Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-10 (of 10 Records) |
Query Trace: Kumari R[original query] |
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Antiviral Approaches against Influenza Virus.
Kumari R , Sharma SD , Kumar A , Ende Z , Mishina M , Wang Y , Falls Z , Samudrala R , Pohl J , Knight PR , Sambhara S . Clin Microbiol Rev 2023 36 (1) e0004022 Preventing and controlling influenza virus infection remains a global public health challenge, as it causes seasonal epidemics to unexpected pandemics. These infections are responsible for high morbidity, mortality, and substantial economic impact. Vaccines are the prophylaxis mainstay in the fight against influenza. However, vaccination fails to confer complete protection due to inadequate vaccination coverages, vaccine shortages, and mismatches with circulating strains. Antivirals represent an important prophylactic and therapeutic measure to reduce influenza-associated morbidity and mortality, particularly in high-risk populations. Here, we review current FDA-approved influenza antivirals with their mechanisms of action, and different viral- and host-directed influenza antiviral approaches, including immunomodulatory interventions in clinical development. Furthermore, we also illustrate the potential utility of machine learning in developing next-generation antivirals against influenza. |
Isolation and characterization of SARS-CoV-2 from the first US COVID-19 patient.
Harcourt J , Tamin A , Lu X , Kamili S , Sakthivel SK , Murray J , Queen K , Tao Y , Paden CR , Zhang J , Li Y , Uehara A , Wang H , Goldsmith C , Bullock HA , Wang L , Whitaker B , Lynch B , Gautam R , Schindewolf C , Lokugamage KG , Scharton D , Plante JA , Mirchandani D , Widen SG , Narayanan K , Makino S , Ksiazek TG , Plante KS , Weaver SC , Lindstrom S , Tong S , Menachery VD , Thornburg NJ . bioRxiv 2020 The etiologic agent of the outbreak of pneumonia in Wuhan China was identified as severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) in January, 2020. The first US patient was diagnosed by the State of Washington and the US Centers for Disease Control and Prevention on January 20, 2020. We isolated virus from nasopharyngeal and oropharyngeal specimens, and characterized the viral sequence, replication properties, and cell culture tropism. We found that the virus replicates to high titer in Vero-CCL81 cells and Vero E6 cells in the absence of trypsin. We also deposited the virus into two virus repositories, making it broadly available to the public health and research communities. We hope that open access to this important reagent will expedite development of medical countermeasures. |
Severe Acute Respiratory Syndrome Coronavirus 2 from Patient with Coronavirus Disease, United States.
Harcourt J , Tamin A , Lu X , Kamili S , Sakthivel SK , Murray J , Queen K , Tao Y , Paden CR , Zhang J , Li Y , Uehara A , Wang H , Goldsmith C , Bullock HA , Wang L , Whitaker B , Lynch B , Gautam R , Schindewolf C , Lokugamage KG , Scharton D , Plante JA , Mirchandani D , Widen SG , Narayanan K , Makino S , Ksiazek TG , Plante KS , Weaver SC , Lindstrom S , Tong S , Menachery VD , Thornburg NJ . Emerg Infect Dis 2020 26 (6) 1266-1273 The etiologic agent of an outbreak of pneumonia in Wuhan, China, was identified as severe acute respiratory syndrome coronavirus 2 in January 2020. A patient in the United States was given a diagnosis of infection with this virus by the state of Washington and the US Centers for Disease Control and Prevention on January 20, 2020. We isolated virus from nasopharyngeal and oropharyngeal specimens from this patient and characterized the viral sequence, replication properties, and cell culture tropism. We found that the virus replicates to high titer in Vero-CCL81 cells and Vero E6 cells in the absence of trypsin. We also deposited the virus into 2 virus repositories, making it broadly available to the public health and research communities. We hope that open access to this reagent will expedite development of medical countermeasures. |
Influenza virus NS1- C/EBPβ gene regulatory complex inhibits RIG-I transcription.
Kumari R , Guo Z , Kumar A , Wiens M , Gangappa S , Katz JM , Cox NJ , Lal RB , Sarkar D , Fisher PB , Garcia-Sastre A , Fujita T , Kumar V , Sambhara S , Ranjan P , Lal SK . Antiviral Res 2020 176 104747 Influenza virus non-structural protein 1 (NS1) counteracts host antiviral innate immune responses by inhibiting Retinoic acid inducible gene-I (RIG-I) activation. However, whether NS1 also specifically regulates RIG-I transcription is unknown. Here, we identify a CCAAT/Enhancer Binding Protein beta (C/EBPbeta) binding site in the RIG-I promoter as a repressor element, and show that NS1 promotes C/EBPbeta phosphorylation and its recruitment to the RIG-I promoter as a C/EBPbeta/NS1 complex. C/EBPbeta overexpression and siRNA knockdown in human lung epithelial cells resulted in suppression and activation of RIG-I expression respectively, implying a negative regulatory role of C/EBPbeta. Further, C/EBPbeta phosphorylation, its interaction with NS1 and occupancy at the RIG-I promoter was associated with RIG-I transcriptional inhibition. These findings provide an important insight into the molecular mechanism by which influenza NS1 commandeers RIG-I transcriptional regulation and suppresses host antiviral responses. |
Longevity of adenovirus vector immunity in mice and its implications for vaccine efficacy
Sayedahmed EE , Kumari R , Shukla S , Hassan AO , Mohammed SI , York IA , Gangappa S , Sambhara S , Mittal SK . Vaccine 2018 36 (45) 6744-6751 There is a high incidence of adenovirus (AdV) infection in humans due to the presence of more than 60 types of human adenoviruses (HAdVs). The majority of individuals are exposed to one or more HAdV types early in their lives, leading to the development of AdV type-specific neutralizing antibodies. Similarly, immunization or gene therapy with AdV vectors leads to immune responses to the AdV vector. This 'vector immunity' is a concern for AdV vector-based applications for vaccines or gene therapy, especially when the repeated administration of a vector is required. The objective of this investigation was to establish whether AdV neutralizing antibody titers decline sufficiently in a year to permit annual vaccination with the same AdV vector. Naive or human adenoviral vector group C, type 5 (HAdV-C5)-primed mice were mock-inoculated (with PBS) or inoculated i.m. with 10(8)PFU of either HAd-GFP [HAdV-C5 vector expressing the green fluorescent protein (GFP)] to mimic the conditions for the first inoculation with an AdV vector-based vaccine. At 1, 3, 6, and 10months post-HAd-GFP inoculation, naive- or HAdV-primed animals were vaccinated i.m. with 10(8)PFU of HAd-H5HA [HAdV-C5 vector expressing hemagglutinin (HA) of H5N1 influenza virus]. There was a significant continual decrease in vector immunity titers with time, thereby leading to significant continual increases in the levels of HA-specific humoral and cell-mediated immune responses. In addition, significant improvement in protection efficacy against challenge with an antigenically heterologous H5N1 virus was observed in HAdV-primed animals at 6months and onwards. These results indicate that the annual immunization with the same AdV vector may be effective due to a significant decline in vector immunity. |
A bovine adenoviral vector-based H5N1 influenza -vaccine provides enhanced immunogenicity and protection at a significantly low dose
Sayedahmed EE , Hassan AO , Kumari R , Cao W , Gangappa S , York I , Sambhara S , Mittal SK . Mol Ther Methods Clin Dev 2018 10 210-222 Several human and nonhuman adenovirus (AdV) vectors including bovine AdV type 3 (BAdV-3) were developed as gene delivery vectors to supplement and/or elude human AdV (HAdV)-specific neutralizing antibodies (vector immunity). Here we evaluated the vaccine immunogenicity and efficacy of BAdV-3 vector (BAd-H5HA) expressing hemagglutinin (HA) of a H5N1 influenza virus in a dose escalation study in mice with the intranasal (IN) or intramuscular (IM) route of inoculation in comparison with the HAdV type C5 (HAdV-C5) vector (HAd-H5HA) expressing HA of a H5N1 influenza virus. Dose-related increases in the immune responses were clearly noticeable. A single IM inoculation with BAd-H5HA resulted in enhanced cellular immune responses compared with that of HAd-H5HA and conferred complete protection following challenge with a heterologous H5N1 virus at the dose of 3 x 10(7) plaque-forming units (PFUs), whereas a significant amount of influenza virus was detected in the lungs of mice immunized with 1 x 10(8) PFUs of HAd-H5HA. Similarly, compared with that of HAd-H5HA, a single IN inoculation with BAd-H5HA produced significantly enhanced humoral (HA-specific immunoglobulin [IgG] and its subclasses, as well as HA-specific IgA) and cellular immune responses, and conferred complete protection following challenge with a heterologous H5N1 virus. Complete protection with BAd-H5HA was observed with the lowest vaccine dose (1 x 10(6) PFUs), but similar protection with HAd-H5HA was observed at the highest vaccine dose (1 x 10(8) PFUs). These results suggest that at least 30-fold dose sparing can be achieved with BAd-H5HA vector compared with HAd-H5HA vaccine vector. |
An integrated genomic and transcriptomic survey of mucormycosis-causing fungi.
Chibucos MC , Soliman S , Gebremariam T , Lee H , Daugherty S , Orvis J , Shetty AC , Crabtree J , Hazen TH , Etienne KA , Kumari P , O'Connor TD , Rasko DA , Filler SG , Fraser CM , Lockhart SR , Skory CD , Ibrahim AS , Bruno VM . Nat Commun 2016 7 12218 Mucormycosis is a life-threatening infection caused by Mucorales fungi. Here we sequence 30 fungal genomes, and perform transcriptomics with three representative Rhizopus and Mucor strains and with human airway epithelial cells during fungal invasion, to reveal key host and fungal determinants contributing to pathogenesis. Analysis of the host transcriptional response to Mucorales reveals platelet-derived growth factor receptor B (PDGFRB) signaling as part of a core response to divergent pathogenic fungi; inhibition of PDGFRB reduces Mucorales-induced damage to host cells. The unique presence of CotH invasins in all invasive Mucorales, and the correlation between CotH gene copy number and clinical prevalence, are consistent with an important role for these proteins in mucormycosis pathogenesis. Our work provides insight into the evolution of this medically and economically important group of fungi, and identifies several molecular pathways that might be exploited as potential therapeutic targets. |
Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.
Holmes MV , Dale CE , Zuccolo L , Silverwood RJ , Guo Y , Ye Z , Prieto-Merino D , Dehghan A , Trompet S , Wong A , Cavadino A , Drogan D , Padmanabhan S , Li S , Yesupriya A , Leusink M , Sundstrom J , Hubacek JA , Pikhart H , Swerdlow DI , Panayiotou AG , Borinskaya SA , Finan C , Shah S , Kuchenbaecker KB , Shah T , Engmann J , Folkersen L , Eriksson P , Ricceri F , Melander O , Sacerdote C , Gamble DM , Rayaprolu S , Ross OA , McLachlan S , Vikhireva O , Sluijs I , Scott RA , Adamkova V , Flicker L , Bockxmeer FM , Power C , Marques-Vidal P , Meade T , Marmot MG , Ferro JM , Paulos-Pinheiro S , Humphries SE , Talmud PJ , Mateo Leach I , Verweij N , Linneberg A , Skaaby T , Doevendans PA , Cramer MJ , Harst Pv , Klungel OH , Dowling NF , Dominiczak AF , Kumari M , Nicolaides AN , Weikert C , Boeing H , Ebrahim S , Gaunt TR , Price JF , Lannfelt L , Peasey A , Kubinova R , Pajak A , Malyutina S , Voevoda MI , Tamosiunas A , Maitland-van der Zee AH , Norman PE , Hankey GJ , Bergmann MM , Hofman A , Franco OH , Cooper J , Palmen J , Spiering W , Jong PA , Kuh D , Hardy R , Uitterlinden AG , Ikram MA , Ford I , Hypponen E , Almeida OP , Wareham NJ , Khaw KT , Hamsten A , Husemoen LL , Tjonneland A , Tolstrup JS , Rimm E , Beulens JW , Verschuren WM , Onland-Moret NC , Hofker MH , Wannamethee SG , Whincup PH , Morris R , Vicente AM , Watkins H , Farrall M , Jukema JW , Meschia J , Cupples LA , Sharp SJ , Fornage M , Kooperberg C , LaCroix AZ , Dai JY , Lanktree MB , Siscovick DS , Jorgenson E , Spring B , Coresh J , Li YR , Buxbaum SG , Schreiner PJ , Ellison RC , Tsai MY , Patel SR , Redline S , Johnson AD , Hoogeveen RC , Hakonarson H , Rotter JI , Boerwinkle E , Bakker PI , Kivimaki M , Asselbergs FW , Sattar N , Lawlor DA , Whittaker J , Davey Smith G , Mukamal K , Psaty BM , Wilson JG , Lange LA , Hamidovic A , Hingorani AD , Nordestgaard BG , Bobak M , Leon DA , Langenberg C , Palmer TM , Reiner AP , Keating BJ , Dudbridge F , Casas JP . BMJ 2014 349 g4164 OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health. |
No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels.
Scott RA , Chu AY , Grarup N , Manning AK , Hivert MF , Shungin D , Tonjes A , Yesupriya A , Barnes D , Bouatia-Naji N , Glazer NL , Jackson AU , Kutalik Z , Lagou V , Marek D , Rasmussen-Torvik LJ , Stringham HM , Tanaka T , Aadahl M , Arking DE , Bergmann S , Boerwinkle E , Bonnycastle LL , Bornstein SR , Brunner E , Bumpstead SJ , Brage S , Carlson OD , Chen H , Chen YD , Chines PS , Collins FS , Couper DJ , Dennison EM , Dowling NF , Egan JS , Ekelund U , Erdos MR , Forouhi NG , Fox CS , Goodarzi MO , Grässler J , Gustafsson S , Hallmans G , Hansen T , Hingorani A , Holloway JW , Hu FB , Isomaa B , Jameson KA , Johansson I , Jonsson A , Jørgensen T , Kivimaki M , Kovacs P , Kumari M , Kuusisto J , Laakso M , Lecoeur C , Lévy-Marchal C , Li G , Loos RJ , Lyssenko V , Marmot M , Marques-Vidal P , Morken MA , Müller G , North KE , Pankow JS , Payne F , Prokopenko I , Psaty BM , Renström F , Rice K , Rotter JI , Rybin D , Sandholt CH , Sayer AA , Shrader P , Schwarz PE , Siscovick DS , Stancáková A , Stumvoll M , Teslovich TM , Waeber G , Williams GH , Witte DR , Wood AR , Xie W , Boehnke M , Cooper C , Ferrucci L , Froguel P , Groop L , Kao WH , Vollenweider P , Walker M , Watanabe RM , Pedersen O , Meigs JB , Ingelsson E , Barroso I , Florez JC , Franks PW , Dupuis J , Wareham NJ , Langenberg C . Diabetes 2012 61 (5) 1291-6 Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) x BMI and SNP x physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (beta = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 x 10(-6)). All SNPs were associated with 2-h glucose (beta = 0.06-0.12 mmol/allele, P ≤ 1.53 x 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions. |
Influenza A virus neuraminidase protein enhances cell survival through interaction with carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) protein
Gaur P , Ranjan P , Sharma S , Patel JR , Bowzard JB , Rahman SK , Kumari R , Gangappa S , Katz JM , Cox NJ , Lal RB , Sambhara S , Lal SK . J Biol Chem 2012 287 (18) 15109-17 The influenza virus neuraminidase (NA) protein primarily aids in the release of progeny virions from infected cells. Here, we demonstrate a novel role for NA in enhancing host cell survival by activating the Src/Akt signaling axis via an interaction with carcinoembryonic antigen-related cell adhesion molecule 6/cluster of differentiation 66c (C6). NA/C6 interaction leads to increased tyrosyl phosphorylation of Src, FAK, Akt, GSK3beta, and Bcl-2, which affects cell survival, proliferation, migration, differentiation, and apoptosis. siRNA-mediated suppression of C6 resulted in a down-regulation of activated Src, FAK, and Akt, increased apoptosis, and reduced expression of viral proteins and viral titers in influenza virus-infected human lung adenocarcinoma epithelial and normal human bronchial epithelial cells. These findings indicate that influenza NA not only aids in the release of progeny virions, but also cell survival during viral replication. |
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