- Professor, Department of Microbiology, Committee on Immunology, Committee on Microbiology
The University of Chicago
924 E. 57th Street
Chicago, Illinois 60637
Phone: (773) 834-7988
Tatyana received her M.S. in Biochemistry from Moscow State University, Moscow, former USSR. She pursued graduate studies at the USSR Academy of Medical Sciences Cancer Research Center, Moscow, USSR in the laboratory of Andrei Gudkov. Her doctoral thesis describes studies on evolution of endogenous retroviruses in mammalian genome. She then joined Susan Ross’ laboratory at the Department of Biochemistry, University of Illinois at Chicago and later moved with the lab to University of Pennsylvania, Department of Microbiology. She obtained an independent position at The Jackson Laboratory in Bar Harbor, ME in 1997 where she studied genetics of resistance to viral infection and in 2005, she re-located her laboratory to the Department of Microbiology at the University of Chicago.
The primary goal of Golovkina’s laboratory is to understand how the innate immune system detects viral infection and initiates virus-neutralizing adaptive immune responses. In addition, she is also interested in mechanisms evolved by viruses to overcome host protective responses. To investigate these important questions, Golovkina’s lab employ virus-resistant mice capable of controlling retroviruses from distinct genera.
Like mice from resistant strains mice from susceptible stocks detect retroviruses in the TLR7-mediated fashion (Kane et al, Immunity 2011). However, the virus sensing in these animals does not lead to the productive anti-virus immune response. Golovkina’s lab found that an orally transmitted retrovirus, when ingested by newborn mice, stimulates a state of unresponsiveness toward viral antigens. This process required the intestinal microbiota, as antibiotic-treated mice or germ-free mice did not transmit infectious virus to their offspring. Subsequently they discovered that the virus binds bacterial lipopolysaccharide (LPS) and triggers Toll-like receptor 4 (TLR4)-mediated induction of the inhibitory cytokine IL-10 (Kane et al, Science 2011). Most recently the lab established LPS binding occurs via LPS receptors integrated in the viral envelope during budding (Wilks et al, Cell Host and Microbe, 2015). Thus, retroviruses exploit the host LPS binding machinery to bind LPS to activate the immune evasion pathway.
All animals, including humans, show different susceptibility to infectious retroviruses. Mice of the I/LnJ strain control both gamma- and betaretroviruses via the same recessive immune mechanism, which involves production of virus-neutralizing antibodies (Purdy et al, J Exp Med 2003; Case et al, J Immunol 2005; Case et al, J Virol 2007). Even though I/LnJ mice become infected with both viruses, they produce anti-virus Abs which coat virions, rendering them uninfectious. As a consequence, retroviruses are eliminated from infected mice. The retrovirus resistance mechanism in I/LnJ mice is controlled by a single locus, virus infectivity controller 1 (vic1), that the lab mapped to Chromosome 17 (Case et a., J Virol, 2007). Using positional cloning approach Golovkina’s lab identified the gene responsible for production of retrovirus-neutralizing antibodies in mice of the I/LnJ strain. It encodes the beta subunit of the non-classical major histocompatibility complex class II (MHC-II)-like molecule H2-O, a negative regulator of antigen presentation. The recessive and functionally null I/LnJ H2-Ob allele supported the production of virus-neutralizing antibodies independently of the classical MHC haplotype. Subsequent bioinformatics and functional analyses of the human H2-Ob homolog, HLA-DOB, revealed both loss- and gain-of-function alleles, which could affect the ability of their carriers to control infections with human hepatitis B (HBV) and C (HCV) viruses (Denzin et. al, 2017, Immunity 47, 310-322).. Thus, understanding of the previously unappreciated role of H2-O (HLA-DO) in immunity to infections may suggest new approaches in achieving neutralizing immunity to viruses.
Retroviruses earned their notoriety by inducing a broad range of tumors in vertebrates. Whereas some retroviruses carry oncogenes in their genome, the vast majority of retroviruses do not encode such elements and thus, must integrate near cellular proto-oncogenes and up-regulate them to induce tumors. Many cellular genes involved in tumorigenesis were first identified as viral oncogenes (v-onc) or genes up-regulated upon retroviral insertion. They are now known to be involved in various types of spontaneous tumors in humans. Up-regulation of cellular protooncogenes via insertional mutagenesis or insertion of v-oncs constitutes a necessary step for tumor induction. However, up-regulation of an oncogene alone is not sufficient for tumor induction and other events are required for tumor development. Preliminary data generated in Golovkina’s lab suggest that the gut commensal bacteria serve as an epigenetic factor that contributes to virally-induced cancer. Using well-defined animal models, Golovkina’s lab is searching for the mechanism(s) by which the commensal microbiota promotes virally induced tumorigenesis.