Langlois, Marc-André - University of Ottawa - Department of Biochemistry, Microbiology and Immunology

研究领域

Repelling retroviruse: Dr Marc-André Langlois discusses his research into the immune response to retroviruses, as well as his new technique for screening DNA for rare mutated proviral sequences. International Innovation. Laboratory of Molecular Virology and Intrinsic Immunity Intrinsic immunity represents the collection of continuously active mechanisms that protect a host from viral pathogens. This unique feature of intrinsic immunity sets it apart from conventional adaptive and innate immune responses in that it does not require priming by the recognition of viral epitopes or pathogen associated molecular patterns (PAMPS), nor does it require a downstream cascade of signaling events. Host-encoded intrinsic restriction factors are proteins that constitute the first line of defense against viral pathogens. Retroviruses pose a unique threat because they permanently insert their genetic material into the genome of their host during the infection. In addition to the disease that may be caused by the virus, integration can lead to gene deregulation and cancer. APOBEC3 proteins are potent intrinsic restriction factors expressed in lymphocytes, macrophages and dendritic cells, all of which play important roles in the infection cycle of retroviruses. Humans express 7 APOBEC3 proteins with APOBEC3G (A3G) being the best-studied member of the APOBEC3 family. To prevent the spread of retroviruses, A3G can mutate retroviral DNA prior to its integration into the host’s genome. A3G can also inhibit the early stages of the retroviral infection by hindering replication and preventing retroviral integration. The sum of these antiviral effects will result in a dramatic decrease in viral DNA being integrated into the host’s genome and in damage to the genetic code of progeny retroviruses that have come into contact with A3G. Our Research interests: there are three main research themes in our laboratory. The first is to study the unintended consequences of viral DNA mutagenesis by APOBEC3 proteins. Although APOBEC3 proteins are retroviral restriction factors, there may exist situations where the mutagenic potential of these host proteins is beneficial for viral fitness and immune evasion. This is now of particular concern in the case of HIV and as such part of this research is funded by the CanCURE Research Consortium. Our second research theme is to study how APOBEC3 work and interact with host proteins and nucleic acids. Although we know a lot about how APOBEC3 proteins mutate viral DNA, there are still large gaps in our knowledge about how these proteins are regulated and how they are prevented from damaging the host’s genomic DNA. Here our research is deciphering the cellular roles of the members of the APOBEC3 family, and how their activities are being regulated. Finally, our third theme of research is to develop new technological approaches called Flow Virometry, that enable single particle analysis of viruses. This technology has significant implications for vaccine design and quality control, and also for acquiring a better understanding of the antigens expressed at the surface of viruses such as HIV.

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Bélanger, K. and Langlois, M.A. (2015) Comparative Analysis of the Gene-Inactivating Potential of Retroviral Restriction Factors APOBEC3F and APOBEC3G. Journal of General Virology. Sep;96(9):2878-87. Rosales Gerpe, M.C., Renner, T.M., Bélanger, K., Lam, C., Aydin, H., and Langlois, M.A.(2015) N-Linked Glycosylation Protects Gammaretroviruses Against Deamination by APOBEC3 Proteins. Journal of Virology. Feb; 89 (4): 2342-57 Bélanger, K. and Langlois, M.A.(2015) RNA-Binding Residues in the N-Terminus of APOBEC3G Influence its DNA Sequence Specificity and Retrovirus Restriction Efficiency. Virology. Volume 483, Sept. 2015, Pages 141-148 Bélanger, K., Savoie, M., Aydin, H., Renner, M.T., Montazeri, Z. and Langlois, M.A. (2014) Deamination intensity profiling of human APOBEC3 protein activity along the near full-length genomes of HIV-1 and MoMLV by HyperHRM analysis. Virology. Volume 448, 5 January 2014, Pages 168–175 Bélanger, K., Savoie, M., Couture, J.F., and Langlois, M.A. (2013) Binding of RNA by APOBEC3G Controls Deamination-Independent Restriction of Retroviruses. Nucleic Acids Research. Aug 1; 41(15):7438-52. Langlois, M.A. (2010) Mother’s Milks and Intrinsic Immunity. Cell Host and Microbe. Dec; 8 (6): 467-469. Langlois, M.A., Kemmerich, K, Rada,C and Neuberger, M.S. (2009) The AKV murine leukemia virus is restricted and hypermutated by mouse APOBEC3. Journal of Virology, November, 83(22): 430 - 439 Langlois, M.A. and Neuberger, M.S. (2008) Human APOBEC3G can restrict Infection in avian cells and acts independently of both UNG and SMUG1. Journal of Virology. May, 82 (9): 4660-4664. Takeda, E., Tsuji-Kawahara, S., Sakamoto, Langlois, M.A., Neuberger, M.S., Rada, C. and Miyazawa, M. (2008) Mouse APOBEC3 restricts Friend leukaemia virus infections and pathogenesis in vivo. Journal of Virology. Nov; 82(22):10998-1008. Conticello, S.G., Langlois, M.A. and Neuberger, M.S. (2007) Insights into DNA deaminases. Nature Structural and Molecular Biology. Jan; 14(1): 7-9. Langlois, M.A., Beale, R.C., Conticello, S.G., and Neuberger, M.S. (2005) Mutational comparaison of the single-domained APOBEC3C and double-domained APOBEC3F/3G antiretroviral cytidine deaminases provides insight into their DNA target site specificities. Nucleic Acids Research. April 4, 33 (6): 1913-1923.