aspiration (FB) using a Luminex system. Linear discriminant analyses were performed to develop predictive models of mild MPP and severe MPP on these children. We observed nearly complete separations of severe MPP group, mild MPP group and control group in linear discriminant analyses. Eleven cytokines significantly increased in children with MPP, and seven cytokines had statistically significant upward linear trends correlated with MPP severity. In addition, compared to control group, both IFNγ/IL4 ratio and IFNγ/IL13 ratio increased in mild MPP and severe MPP groups. Our results suggest that children MPP can alter BALF cytokines signatures which associate with disease severity and can be characterized by a distinct airway molecular phenotype that has elevated Th1/Th2 ratios.
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http://dx.doi.org/10.1038/s41598-019-54313-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882793PMC
November 2019

TCR Ligand Discovery via T-Scan.

Trends Immunol 2019 12 5;40(12):1075-1077. Epub 2019 Nov 5.

Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China. Electronic address:

T cell receptor (TCR) ligand discovery is crucial to monitoring T cell responses to antigen and to identifying antigens reactive against orphan TCRs of interest. In a recent article, Elledge and colleagues describe a functional T cell ligand screening platform for unbiased TCR ligand discovery.
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http://dx.doi.org/10.1016/j.it.2019.10.003DOI Listing
December 2019

NF-κB-Dependent IFIT3 Induction by HBx Promotes Hepatitis B Virus Replication.

Front Microbiol 2019 11;10:2382. Epub 2019 Oct 11.

Department of Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.

Therapeutic administration of type I IFN (IFN-I) is a common treatment option for individuals suffering from hepatitis B virus (HBV) infection. IFN-I therapy, however, has a relatively low response rate in HBV-infected patients and can induce serious side-effects, limiting its clinical efficacy. There is, thus, a clear need to understand the molecular mechanisms governing the influence of IFN-I therapy in HBV treatment in order to improve patient outcomes. In this study, we explored the interactions between HBV and IFITs (IFN-induced proteins with tetratricopeptide repeats), which are classical IFN-inducible genes. Specifically, we found that HBV patients undergoing IFN-I therapy exhibited elevated expression of IFITs in their peripheral blood mononuclear cells (PBMCs). We further observed upregulation in the expressions of IFIT1, IFIT2, and IFIT3 in cells transfected with the pHBV1.3 plasmid, which yields infectious virions in hepatic cells. We additionally found that HBx, which is the only regulatory protein encoded within the HBV genome, activates NF-κB, which in turn directly drives IFIT3 transcription. When IFIT3 was overexpressed in HepG2 cells, HBV replication was enhanced. Together, these results suggest that IFIT genes may unexpectedly enhance viral replication, thus making these genes potential therapeutic targets in patients with HBV.
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http://dx.doi.org/10.3389/fmicb.2019.02382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797949PMC
October 2019

Regulation of Early Host Immune Responses Shapes the Pathogenicity of Avian Influenza A Virus.

Front Microbiol 2019 11;10:2007. Epub 2019 Sep 11.

Suzhou Institute of Systems Medicine, Suzhou, China.

Avian influenza A viruses (IAV) can cross the species barrier and cause disease in humans. Understanding the pathogenesis of avian IAV remains a challenge. Interferon-mediated antiviral responses and multiple cytokines production are important host cellular antiviral immunity against IAV infection. To elucidate the pathogenicity of avian IAV, a system approach was adopted to investigate dysregulation of the two host cellular antiviral immune responses in contrast with human IAV. As a result, we revealed that avian IAV not only disrupted normal early host cellular interferon-mediated antiviral responses, but also caused abnormal cytokines production through different pathways. For avian IAV infection, dysregulation of STAT2 was mainly responsible for abnormal cellular interferon-mediated antiviral responses, and IRF5 and NFKB1 played crucial roles in unusual cytokines production. In contrast, for human IAV infection, IRF1, IRF7, and STAT1 contributed to cellular cytokines production. Furthermore, differential activation of pattern recognition receptors (PRRs) likely led to avian IAV-related abnormal early host cellular antiviral immunity, where TLR7 and RIG-I were activated by avian and human IAV, respectively. Finally, a pathogenesis model was proposed that combined of early host cellular interferon-mediated antiviral responses with cytokines production could partly explain the pathogenicity of avian IAV. In conclusion, our study provides a new perspective of the pathogenesis of avian IAV, which will be helpful in preventing their infections in the future.
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http://dx.doi.org/10.3389/fmicb.2019.02007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749051PMC
September 2019

Azithromycin Protects against Zika virus Infection by Upregulating virus-induced Type I and III Interferon Responses.

Antimicrob Agents Chemother 2019 Sep 16. Epub 2019 Sep 16.

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.

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. Herein, we report that AZM effectively suppresses ZIKV infection by targeting a late stage in the viral life cycle. Besides that, AZM upregulates the expression of host type I and III interferons and several of their downstream interferon-stimulated genes (ISGs) in response to ZIKV infection. In particular, we found that AZM upregulates the expression of MDA5 and RIG-I, pathogen recognition receptors (PRRs) induced by ZIKV infection, and increases the levels of phosphorylated TBK1 and IRF3. Interestingly, AZM treatment upregulates phosphorylation of TBK1, without inducing phosphorylation of IRF3 by itself. These findings highlight the potential use of AZM as a broad antiviral agent to combat viral infection and prevent ZIKV associated devastating clinical outcomes, such as congenital microcephaly.
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http://dx.doi.org/10.1128/AAC.00394-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879226PMC
September 2019

Cellular Signaling Analysis shows antiviral, ribavirin-mediated ribosomal signaling modulation.

Antiviral Res 2019 11 9;171:104598. Epub 2019 Sep 9.

Pharmaceutical Sciences Department, Western University of Health Sciences, Pomona, CA, USA. Electronic address:

As antiviral drug resistance develops and new viruses emerge there is a pressing need to develop strategies to rapidly develop antiviral therapeutics. Here we use phospho-specific flow cytometry to assess perturbations of many different cellular signaling pathways during treatment with drug combinations that are highly effective in blocking Herpes simplex virus type 1 (HSV-1) infection. We discovered two antiviral drug combinations act on distinct signaling pathways, either STAT1 or S6 phosphorylation, to block HSV-1 infection. We focused on upregulation of S6 phosphorylation by HSV-1 infection, and our subsequent finding that ribavirin antagonizes this upregulation of S6 phosphorylation. We go on to show that the S6 kinase inhibitor SL0101 blocks HSV-1 replication in vitro and in an in vivo animal model of HSV-1 infection. Overall, we have used an unbiased analysis of cellular signaling pathways during treatment by antiviral drug combinations to discover a novel antiviral drug target against HSV-1 infection. The outcomes of the approach we present highlight the importance of analyzing how antiviral drugs modulate cellular and pathogen-induced signaling as a method to discover new drug therapy targets.
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http://dx.doi.org/10.1016/j.antiviral.2019.104598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7114107PMC
November 2019

Comprehensive Mutagenesis of Herpes Simplex Virus 1 Genome Identifies UL42 as an Inhibitor of Type I Interferon Induction.

J Virol 2019 12 13;93(23). Epub 2019 Nov 13.

Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA

In spite of several decades of research focused on understanding the biology of human herpes simplex virus 1 (HSV-1), no tool has been developed to study its genome in a high-throughput fashion. Here, we describe the creation of a transposon insertion mutant library of the HSV-1 genome. Using this tool, we aimed to identify novel viral regulators of type I interferon (IFN-I). HSV-1 evades the host immune system by encoding viral proteins that inhibit the type I interferon response. Applying differential selective pressure, we identified the three strongest viral IFN-I regulators in HSV-1. We report that the viral polymerase processivity factor UL42 interacts with the host transcription factor IFN regulatory factor 3 (IRF-3), inhibiting its phosphorylation and downstream beta interferon (IFN-β) gene transcription. This study represents a proof of concept for the use of high-throughput screening of the HSV-1 genome in investigating viral biology and offers new targets both for antiviral therapy and for oncolytic vector design. This work is the first to report the use of a high-throughput mutagenesis method to study the genome of HSV-1. We report three novel viral proteins potentially involved in regulating the host type I interferon response. We describe a novel mechanism by which the viral protein UL42 is able to suppress the production of beta interferon. The tool we introduce in this study can be used to study the HSV-1 genome in great detail to better understand viral gene functions.
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http://dx.doi.org/10.1128/JVI.01446-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854482PMC
December 2019

Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children.

Nat Med 2019 08 8;25(8):1213-1217. Epub 2019 Jul 8.

Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.

We report neurodevelopmental outcomes in 216 infants followed since the time of PCR-confirmed maternal Zika virus (ZIKV) infection in pregnancy during the Rio de Janeiro epidemic of 2015-2016 (refs. ). Neurodevelopment was assessed by Bayley Scales of Infant and Toddler Development, third edition (Bayley-III; cognitive, language and motor domains) in 146 children and through neurodevelopment questionnaires/neurological examinations in 70 remaining children. Complete eye exams (n = 137) and hearing assessments (n = 114) were also performed. Below-average neurodevelopment and/or abnormal eye or hearing assessments were noted in 31.5% of children between 7 and 32 months of age. Among children assessed by Bayley-III, 12% scored below -2 s.d. (score <70; a score of 100 ± 2 s.d. is the range) in at least one domain; and 28% scored between -1 and -2 s.d. in any domain (scores <85-70). Language function was most affected, with 35% of 146 children below average. Improved neurodevelopmental outcomes were noted in female children, term babies, children with normal eye exams and maternal infection later in pregnancy (P = 0.01). We noted resolution of microcephaly with normal neurodevelopment in two of eight children, development of secondary microcephaly in two other children and autism spectrum disorder in three previously healthy children in the second year of life.
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http://dx.doi.org/10.1038/s41591-019-0496-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689256PMC
August 2019

TLR3 Ligand PolyI:C Prevents Acute Pancreatitis Through the Interferon-β/Interferon-α/β Receptor Signaling Pathway in a Caerulein-Induced Pancreatitis Mouse Model.

Front Immunol 2019 3;10:980. Epub 2019 May 3.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Department of Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Acute pancreatitis (AP) is a common and devastating inflammatory disorder of the pancreas. However, there are still no effective treatments available for the disease. Therefore, it is important to discover new therapeutic targets and strategies for better treatment and prognosis of AP patients. Toll-like receptor 3 (TLR3) ligand polyI:C is a double-stranded RNA mimic that can be used as an immune stimulant. Our current study indicates that polyI:C exerted excellent anti-inflammatory effects in a caerulein-induced AP mouse model and taurocholate-induced pancreatic acinar cell line injury model. We found that polyI:C triggers type I interferon (IFN) production and downstream IFN-α/β receptor (IFNAR)-dependent signaling, which play key roles in protecting the pancreas from inflammatory injury. Knockout of IFN-β and IFNAR in mice abolished the preventive effects of polyI:C on caerulein-induced AP symptoms, which include pancreatic edema, neutrophil infiltration, the accumulation of reactive oxygen species (ROS), and inflammatory gene expression. Treating pancreatic acinar 266-6 cells with an IFNAR inhibitor, which blocks the interaction between type I IFN and IFNAR, diminishes the downregulation of oxidative stress by polyI:C. Additionally, a subsequent transcriptome analysis on the role of polyI:C in treating pancreatitis suggested that chemotaxis of neutrophils and the production of ROS were inhibited by polyI:C in the pancreases damaged by caerulein injection. Thus, polyI:C may act as a type I IFN inducer to alleviate AP, and it has the potential to be a promising therapeutic agent used at the early stages of AP.
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http://dx.doi.org/10.3389/fimmu.2019.00980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509240PMC
October 2020

Autophagy links antimicrobial activity with antigen presentation in Langerhans cells.

JCI Insight 2019 04 18;4(8). Epub 2019 Apr 18.

Division of Dermatology, Department of Medicine, and.

DC, through the uptake, processing, and presentation of antigen, are responsible for activation of T cell responses to defend the host against infection, yet it is not known if they can directly kill invading bacteria. Here, we studied in human leprosy, how Langerhans cells (LC), specialized DC, contribute to host defense against bacterial infection. IFN-γ treatment of LC isolated from human epidermis and infected with Mycobacterium leprae (M. leprae) activated an antimicrobial activity, which was dependent on the upregulation of the antimicrobial peptide cathelicidin and induction of autophagy. IFN-γ induction of autophagy promoted fusion of phagosomes containing M. leprae with lysosomes and the delivery of cathelicidin to the intracellular compartment containing the pathogen. Autophagy enhanced the ability of M. leprae-infected LC to present antigen to CD1a-restricted T cells. The frequency of IFN-γ labeling and LC containing both cathelicidin and autophagic vesicles was greater in the self-healing lesions vs. progressive lesions, thus correlating with the effectiveness of host defense against the pathogen. These data indicate that autophagy links the ability of DC to kill and degrade an invading pathogen, ensuring cell survival from the infection while facilitating presentation of microbial antigens to resident T cells.
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http://dx.doi.org/10.1172/jci.insight.126955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538337PMC
April 2019

Nrf2 signaling and autophagy are complementary in protecting lipopolysaccharide/d-galactosamine-induced acute liver injury by licochalcone A.

Cell Death Dis 2019 04 5;10(4):313. Epub 2019 Apr 5.

Institute of Translational Medicine, The First Hospital, Jilin University, 130001, Changchun, China.

Licochalcone A (Lico A), isolated from Xinjiang licorice Glycyrrhiza inflate, has been shown to have antioxidative potential via the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) activation, which is involved in the prevention of acetaminophen-induced hepatotoxicity. The purpose of the current study was to further explore the protective effect of Lico A against lipopolysaccharide/d-galactosamine (LPS/GalN)-induced acute liver injury (ALI) and its underlying molecular mechanisms. Our results found that treatment with Lico A significantly reduced in LPS/GalN-induced hepatotoxicity by lessening lethality, alleviating histopathological liver changes, decreasing the alanine transaminase, and aspartate aminotransferase levels, attenuating the secretion of inflammatory cytokines, and regulating oxidative markers. Furthermore, Lico A efficiently alleviated LPS-induced inflammatory response by inhibiting TLR4-MAPK and -NF-κB, as well as the Txnip-NLRP3 signaling pathway. Meanwhile, Lico A induced the activation of Nrf2 and QSTM1 (P62) signaling and promoted autophagy involved in AMP-activated protein kinase (AMPK)-the transcription factor EB (TFEB) signaling, which may contribute to its hepatoprotective activity. Additional mechanistic investigations to evaluate the dependence of the hepatoprotective role of Lico A on Nrf2 revealed that a lack of Nrf2 promoted Lico A-induced autophagy, which contributed to the hepatoprotective effect of Lico A in Nrf2 mice. In addition, cotreatment with autophagy inhibitor (3-methyladenine, 3-MA) alleviated but did not abrogate the hepatoprotective effect of Lico A, which may be attributed to its ability to activate Nrf2. Our study firstly suggests that Lico A has protective potential against LPS/GalN-induced hepatotoxicity, which may be strongly associated with activation of Nrf2 and autophagy.
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http://dx.doi.org/10.1038/s41419-019-1543-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450927PMC
April 2019

IL-26 contributes to host defense against intracellular bacteria.

J Clin Invest 2019 04 2;129(5):1926-1939. Epub 2019 Apr 2.

Division of Dermatology, Department of Medicine.

IL-26 is an antimicrobial protein secreted by Th17 cells that has the ability to directly kill extracellular bacteria. To ascertain whether IL-26 contributes to host defense against intracellular bacteria, we studied leprosy, caused by the obligate intracellular pathogen Mycobacterium leprae, as a model. Analysis of leprosy skin lesions by gene expression profiling and immunohistology revealed that IL-26 was more strongly expressed in lesions from the self-limited tuberculoid compared with expression in progressive lepromatous patients. IL-26 directly bound to M. leprae in axenic culture and reduced bacteria viability. Furthermore, IL-26, when added to human monocyte-derived macrophages infected with M. leprae, entered the infected cell, colocalized with the bacterium, and reduced bacteria viability. In addition, IL-26 induced autophagy via the cytoplasmic DNA receptor stimulator of IFN genes (STING), as well as fusion of phagosomes containing bacilli with lysosomal compartments. Altogether, our data suggest that the Th17 cytokine IL-26 contributes to host defense against intracellular bacteria.
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http://dx.doi.org/10.1172/JCI99550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486355PMC
April 2019

Inhibition of Influenza A Virus Replication by TRIM14 via Its Multifaceted Protein-Protein Interaction With NP.

Front Microbiol 2019 26;10:344. Epub 2019 Feb 26.

Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, China.

Influenza A virus (IAV) is a worldwide ongoing health threat causing diseases in both humans and animals. The interaction between IAV and host is a dynamic and evolving process that influences the pathogenicity and host specificity of the virus. TRIM14, a member of tripartite motif (TRIM) family, has been demonstrated to possess a strong capability of regulating type I interferon and NF-κB induction in host defense against viral infection. In this study, we found that TRIM14 could restrict the replication of IAV in a type I interferon and NF-κB independent manner. Mechanistically, different domains of TRIM14 could selectively interact with the viral nucleoprotein (NP), resulting in disparate influences on the RNP formation and viral replication. In particular, the PRYSPRY domain of TRIM14 exhibited a potent inhibitory activity on NP protein stability and IAV replication. On the contrary, the ΔS2 domain could rather antagonize the function of PRYSPRY domain and promote the IAV RNP formation by stabilizing NP. At the biochemical level, TRIM14-NP interaction could induce the K48-linked ubiquitination and proteasomal degradation of NP. Moreover, due to the rapid degradation of newly synthesized NP, TRIM14 could effectively block the translocation of NP from cytoplasm to nucleus thus further restrain the propagation of IAV in host cells. Taken together, our study has unraveled a previously unknown mechanism of TRIM14 mediated inhibition on RNP formation and influenza virus replication, and provides a new paradigm of complex and multifaceted host-pathogen interaction between ISG and viral protein.
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http://dx.doi.org/10.3389/fmicb.2019.00344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401474PMC
February 2019

The Aftermath of Surviving Acute Radiation Hematopoietic Syndrome and its Mitigation.

Radiat Res 2019 04 7;191(4):323-334. Epub 2019 Feb 7.

a Department of Radiation Oncology, University of California at Los Angeles, Los Angeles, California.

Intensive research is underway to find new agents that can successfully mitigate the acute effects of radiation exposure. This is primarily in response to potential counterthreats of radiological terrorism and nuclear accidents but there is some hope that they might also be of value for cancer patients treated with radiation therapy. Research into mitigation countermeasures typically employs classic animal models of acute radiation syndromes (ARS) that develop after whole-body irradiation (WBI). While agents are available that successfully mitigate ARS when given after radiation exposure, their success raises questions as to whether they simply delay lethality or unmask potentially lethal radiation pathologies that may appear later in time. Life shortening is a well-known consequence of WBI in humans and experimental animals, but it is not often examined in a mitigation setting and its causes, other than cancer, are not well-defined. This is in large part because delayed effects of acute radiation exposure (DEARE) do not follow the strict time-dose phenomena associated with ARS and present as a diverse range of symptoms and pathologies with low mortality rates that can be evaluated only with the use of large cohorts of subjects, as in this study. Here, we describe chronically increased mortality rates up to 660 days in large numbers of mice given LD doses of WBI. Systemic myeloid cell activation after WBI persists in some mice and is associated with late immunophenotypic changes and hematopoietic imbalance. Histopathological changes are largely of a chronic inflammatory nature and variable incidence, as are the clinical symptoms, including late diarrhea that correlates temporally with changes in the content of the microbiome. We also describe the acute and long-term consequences of mitigating hematopoietic ARS (H-ARS) lethality after LD doses of WBI in multiple cohorts of mice treated uniformly with radiation mitigators that have a common 4-nitro-phenylsulfonamide (NPS) pharmacophore. Effective NPS mitigators dramatically decrease ARS mortality. There is slightly increased subacute mortality, but the rate of late mortalities is slowed, allowing some mice to live a normal life span, which is not the case for WBI controls. The study has broad relevance to radiation late effects and their potential mitigation and epitomizes the complex interaction between radiation-damaged tissues and immune homeostasis.
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http://dx.doi.org/10.1667/RR15231.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482953PMC
April 2019

Regulating Innate and Adaptive Immunity for Controlling SIV Infection by 25-Hydroxycholesterol.

Front Immunol 2018 21;9:2686. Epub 2018 Nov 21.

School of Public Health (Shenzhen), Sun Yat-sen University, Guangdong, China.

Persistent inflammation and extensive immune activation have been associated with HIV-1/SIV pathogenesis. Previously, we reported that cholesterol-25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25-HC) had a broad antiviral activity in inhibiting Zika, Ebola, and HIV-1 infection. However, the underlying immunological mechanism of CH25H and 25-HC in inhibiting viral infection remains poorly understood. We report here that 25-HC effectively regulates immune responses for controlling viral infection. CH25H expression was interferon-dependent and induced by SIV infection in monkey-derived macrophages and PBMC cells, and 25-HC inhibited SIV infection both in permissive cell lines and primary monkey lymphocytes. 25-HC also strongly inhibited bacterial lipopolysaccharide (LPS)-stimulated inflammation and restricted mitogen-stimulated proliferation in primary monkey lymphocytes. Strikingly, 25-HC promoted SIV-specific IFN-γ-producing cellular responses, but selectively suppressed proinflammatory CD4+ T lymphocytes secreting IL-2 and TNF-α cytokines in vaccinated mice. In addition, 25-HC had no significant immunosuppressive effects on cytotoxic CD8+ T lymphocytes or antibody-producing B lymphocytes. Collectively, 25-HC modulated both innate and adaptive immune responses toward inhibiting HIV/SIV infection. This study provides insights into improving vaccination and immunotherapy regimes against HIV-1 infection.
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http://dx.doi.org/10.3389/fimmu.2018.02686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262225PMC
October 2019

Biomarkers and immunoprofiles associated with fetal abnormalities of ZIKV-positive pregnancies.

JCI Insight 2018 11 2;3(21). Epub 2018 Nov 2.

Department of Molecular Microbiology and Immunology and.

Background: An intricate fetal-maternal immune crosstalk during pregnancy is essential for a healthy birth. Hence, the infection-induced alterations of maternal immunity often lead to adverse outcomes for mother and/or child. The emergence of Zika virus (ZIKV) infection in pregnant women has been associated with more than 3,000 cases of microcephaly and nervous system malformations.

Methods: To explore the potential correlation of ZIKV-induced alteration of maternal immunity with fetal abnormalities, we performed extensive sera immunoprofiling of 74 pregnant women: 30 symptomatic ZIKV+ pregnant patients and 30 healthy pregnant controls in ZIKV-endemic Rio de Janeiro, along with 14 healthy pregnant controls in non-endemic Los Angeles.

Results: Extensive multiplexing analysis of 69 cytokines revealed that CXCL10, CCL2, and CCL8 chemokines were specifically associated with symptomatic ZIKV+ infection during pregnancy, and distinct immunoprofiles were detected at different trimesters in ZIKV-infected pregnant women. Intriguingly, the high CCL2 level and its inverse correlation with CD163, TNFRSF1A, and CCL22 levels was apparently associated with ZIKV-induced abnormal birth.

Conclusion: Our findings provide insights into the alteration of ZIKV-elicited maternal immunity, serving as a potential clinical biomarker platform.

Funding: NIH (CA200422, CA180779, DE023926, AI073099, AI116585, AI129496, AI140705, AI069120, AI056154, AI078389, AI28697, AI40718 and AI129534-01), Hastings Foundation, Fletcher Jones Foundation, Departamento de Ciência e Tecnologia (DECIT/25000.072811/2016-17) do Ministério da Saúde do Brasil, and Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior CAPES/88887.116627/2016-01.
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http://dx.doi.org/10.1172/jci.insight.124152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238739PMC
November 2018