Abstract:
UNLABELLED:The cellular response to virus infection is initiated when pathogen recognition receptors (PRR) engage viral pathogen-associated molecular patterns (PAMPs). This process results in induction of downstream signaling pathways that activate the transcription factor interferon regulatory factor 3 (IRF3). IRF3 plays a critical role in antiviral immunity to drive the expression of innate immune response genes, including those encoding antiviral factors, type 1 interferon, and immune modulatory cytokines, that act in concert to restrict virus replication. Thus, small molecule agonists that can promote IRF3 activation and induce innate immune gene expression could serve as antivirals to induce tissue-wide innate immunity for effective control of virus infection. We identified small molecule compounds that activate IRF3 to differentially induce discrete subsets of antiviral genes. We tested a lead compound and derivatives for the ability to suppress infections caused by a broad range of RNA viruses. Compound administration significantly decreased the viral RNA load in cultured cells that were infected with viruses of the family Flaviviridae, including West Nile virus, dengue virus, and hepatitis C virus, as well as viruses of the families Filoviridae (Ebola virus), Orthomyxoviridae (influenza A virus), Arenaviridae (Lassa virus), and Paramyxoviridae (respiratory syncytial virus, Nipah virus) to suppress infectious virus production. Knockdown studies mapped this response to the RIG-I-like receptor pathway. This work identifies a novel class of host-directed immune modulatory molecules that activate IRF3 to promote host antiviral responses to broadly suppress infections caused by RNA viruses of distinct genera. IMPORTANCE:Incidences of emerging and reemerging RNA viruses highlight a desperate need for broad-spectrum antiviral agents that can effectively control infections caused by viruses of distinct genera. We identified small molecule compounds that can selectively activate IRF3 for the purpose of identifying drug-like molecules that can be developed for the treatment of viral infections. Here, we report the discovery of a hydroxyquinoline family of small molecules that can activate IRF3 to promote cellular antiviral responses. These molecules can prophylactically or therapeutically control infection in cell culture by pathogenic RNA viruses, including West Nile virus, dengue virus, hepatitis C virus, influenza A virus, respiratory syncytial virus, Nipah virus, Lassa virus, and Ebola virus. Our study thus identifies a class of small molecules with a novel mechanism to enhance host immune responses for antiviral activity against a variety of RNA viruses that pose a significant health care burden and/or that are known to cause infections with high case fatality rates.
journal_name
J Viroljournal_title
Journal of virologyauthors
Pattabhi S,Wilkins CR,Dong R,Knoll ML,Posakony J,Kaiser S,Mire CE,Wang ML,Ireton RC,Geisbert TW,Bedard KM,Iadonato SP,Loo YM,Gale M Jrdoi
10.1128/JVI.02202-15subject
Has Abstractpub_date
2015-12-16 00:00:00pages
2372-87issue
5eissn
0022-538Xissn
1098-5514pii
JVI.02202-15journal_volume
90pub_type
杂志文章abstract::Recently we reported that in vitro RNA transcripts complementary to the genome of hepatitis delta virus (HDV) contain a unique site at which self-cleavage can occur. Subsequent studies showed that a similar self-cleavage site was present on in vitro RNA transcripts of genomic HDV RNA. The same self-cleavage reactions ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.62.12.4439-4444.1988
更新日期:1988-12-01 00:00:00
abstract::The fraction of the adenovirus type 5 genome expressed as mRNA in a rat cell line, 5RK, transformed by the HsuI-G restriction fragment was analyzed by saturation hybridization using separated strands of 32P-labeled HindIII-G fragment. It was found that 45 to 50% of G fragment (about 8 X 10(5) daltons) is expressed as ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.28.3.1011-1014.1978
更新日期:1978-12-01 00:00:00
abstract::Rinderpest virus is a morbillivirus and is the causative agent of a widespread and important disease of cattle. The viral genome is a single strand of RNA in the negative sense. We have constructed plasmids containing cDNA copies of the 5' and 3' termini of the virus separated by a reporter gene and have shown that an...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.2.1265-1271.1997
更新日期:1997-02-01 00:00:00
abstract::Although hepatitis A virus (HAV) is typically transmitted by the fecal-oral route, little is known of its interactions with cells of the gastrointestinal tract. We studied the replication of HAV in polarized cultures of Caco-2 cells, a human cell line which retains many differentiated functions of small intestinal epi...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.74.14.6476-6484.2000
更新日期:2000-07-01 00:00:00
abstract::While the facile transmission of chronic wasting disease (CWD) remains incompletely elucidated, studies in rodents suggest that exposure of the respiratory mucosa may be an efficient pathway. The present study was designed to address this question in the native cervid host. Here, we demonstrate aerosol transmission of...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02852-12
更新日期:2013-02-01 00:00:00
abstract::A malignant glioma cell line was infected with the human T-lymphotropic virus type IIIB isolate of the human immunodeficiency virus. Infection appeared to be latent rather than productive. Through contact with monocytic or lymphoid cells, the virus present in the glioma cells could be transmitted and gave rise to a fu...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.61.4.1244-1247.1987
更新日期:1987-04-01 00:00:00
abstract::The role of the T4 bacteriophage regA gene in stabilizing early mRNA was investigated by assaying the level of functional mRNA from eight prereplicative genes (56 [dCMP hydroxymethylase], cd [dCMP deaminase], 1 [deoxynucleotide kinase], rIIA, rIIB, 46 [DNA arrest], and 45) during extended infection of Escherichia coli...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.17.2.538-549.1976
更新日期:1976-02-01 00:00:00
abstract::We are exploring the use of interferon (IFN) genes for somatic cell gene therapy and have investigated the possibility of transforming cells into low constitutive IFN producers over prolonged periods of time without impeding cell survival or replication. Here we report the possibility of conferring a permanent antivir...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.65.2.664-671.1991
更新日期:1991-02-01 00:00:00
abstract::The sequence of 2,191 nucleotides encoding the env gene of murine retrovirus Akv was determined by using a molecular clone of the Akv provirus. Deduction of the encoded amino acid sequence showed that a single open reading frame encodes a 638-amino acid precursor to gp70 and p15E. In addition, there is a typical leade...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.42.2.519-529.1982
更新日期:1982-05-01 00:00:00
abstract::Cas-Br-M is an ecotropic murine leukemia virus (MuLV) of wild-mouse origin that causes neurogenic hind-limb paralysis. By virtue of its N-tropism, the virus replicates well in tissues of mice bearing the n but not the b allele at the Fv-1 locus. To determine if different Fv-1n strains of mice were equally susceptible ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.53.1.40-43.1985
更新日期:1985-01-01 00:00:00
abstract::Divergent Toll-like receptor 7 (TLR7) and TLR9 signaling has been proposed to distinguish pathogenic from nonpathogenic simian immunodeficiency virus infection in primate models. We demonstrate here that increased expression of type I interferon in pathogenic rhesus macaques compared to nonpathogenic African green mon...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01496-09
更新日期:2010-02-01 00:00:00
abstract::Zyxin, a focal adhesion molecule, interacts specifically with the E6 protein from human papillomavirus (HPV) type 6 in a yeast two-hybrid screen of a cDNA library prepared from human keratinocytes. Zyxin does not interact significantly with E6 proteins from HPV types 11, 16, or 18. The interaction was confirmed by in ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.75.23.11791-11802.2001
更新日期:2001-12-01 00:00:00
abstract::Our previous studies have shown that targeting DNA vaccine-encoded major histocompatibility complex class I epitopes to the proteasome enhanced CD8(+) T-cell induction and protection against lymphocytic choriomeningitis virus (LCMV) challenge. Here, we expand these studies to evaluate CD4(+) T-cell responses induced b...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.75.21.10421-10430.2001
更新日期:2001-11-01 00:00:00
abstract::Polymorphonuclear leukocytes (PMN) were studied for their ability to mediate cytotoxicity against varicella-zoster virus (VZV)-infected and uninfected human fibroblasts in 51Cr release assays. PMN were capable of mediating antibody-dependent cellular cytotoxicity (ADCC) against VZV-infected targets. Maximal ADCC was o...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.51.1.110-116.1984
更新日期:1984-07-01 00:00:00
abstract::Epstein-Barr virus (EBV) undergoes latent and lytic replication cycles, and its reactivation from latency to lytic replication is initiated by expression of the two viral immediate-early transactivators, Zta and Rta. In vitro, reactivation of EBV can be induced by anti-immunoglobulin, tetradecanoyl phorbol acetate, an...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01602-10
更新日期:2011-03-01 00:00:00
abstract::Necroptosis, a regulated form of necrotic cell death, requires the activation of the RIP3 kinase. Here, we identify that infection of host cells with reovirus can result in necroptosis. We find that necroptosis requires sensing of the genomic RNA within incoming virus particles via cytoplasmic RNA sensors to produce t...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02404-16
更新日期:2017-02-28 00:00:00
abstract::Two second-site mutations in Moloney murine leukemia virus envelope surface protein (SU) were previously shown to rescue infection of two different SU mutants, a fusion-defective point mutant and a fusion-defective modified SU that exhibits weak subunit association. We report here that they also rescue infection of a ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.75.23.11881-11885.2001
更新日期:2001-12-01 00:00:00
abstract::Infection of microglia and other cells of the macrophage/monocyte lineage in the central nervous system (CNS) by human immunodeficiency virus type I (HIV-1) underlies the development of giant cell encephalitis (GCE). It is currently unknown whether GCE depends on the emergence of virus populations specifically adapted...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.75.23.11686-11699.2001
更新日期:2001-12-01 00:00:00
abstract:UNLABELLED:Transmission of chronic wasting disease (CWD) between cervids is influenced by the primary structure of the host cellular prion protein (PrP(C)). In white-tailed deer, PRNP alleles encode the polymorphisms Q95 G96 (wild type [wt]), Q95 S96 (referred to as the S96 allele), and H95 G96 (referred to as the H95 ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02010-15
更新日期:2015-12-01 00:00:00
abstract:UNLABELLED:A balance between the functions of the influenza virus surface proteins hemagglutinin (HA) and neuraminidase (NA) is thought to be important for the transmission of viruses between humans. Here we describe two pandemic H1N1 viruses, A/swine/Virginia/1814-1/2012 and A/swine/Virginia/1814-2/2012 (pH1N1low-1 an...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02537-14
更新日期:2015-06-01 00:00:00
abstract::The antiviral activity of the double-stranded complex poly(rI) . poly(rC) in cell culture was restored or even surpassed if the constituent homopolymers were administered separately. Poly(rI) primed the cells for the antiviral activity of poly(rC) and poly(rC) primed for poly(rI), but neither poly(rI) nor poly(rC) pri...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.9.5.721-731.1972
更新日期:1972-05-01 00:00:00
abstract::Chinese hamster X mouse somatic cell hybrids were analyzed by Southern blot hybridization with a probe specific for the cellular c-fms proto-oncogene. Results demonstrate that Fms, the genetic locus containing this sequence, maps to mouse chromosome 18. Mouse Fms is thus not linked to the same set of genes involved in...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.62.3.1055-1056.1988
更新日期:1988-03-01 00:00:00
abstract::Respiratory syncytial virus (RSV) is the most important cause of severe, lower respiratory tract infections in infants, and RSV infections have been associated with chronic wheezing and asthma during childhood. However, the mechanism of RSV-induced airway inflammation and airway hyperresponsiveness (AHR) is poorly und...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.05869-11
更新日期:2011-12-01 00:00:00
abstract::Porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV), a positive-strand RNA virus that belongs to the Arteriviridae family of Nidovirales, has been identified as the causative agent of PRRS. Nsp1alpha is the amino (N)-terminal protein in a polyprotein encoded by the PRRSV genome and is reported to be cru...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02579-08
更新日期:2009-11-01 00:00:00
abstract::EBNA2 transcriptional activation and regulated EBNALP coactivation are critical for Epstein-Barr virus-infected primary B-lymphocyte growth transformation. EBNALP coactivation requires the EBNA2 acidic activation domain (E2AD); EBNALP can bind to E2AD. EBNALP has now been found to bind less well to EBNA2 amino acids 1...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.78.20.11439-11442.2004
更新日期:2004-10-01 00:00:00
abstract::We sought proof of principle that one of the safest human vaccines, measles virus Edmonston B (MV-Edm), can be genetically modified to allow entry via cell surface molecules other than its receptor CD46. Hybrid proteins consisting of the epidermal growth factor (EGF) or the insulin-like growth factor 1 (IGF1) linked t...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.74.21.9928-9936.2000
更新日期:2000-11-01 00:00:00
abstract::In the search for effective immunologic interventions to prevent and treat HIV-1 infection, standardized reference reagents are a cost-effective way to maintain robustness and reproducibility among immunological assays. To support planned and ongoing studies where clade C predominates, here we describe three virus pan...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00991-17
更新日期:2017-09-12 00:00:00
abstract::The polycistronic P/C mRNA of Sendai virus is translated under cell-free conditions into five proteins (P, C', C, Y1, and Y2) from overlapping reading frames. In this study, we showed that in addition to the P, C', and C proteins, Y1 and Y2 were expressed by six different Sendai virus strains in infected cells. The Y ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.63.2.974-977.1989
更新日期:1989-02-01 00:00:00
abstract::We isolated, purified, and characterized the hemagglutinin-neuraminidase (HN) of human parainfluenza virus type 1, with the ultimate goal of producing crystals suitable for three-dimensional X-ray structure analysis. Pronase was used to cleave the globular head of the HN molecule directly from virus particles, forming...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.66.12.7597-7600.1992
更新日期:1992-12-01 00:00:00
abstract::Analyses of the breadth and specificity of virus-specific CD8(+) T cell responses associated with control of HIV have largely relied on measurement of cytokine secretion by effector T cells. These have resulted in the identification of HIV elite controllers with low or absent responses in which non-T-cell mechanisms o...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00531-12
更新日期:2012-06-01 00:00:00