H1N1 신종플루 바이러스가 인간에게 효과적으로 전파되기 위하여 새로운 생화학적 속임수를 사용했다는 연구결과가 발표되었다는 소식입니다.
위스콘신대학교의 수의학과의 요시히로 가와오카 교수(Prof. Yoshihiro Kawaoka) 가 이끄는 일본, 미국, 인도네시아 등 다국적 연구진들이 2010년 8월 5일자 [PLoS Pathogens]에 발표한 ‘인플루엔자 바이러스의 숙주-적응 아미노산의 생물학적 및 구조적 특징’이라는 논문에 따르면, 독감 바이러스가 다른 동물 숙주로 종간장벽을 뛰어넘기 위해서는 주요 조류 바이러스 단백질(PB2)의 특정한 부위에 있는 라이신(lysine)과 아스파라긴(asparagines)이라는 2개의 아미노산((lysine at position 627 or asparagine at position 701)이 존재해야 하는데… H1N1 바이러스는 이러한 아미노산들을 형성하는 능력이 결핍되어 있어 과학자들을 혼란에 빠뜨렸습니다. 다시 말해 조류-유사 PB2 유전자를 가지고 있는 대유행 H1N1 바이러스는 인간-형태의 아미노산 PB2-627K와 PB2-701N를 암호화(encode)할 수 없음이 밝혀진 바 있습니다.
그런데 이번에 생쥐를 이용한 동물실험에서 독감 바이러스 단백질의 완전히 다른 부위(position 591 of PB2)에 있는 라이신 아미노산의 잔기(resides)가 인간세포를 흡수하고 적응하여 효과적으로 자신을 복제할 수 있는 능력을 가지고 있다는 사실이 밝혀졌습니다.
또한 바이러스 단백질의 다른 부위(position 591 of PB2)에 있는 기본적인 아미노산이 조류독감 바이러스 H5N1에 감염된 쥐의 치사율을 높여준다는 사실도 밝혀졌습니다.
연구진들은 2009 대유행 H1N1 바이러스의 PB2 단백질 C-말단의 방사선 결정학적 구조도 규명했습니다. 특히 position 591의 아미노산 구조의 차이는 단백질과 바이러스 및(또는) 세포인자의 상호작용에 영향을 끼칠 수 있으며, 이로인해 포유류에서 바이러스가 자기복제를 할 능력을 지닐 수 있다고 합니다.
위스콘신대학교의 수의학과의 요시히로 가와오카 교수팀은 올해 초 인플루엔자 바이러스 치료에 효과가 있는 새로운 뉴라미니데이즈 저해제(neuraminidase inhibitor)인 R-125489와 이의 전구물질인 CS-8958을 발견했다고 발표한 바 있습니다.(Efficacy of the New Neuraminidase Inhibitor CS-8958 against H5N1 Influenza Viruses. PLoS Pathog, 6(2))
요시히로 가와오카 교수팀는 자신이 발견한 물질이 한번 투약으로 치료와 예방효과를 모두 보였으며, 유행성 독감과 계절성 독감에 모두 효과가 있다고 주장한 바 있습니다.
이들이 발견한 약물이 실제 임상에 적용되기 위해서는 추가적인 연구가 필요한 상황입니다.
요시히로 가와오카 교수가 이끄는 일본, 미국, 인도네시아 등 다국적 연구진들이 발표한 논문의 초록은 아래에 있으며, 논문의 전문은 첨부파일에 있습니다.
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Biological and Structural Characterization of a Host-Adapting Amino Acid in Influenza Virus
출처 : Yamada S, Hatta M, Staker BL, Watanabe S, Imai M, et al. (2010)
PLoS Pathog 6(8): e1001034. doi:10.1371/journal.ppat.1001034
http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1001034
1 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan, 2 Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America, 3 Emerald BioStructures, Inc., Bainbridge Island, Washington, United States of America, 4 Seattle Structural Genomics Center for Infectious Disease, Washington, United States of America, 5 Department of Microbiology and Infectious Diseases, Kobe University, Hyogo, Japan, 6 Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan, 7 ERATO Infection-Induced Host Responses Project, Saitama, Japan, 8 Seattle Biomedical Research Institute, Seattle, Washington, United States of America, 9 Departments of Global Health and Medical Education & Biomedical Informatics, University of Washington, Seattle, Washington, United States of America, 10 Faculty of Veterinary Medicine, Tropical Disease Centre, Airlangga University, Surabaya, Indonesia, 11 Collaborating Research Center-Emerging and Reemerging Infectious Diseases, Tropical Disease Centre, Airlangga University, Surabaya, Indonesia, 12 Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America, 13 Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America, 14 Creative Research Initiative, Sousei, Hokkaido University, Sapporo, Japan
Abstract
Two amino acids (lysine at position 627 or asparagine at position 701) in the polymerase subunit PB2 protein are considered critical for the adaptation of avian influenza A viruses to mammals. However, the recently emerged pandemic H1N1 viruses lack these amino acids. Here, we report that a basic amino acid at position 591 of PB2 can compensate for the lack of lysine at position 627 and confers efficient viral replication to pandemic H1N1 viruses in mammals. Moreover, a basic amino acid at position 591 of PB2 substantially increased the lethality of an avian H5N1 virus in mice. We also present the X-ray crystallographic structure of the C-terminus of a pandemic H1N1 virus PB2 protein. Arginine at position 591 fills the cleft found in H5N1 PB2 proteins in this area, resulting in differences in surface shape and charge for H1N1 PB2 proteins. These differences may affect the protein’s interaction with viral and/or cellular factors, and hence its ability to support virus replication in mammals.
Author Summary
Influenza viruses that originate from avian species likely have to acquire adapting amino acid changes to replicate efficiently in mammals. Two amino acid changes in the polymerase PB2 protein—a glutamic acid to lysine change at position 627 or an aspartic acid to asparagine change at position 701—are known to allow influenza viruses of avian origin to replicate efficiently in mammals. Interestingly, the pandemic H1N1 viruses (which possess an avian-like PB2 gene) do not encode the ‘human-type’ amino acids PB2-627K and PB2-701N. Here, we report that a basic amino acid at position 591 of PB2 can compensate for the lack of PB2-627K and allows efficient replication of highly pathogenic H5N1 and pandemic H1N1 viruses in mammalian species. We also present the X-ray crystal structure of the C-terminal portion of a pandemic H1N1 PB2 protein. The basic amino acid at position 591 fills a distinctive cleft found in the PB2 proteins of H5N1 viruses. We also speculate on the biological significance of the altered surface of the H1N1 PB2 protein.
Citation: Yamada S, Hatta M, Staker BL, Watanabe S, Imai M, et al. (2010) Biological and Structural Characterization of a Host-Adapting Amino Acid in Influenza Virus. PLoS Pathog 6(8): e1001034. doi:10.1371/journal.ppat.1001034
Editor: Daniel R. Perez, University of Maryland, United States of America
Received: March 9, 2010; Accepted: July 12, 2010; Published: August 5, 2010
Copyright: © 2010 Yamada et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by a National Institute of Allergy and Infectious Diseases Public Health Service research grants (R01 AI069274), by an NIAID-funded Center for Research on Influenza Pathogenesis (CRIP, HHSN266200700010C), by Grant-in-Aid for Specially Promoted Research, by a contract research fund for the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases from the Ministry of Education, Culture, Sports, Science and Technology, and by grants-in-aid from the Ministry of Health and by ERATO (Japan Science and Technology Agency). This research was also funded by NIAID under Federal Contract No. HHSN272200700057C which supports the Seattle Structural Genomics Center for Infectious Disease (www.SSGCID.org). Support for deep sequence analysis was provided by US National Center for Research Resources grant P51 RR000167 to the Wisconsin National Primate Research Center. Dr. Shinya was supported by Precursory Research for Embryonic Science and Technology (PRESTO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: kawaokay@svm.vetmed.wisc.edu (YK, for virological research aspects); lstewart@embios.com (LJS, for structural research aspects)
