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Pascua, Philippe Noriel Q.,Song, Min-Suk,Kwon, Hyeok-Il,Lim, Gyo-Jin,Kim, Eun-Ha,Park, Su-Jin,Lee, Ok-Jun,Kim, Chul-Joong,Webby, Richard J.,Webster, Robert G.,Choi, Young-Ki American Society for Microbiology 2013 Journal of virology Vol.87 No.19
<P>We previously reported that influenza A/swine/Korea/1204/2009(H1N2) virus was virulent and transmissible in ferrets in which the respiratory-droplet-transmissible virus (CT-Sw/1204) had acquired simultaneous hemagglutinin (HA<SUB>D225G</SUB>) and neuraminidase (NA<SUB>S315N</SUB>) mutations. Incorporating these mutations into the nonpathogenic A/swine/Korea/1130/2009(H1N2, Sw/1130) virus consequently altered pathogenicity and growth in animal models but could not establish efficient transmission or noticeable disease. We therefore exploited various reassortants of these two viruses to better understand and identify other viral factors responsible for pathogenicity, transmissibility, or both. We found that possession of the CT-Sw/1204 tripartite viral polymerase enhanced replicative ability and pathogenicity in mice more significantly than did expression of individual polymerase subunit proteins. In ferrets, homologous expression of viral RNA polymerase complex genes in the context of the mutant Sw/1130 carrying the HA<SUB>225G</SUB> and NA<SUB>315N</SUB> modifications induced optimal replication in the upper nasal and lower respiratory tracts and also promoted efficient aerosol transmission to respiratory droplet contact ferrets. These data show that the synergistic function of the tripartite polymerase gene complex of CT-Sw/1204 is critically important for virulence and transmission independent of the surface glycoproteins. Sequence comparison results reveal putative differences that are likely to be responsible for variation in disease. Our findings may help elucidate previously undefined viral factors that could expand the host range and disease severity induced by triple-reassortant swine viruses, including the A(H1N1)pdm09 virus, and therefore further justify the ongoing development of novel antiviral drugs targeting the viral polymerase complex subunits.</P>
Virulence of pandemic (H1N1) 2009 influenza A polymerase reassortant viruses.
Song, Min-Suk,Pascua, Philippe Noriel Q,Choi, Young Ki Landes Bioscience 2011 Virulence Vol.2 No.5
<P>Infections due to the pandemic (H1N1) 2009 influenza A viruses have been considerably mild relative to previous pandemics. However, its continued circulation among human and animal populations heightened concerns for the generation of virulent variants with greater threat to public health. Thus, we explored the potential role of the influenza viral polymerases, including known molecular markers, in altering the virulence phenotype of the 2009 pandemic A/California/04/09 (CA04, H1N1) virus. By examining in vitro polymerase activities and in vivo pathogenicities in mice model, we were able to show that individual or simultaneous expression of virulence factors in PB2, PB1, and PA might not significantly elevate pathogenicity. Nevertheless, we demonstrated that PB2(627K) or PA(97I) derived from different genetic backgrounds and other unknown polymerase markers have the potential to enhance virulence of CA04. Virus rescue and replication studies identified PA as a critical factor in maintaining genetic stability of the CA04 (H1N1) virus.</P>
Evaluation of the Efficacy of a Pre-pandemic H5N1 Vaccine (MG1109) in Mouse and Ferret Models
송민석,문호진,권혁일,Philippe Noriel Q. Pascua,이준한,백윤희,우규진,최주희,이상호,유현승,오인경,윤엽,노종복,성문희,홍승표,김철중,최영기 한국미생물학회 2012 The journal of microbiology Vol.50 No.3
The threat of a highly pathogenic avian influenza (HPAI) H5N1 virus causing the next pandemic remains a major concern. In this study, we evaluated the immunogenicity and efficacy of an inactivated whole-virus H5N1 pre-pandemic vaccine (MG1109) formulated by Green Cross Co., Ltd containing the hemagglutinin (HA) and neuraminidase (NA) genes of the clade 1 A/Vietnam/1194/04 virus in the backbone of A/Puerto Rico/8/34 (RgVietNam/04xPR8/34). Administration of the MG1109 vaccine (2-doses) in mice and ferrets elicited high HI and SN titers in a dose-dependent manner against the homologous (RgVietNam/04xPR8/34) and various heterologous H5N1 strai(RgKor/W149/06xPR8/34,RgCambodia/ 04xPR8/34,RgGuangxi/05xPR8/34), including a heterosubtypic H5N2 (A/Aquatic bird/orea/W81/05) virus. However, efficient cross-reactivity was not observed against heterosubtypic H9N2 (A/Ck/Korea/H0802/08) and H1N1 (PR/8/34) viruses. Mice immunized with 1.9 μg HA/dose of MG1109 were completely protected from lethal challenge with heterologous wild-type HPAI H5N1 A/EM/Korea/W149/06 (clade 2.2) and mouse-adapted H5N2 viruses. Furthermore, ferrets administered at least 3.8 μg HA/dose efficiently suppressed virus growth in the upper respiratory tract and lungs. Vaccinated mice and ferrets also demonstrated attenuation of clinical disease signs and limited virus spread to other organs. Thus, this vaccine provided immunogenic responses in mouse and ferret models even against challenge with heterologous HPAI H5N1 and H5N2 viruses. Since the specific strain of HPAI H5N1 virus that would potentially cause the next outbreak is unknown, pre-pandemic vaccine preparation that could provide crossprotection against various H5 strains could be a useful approach in the selection of promising candidate vaccines in the future.
Isolation and Genetic Characterization of H5N2 Influenza Viruses from Pigs in Korea
Lee, Jun Han,Pascua, Philippe Noriel Q.,Song, Min-Suk,Baek, Yun Hee,Kim, Chul-Joong,Choi, Hwan-Woon,Sung, Moon-Hee,Webby, Richard J.,Webster, Robert G.,Poo, Haryoung,Choi, Young Ki American Society for Microbiology 2009 Journal of virology Vol.83 No.9
<B>ABSTRACT</B><P>Due to dual susceptibility to both human and avian influenza A viruses, pigs are believed to be effective intermediate hosts for the spread and production of new viruses with pandemic potential. In early 2008, two swine H5N2 viruses were isolated from our routine swine surveillance in Korea. The sequencing and phylogenetic analysis of surface proteins revealed that the Sw/Korea/C12/08 and Sw/Korea/C13/08 viruses were derived from avian influenza viruses of the Eurasian lineage. However, although the Sw/Korea/C12/08 isolate is an entirely avian-like virus, the Sw/Korea/C13/08 isolate is an avian-swine-like reassortant with the PB2, PA, NP, and M genes coming from a 2006 Korean swine H3N1-like virus. The molecular characterization of the two viruses indicated an absence of significant mutations that could be associated with virulence or binding affinity. However, animal experiments showed that the reassortant Sw/Korea/C13/08 virus was more adapted and was more readily transmitted than the purely avian-like virus in a swine experimental model but not in ferrets. Furthermore, seroprevalence in swine sera from 2006 to 2008 suggested that avian H5 viruses have been infecting swine since 2006. Although there are no known potential clinical implications of the avian-swine reassortant virus for pathogenicity in pigs or other species, including humans, at present, the efficient transmissibility of the swine-adapted H5N2 virus could facilitate virus spread and could be a potential model for pandemic, highly pathogenic avian influenza (e.g., H5N1 and H7N7) virus outbreaks or a pandemic strain itself.</P>
Song, Min-Suk,Pascua, Philippe Noriel Q.,Lee, Jun Han,Baek, Yun Hee,Lee, Ok-Jun,Kim, Chul-Joong,Kim, Hyunggee,Webby, Richard J.,Webster, Robert G.,Choi, Young Ki American Society for Microbiology 2009 Journal of virology Vol.83 No.23
<B>ABSTRACT</B><P>Adaptation of influenza A viruses to a new host species usually involves the mutation of one or more of the eight viral gene segments, and the molecular basis for host range restriction is still poorly understood. To investigate the molecular changes that occur during adaptation of a low-pathogenic avian influenza virus subtype commonly isolated from migratory birds to a mammalian host, we serially passaged the avirulent wild-bird H5N2 strain A/Aquatic bird/Korea/W81/05 (W81) in the lungs of mice. The resulting mouse-adapted strain (ma81) was highly virulent (50% mouse lethal dose = 2.6 log10 50% tissue culture infective dose) and highly lethal. Nonconserved mutations were observed in six viral genes (those for PB2, PB1, PA, HA, NA, and M). Reverse genetic experiments substituting viral genes and mutations demonstrated that the PA gene was a determinant of the enhanced virulence in mice and that a Thr-to-Iso substitution at position 97 of PA played a key role. In growth kinetics studies, ma81 showed enhanced replication in mammalian but not avian cell lines; the PA97I mutation in strain W81 increased its replicative fitness in mice but not in chickens. The high virulence associated with the PA97I mutation in mice corresponded to considerably enhanced polymerase activity in mammalian cells. Furthermore, this characteristic mutation is not conserved among avian influenza viruses but is prevalent among mouse-adapted strains, indicating a host-dependent mutation. To our knowledge, this is the first study that the isoleucine residue at position 97 in PA plays a key role in enhanced virulence in mice and is implicated in the adaptation of avian influenza viruses to mammalian hosts.</P>
Park, Su-Jin,Kim, Eun-Ha,Pascua, Philippe Noriel Q.,Kwon, Hyeok-Il,Lim, Gyo-Jin,Decano, Arun,Kim, Se Mi,Song, Man Ki,Shin, Eui-Cheol,Choi, Young-Ki Society for General Microbiology 2014 The Journal of general virology Vol.95 No.4
<P>The threat of highly pathogenic avian influenza (HPAI) H5N1 viruses to cause the next pandemic remains a major concern. Here, we evaluated the cross-protection induced by natural infection of human seasonal influenza strains or immunization with trivalent inactivated influenza vaccine (TIV) against HPAI H5N1 (A/Vietnam/1203/2004) virus in ferrets. Groups were treated with PBS (group A), infected with H1N1 (group B) or H3N2 (group C) virus, or immunized with TIV (group D). Twelve weeks after the last treatment, serological assays revealed that groups B and C, but not group D, sustained moderate immunogenicity against homologous viruses; cross-reactivity against the H5N1 virus was not detected in any group. Following challenge with A/Vietnam/1203/2004 (H5N1) virus, only groups B and C exhibited attenuated viral loads leading to 100 % survival. Our data suggest that natural infection with human seasonal strains could potentially provide better heterosubtypic protection against HPAI H5N1 virus infection compared to TIV immunization.</P>
Adjuvant Efficacy of mOMV against Avian Influenza Virus Infection in Mice
Byeong-Jae Lee,Sang-Ho Lee,송민석,Philippe Noriel Q. Pascua,권혁일,박수진,김은하,Arun Decano,Se Mi Kim,임규진,김두진,장규태,김상현,최영기 한국미생물학회 2013 The journal of microbiology Vol.51 No.5
Highly pathogenic avian influenza H5N1 viruses are found chiefly in birds and have caused severe disease and death in infected humans. Development of influenza vaccines capable of inducing heterosubtypic immunity against a broad range of influenza viruses is the best option for the preparedness,since vaccination remains the principal method in controlling influenza viral infections. Here, a mOMV-adjuvanted recombinant H5N2 (rH5N2) whole virus antigen vaccine with A/Environment/Korea/W149/06(H5N1)-derived H5 HA and A/Chicken/Korea/ma116/04(H9N2)-derived N2 NA in the backbone of A/Puerto Rico/8/34(H1N1) was prepared and generated by reverse genetics. Groups of mice were vaccinated by a prime-boost regime with the rH5N2 vaccine (1.75 μg of HA with/without 10 μg mOMV or aluminum hydroxide adjuvant for comparison). At two weeks post-immunizations,vaccinated mice were challenged with lethal doses of 103.5 EID50/ml of H5N1 or H9N2 avian influenza viruses, and were monitored for 15 days. Both mOMV- and alum-adjuvant vaccine groups had high survival rates after H5N1 infection and low levels of body weight changes compared to control groups. Interestingly, the mOMV-adjuvanted group induced better cross-reactive antibody responses serologically and promoted cross-protectivity against H5N1and H9N2 virus challenges. Our results suggest that mOMV could be used as a vaccine adjuvant in the development of effective vaccines used to control influenza A virus transmission.
Adjuvant Efficacy of mOMV Against Avian Influenza Virus Infection in Mice
Byeong-Jae Lee,Min-Suk Song,Philippe Noriel Q. Pascua,Hyeok-il Kwon,Su-Jin Park,Eun-Ha Kim,Arun Decano,Se Mi Kim,Gyo Jin Lim,Sang-Ho Lee,Kyu-Tae Chang,Sang-Hyun Kim,Young Ki Choi 한국실험동물학회 2014 한국실험동물학회 학술발표대회 논문집 Vol.2014 No.2
백윤희,Jeung Hyun Park,송영진,송민석,Philippe Noriel Q. Pascua,한윤수,한헌석,이옥준,김기순,강춘,최영기 한국미생물학회 2009 The journal of microbiology Vol.47 No.1
To investigate the genetic characteristics of human influenza viruses circulating in Chungbuk province, we tested 510 clinical samples of nasopharyngeal suction from pediatric patients diagnosed with respiratory illness between June 2007 and June 2008. Genetic characterization of the HA genes of H3N2 isolates indicated the relative higher similarity to A/Virginia/04/07 (99.6%) rather than that of A/Wisconsin/67/2005 (98.4%), a Northern Hemisphere 2007~2008 vaccine strain, based on amino acid sequences. We found several altered amino acids at the H3 HA1 antigenic sites compared with the vaccine strain; K140I at site A, K158R at site B, and K173N (H471) or K173Q, and S262N at site E, but there was no antigenic shift among the H3N2 viruses. Interestingly, A/Cheongju/H383/08 and A/Cheongju/H407/08 isolates had single amino acid substitution at D151G on the catalytic site of the N2 NA while A/Cheongju/H412/08 and A/Cheongju/ H398/07 isolates had one amino acid deletion at residue 146. Furthermore, we found that 25% (3 out of 12 isolates) of the H3N2 subtype viruses had the amino acid substitution at position 31 on the M2 protein (Aspartic acid to Asparagine) and confirmed their drug-resistance by biological assays. Taken together, the results of this study demonstrated continuous evolutions of human H3N2 viruses by antigenic drift and also highlighted the need to closely monitor antigenic drug resistance in influenza A viruses to aid in the early detection of potentially pandemic strains, as well as underscore the need for new therapeutics.