Shan-Lu Liu

Professor, Director - Viruses and Emerging Pathogens Program, Infectious Disease Institute
Graduate Faculty

Research Interests

  • Host restriction to viral infection and viral countermeasures
  • Viral cell-to-cell transmission
  • Innate immunity and sensing of viral infection
  • Mechanisms of viral membrane fusion and entry
  • Cell signaling, viral oncogenes, and human lung cancer
  • Model viruses of study – HIV, Ebola virus, Influenza A virus, Zika virus, hepatitis C virus, and oncogenic sheep retroviruses

1.IFITM restriction of viral infection

The interferon (IFN) system is the first line of host defense against pathogen invasion, including viral infections. Shortly after IFN induction or viral infection, cells express hundreds of IFN-stimulated genes (ISGs) that modulate diverse biological processes, including the establishment of antiviral states. The IFN-induced transmembrane (IFITM) protein family belongs to a group of small ISGs (~15 kD) that block the early stages of viral replication. Specifically, IFITM proteins restrict entry of a wide range of viruses, including highly pathogenic influenza A virus (IAV), SARS coronarvirus, Ebolavirus (EBOV), and HIV.

Recent work from our lab and others showed that IFITM proteins inhibit cell-cell fusion by IAV HA, Semliki Forest virus (SFV) E1, and vesicular stomatitis virus (VSV) G proteins, which represent class I, II and III viral fusion proteins, respectively. Interestingly, we have found that some viruses are more sensitive than others to inhibition by particular types of IFITMs, suggesting that IFITM-mediated restriction of viral entry can be virus-strain specific and IFITM-species dependent (Li et al, PLoS Pathogens 2013). Indeed, we showed that IFITM2 and IFITM3, but not IFITM2, specifically interact with HIV-1 Env, thus inhibiting its processing and viral infectivity (Yu et al, Cell Reports, 2015). Currently, we are using a variety of biophysical, biochemical, forward genetics, as well as molecular approaches to dissect the distinct mechanisms of IFITM restriction of viral entry and cell-cell spread. The model viruses applied to this project include IAV, Ebola virus (EBOV), and HIV-1.

IFITMs-Inhibit-Cell-HIV-Producing-Cell

2.Viral entry, fusion and cell-to-cell transmission

Entry is the first step of viral replication and essential for viral pathogenesis. While the core mechanism of virus fusion and entry is known, it remains poorly understood how exactly viral fusion proteins are activated and how the entry process is controlled for most pathogenic animal viruses. The objective of this project is to better understand the mechanisms of membrane fusion and entry by EBOV and Zika virus. We are particularly focused on cellular and viral factors in the fusion triggering and entry process, including receptor binding, low pH, and additional cellular and viral determinants.

EBOV is a highly pathogenic filovirus that causes severe hemorrhagic fever in humans, with a fatality rate of up to 90%. Currently, there is no effective antiviral drug or FDA-approved vaccine against this deadly virus. Entry of EBOV into host cell is mediated by its sole glycoprotein, known as GP. It is believed that EBOV enters host cells through macropinocytosis, which is initiated by the binding of EBOV GP to attachment factors or cell surface receptors, such as DC-SIGN and TIM-1.Following the uptake of viral particles into late endosome and lysosome, GP is cleaved by cellular proteases, especially cathepsin L (CatL) and B (CatB), to a 19 kDa intermediate. The 19 kDa species then binds to human Niemann-Pick C1 (NPC1), the newly identified intracellular receptor of EBOV in endolysosomes, where virus-cell membrane fusion takes place. One recent interesting finding from our lab, in collaboration with Fredric Cohen’s lab at Rush University, is that low pH per se is not a trigger but that low pH-dependent cathepsin’s activity is critical for GP-mediated fusion (Markosan and Miao et al, PLoS Pathogens, 2016). Current experiments are focused on the exact mechanisms of triggering and fusion, with an ultimate goal to develop novel fusion inhibitors against EBOV. Similar efforts have been put on Zika virus, a flavivirus family member with distinct biological properties that are associated with microcephaly and neuronal damaging.

Because cell-to-cell transmission has been shown to be more efficient than the cell-free virus infection, we are also currently investigating viral and cellular factors that regulate EBOV and HIV-1 cell-to-cell transmission.

3.TIM, SERINC and HIV Nef

We recently discovered that TIM-family proteins potently inhibit release of HIV and other viruses in addition to promoting viral entry (Li et al. PNAS USA, 2014).  Specifically, we showed that expression of TIM-1 protein potently blocks HIV-1 

Gag release, resulting in accumulation of mature viral particles on the plasma membrane. Notably, TIM-1 mutants deficient for PS binding are incapable of blocking HIV-1 release. The inhibitory effect of TIM family proteins on viral release

TIM,SERINC, AND HIV Nefcan be extended to some other PS receptors, including AxL and RAGE, underscoring a general role of PS in HIV and other viral infections. However, it is currently unclear how viruses counteract TIM-mediated inhibition of viral release. The goal of this project is to understand how HIV-1 Nef protein might antagonize TIM-mediated restriction and how the newly discovered SERINC proteins, which are known to impair HIV infectivity but are antagonized by Nef, participate in this process.

 

4.Cell signaling, viral oncogene and human lung cancer

Retroviruses have played fundamental roles in our current understanding of the molecular and genetic basis of cancer. One focus of our lab is to better understand the novel mechanisms of cell transformation by some oncogenic viruses, including retroviruses. We have been focused on two oncogenic sheep retroviruses, Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), which cause contagious lung and nasal adenocarcinomas, respectively, in sheep and goats. Distinct from most acutely transforming retroviruses, the envelope (Env) proteins of JSRV and ENTV are active oncogenes that induce malignant transformation in vitro and in vivo. More interestingly, the sheep lung tumor induced by JSRV strongly resembles human bronchiolo-alveolar carcinoma (BAC), a subclass of human pulmonary adenocarcinomas that is less associated with cigarette smoking. Hence, JSRV could provide a useful model for understanding the etiology and carciogenesis of human lung cancer. Current projects include molecular characterizations of cell signaling events triggered by some viral oncogenes as well as discovery of new human viruses associated with human lung cancers.


Memberships

Member, Infectious Disease Institute

Member, Center for Retrovirus Research

Member, Biomedical Sciences Graduate Program (BSGP)

Member, Molecular, Cellular, and Developmental Biology (MCDB) Program

Member, Medical Scientist Training Program (MSTP)


Relevent Publications

  • Yu, J., C. Liang and S.-L. Liu*. 2017. Interferon-inducible LY6E Protein Promotes HIV Infection. J. Biol. Chem. 292(11):4674-4685.
  • Wang, Y., Q. Pan, Z. Wang, J. Yu, S.-L. Liu and C. Liang. 2017. The V3-loop of HIV-1 Env Determines Viral Susceptibility to IFITM3 Impairment of Viral Infectivity. J. Virol. 91(7). pii: e02441-16.
  • Cui, B., W. Liu, X. Wang, Y. Chen, Q. Du, X. Zhao, H. Zhang, S.-L. Liu, D. Tong, Y. Huang. 2017. Brucella Omp25 upregulates miR-155, miR-21-5p and miR-23b to inhibit IL-12 production via modulation of PD-1 signaling in human monocyte/macrophages. Frontiers in Immunology. June 26.
  • Miller, A.D., M. de Las Heras, J. Yu, F. Zhang, S.-L. Liu, A. E. Vaughan, T. L. Vaughan, R. Rosadio, S. Rocca, G. Palmieri, J. J.Goedert, J. Fujimoto, I. I. Wistuba. 2017. Evidence against a role for Jaagsiekte sheep retrovirus in human lung cancer. Retrovirology. 14(1):3.
  • Kodigepalli, K. M., M. Li, S.-L. Liu, and L. Wu. Exogenous Expression of SAMHD1 Inhibits Proliferation and Induces Apoptosis in Cutaneous T-cell Lymphoma-derived HuT78 Cells. 2016. Cell Cycle. Dec 8, 1-10.
  • Markosyan, R.M.#, C. Miao#, Y.-M. Zheng, G.B. Melikian, S.-L. Liu* and F.S. Cohen*. 2016. Induction of Cell-Cell Fusion by Ebola Virus Glycoprotein: Low pH Is not a Trigger. PLoS Pathogens. 12(1):e1005373. (# Co-first author)
  • Wilkins, J, Y.-M. Zheng, J. Yu, C. Liang, and S.-L. Liu*. 2016. Nonhuman Primate IFITM Proteins Are Potent Inhibitors of HIV and SIV. PLoS One. 11(6): e0156739.
  • Ji, H.-L., H.-G. Nie, Y. Chang, Q. Lian, and S.-L. Liu. CPT-cGMP. 2016. CPT-cGMP Is a New Ligand of Epithelial Sodium Channels. Int. J Biol Sci. 12:359-366.
  • Huo, R., L. Wang, X. Wang, Y. Zhao, Y. Wang, X. Zhao, L. Chang, S.-L. Liu, D. Tong, H. Zhang, and Y. Huang. 2016. Removal of Regulatory T Cells Prevents Secondary Chronic Infection but Increases the Mortality of Subsequent Sub-acute Infection in Sepsis Mice. Oncotarget. 7(10):10962-10975.
  • Miao, C, M. Li, Y.-M. Zheng, F. S. Cohen and S.-L. Liu*. 2015. Cell-cell Contact Promotes Ebola Virus GP-mediated Infection. Virology. 488:202-215.
  • Yu, J, M. Li, J. Wilkins, S. Ding, T. H. Swartz, A. M. Esposito, Y.-M. Zheng, E. O. Freed, C. Liang, B. K. Chen, and S.-L. Liu*. 2015. IFITM Proteins Antagonize HIV-1 Envelope to Restrict Cell-to-cell Infection. Cell Reports 13: 145-156.
  • Jia R, S. Ding, Q. Pan, S.-L. Liu, W. Qiao, and C. Liang. 2015. The C-terminal sequence of IFITM1 regulates its anti-HIV-1 activity. PLoS One.10(3):e0118794.
  • Li, K, R. Jia, M. Li, Y.-M. Zheng, C. Miao, Y. Yao, H. Ji, Y. Geng, W. Qiao, Lorraine M. Albritton, Chen Liang, and S.-L. Liu*. 2015. A Sorting Signal Intrinsically Suppresses IFITM1 Restriction of Viral Entry. J. Biol. Chem. 290 (7): 4248-4259.
  • Qian J, Y. L Duff, Y. Wang, Q. Pan, S. Ding, Y.-M. Zheng, S.-L. Liu, and C. Liang. 2015. Primate Lentiviruses Are Differentially Inhibited by Interferon-Induced Transmembrane Proteins. Virology. 474: 10-18.
  • Li, M, S. Ablan, C. Miao, Y.-M. Zheng, M. S. Fuller, P.D. Rennert, W. Maury, M. Johnson, E. O. Freed, and S.-L. Liu*. 2014 TIM Family Proteins Inhibit HIV-1 Release. Proc Natl Acad Sci USA. 111(35): E3699-707.
  • Ding, S, Q. Pan, S.-L. Liu*, and C. Liang*. 2014. HIV-1 mutates to escape IFITM1 restriction. Virology 454-455: 11-24
  • Jia R, F. Xu, Y. Yao, J. Qian, Y. Yao, C. Miao, Y.-M. Zheng, S.-L. Liu, F. Guo, Y. Geng, W. Qiao, and C.  Liang. 2014. Identification of an Endotyctic Signal Essential for the antiviral action of IFITM3. Cell Microbiol. 16: 1080-1093.
  • Li K#, R. M. Markosyan#, Y.-M. Zheng#, O. Golfetto, B. Bungart, M. Li, S. Ding, Y. He, C. Liang, J. C. Lee, E. Gratton, F. S. Cohen, and S.-L. Liu*. 2013. IFITM Proteins Restrict Viral Membrane Hemifusion. PLoS Pathogens. 9 (1): e1003124. (# equal contribution)
  • Jia R, Q. Pan, S. Ding, L, Rong, S.-L. Liu, Y. Geng, W. Qiao and C. Liang. 2012. The N-terminal region of IFITM3 modulates its antiviral activity through regulating IFITM3 cellular location. J. Virol. 86: 13697-13707.
  • Côté M.#, Y.-M. Zheng#, and S.-L. Liu*. 2012. Membrane fusion and cell entry of XMRV is pH-independent and modulated by the envelope glycoprotein’s cytoplasmic tail. PLoS ONE. 7(3):e33734. (#equal contribution)
  • Côté M#, Y.-M. Zheng#, Kun Li, S-H Xiang, Lorraine M. Albritton and S.-L. Liu*. 2012. Critical Role of a Leucine-Valine Change in the Distinct Low pH Requirements for Membrane Fusion between Two Related Retrovirus Envelopes. J. Bio. Chem. 287(10):7640-51. (#equal contribution)
  • Côté M., Y.-M. Zheng and S.-L. Liu*. 2011. Single Residues in the Surface Subunits of Oncogenic Sheep Retrovirus Envelopes Distinguish Their Receptor-mediated Triggering for Fusion at Low pH and Infection. Virology 421(2): 173-183.
  • Lu J, Q. Pan Q, L. Rong, S.-L. Liu, and Liang C. 2011. The IFITM proteins inhibit HIV-1 infection. J. Virol. 85: 2126-2137.
  • Côté M., Y.-M. Zheng and S.-L. Liu*. 2009.  Receptor Binding and Low pH   Coactivate Oncogenic Retrovirus Envelope-mediated Fusion. J. Virol. 83: 1144-11455.
  • Côté M., T. Kucharski, Y.-M. Zheng and S.-L. Liu*. 2008. Enzootic Nasal Tumor Virus Requires a Very Acidic pH for Fusion Activation and Infection. J. Virol. 82: 9023-9034.
  • Côté M., Y.-M. Zheng, L. M. Albritton, and S.-L. Liu*. 2008. The Fusogenicity of Jaagsiekte Sheep Retrovirus Envelope Glycoprotein is Dependent on Low pH and Is Enhanced by the Cytoplasmic Tail Truncations.  J. Virol. 82: 2543-2554.
  • Bertrand P., M. Côté, Y.-M. Zheng, L. M. Albritton, and S.-L. Liu*. 2008. Jaagsiekte Sheep Retrovirus Utilizes a pH-dependent Endocytosis Pathway for Entry. J. Virol. 82:2555-2559.
  • Liu S.-L.* and A. D. Miller. 2007. Oncogenic Transformation by the Jaagsiekte Sheep Retrovirus Envelope Protein. Oncogene. 26:789-01.
  • M. Cote, A. D. Miller, and S.-L. Liu*. 2007. Human RON Receptor Tyrosine Kinase Induces Complete Epithelial-To-Mesenchymal Transition but Impairs Cell Proliferation. Biochem. Biophys. Res. Commun. 360:219-25.
  • Liu S.-L. and A. D. Miller. 2005. Transformation of Madin-Darby Canine kidney (MDCK) Epithelial Cells by Sheep Retrovirus Env Proteins. J. Virol. 79: 927-933.
  • Liu S.-L., C. L. Halbert, and A. D. Miller. 2004. The Env Glycoprotein of Jaagsiekte Sheep Retrovirus Efficiently Pseudotypes the HIV-1 Lentiviral Vectors. J. Virol. 78: 2642-2647.
  • Miller A. D., N. S. V. Hoeven, and S.-L. Liu. 2004.  Transformation and Scattering Activities of the Receptor Tyrosine Kinase RON/Stk in Rodent Fibroblasts and Lack of Regulation by Hyaluronidase 2. BMC Cancer 4:64.
  • Gottlieb G. S., D. C. Nickle, M. A. Jensen, K. G. Wong, F. Li, S.-L. Liu, C. Rademeyer, G. H. Learn, C. Williamson, L. Corey, J. M. Margolick, and J. I. Mullins. 2004. Dual HIV-1 Infection and Rapid Disease Progression. Lancet. 363: 619-622.
  • Liu S.–L., M. I. Lerman, and A. D. Miller. 2003. Putative PI3K Binding Motifs in Ovine Betaretrovirus Env Proteins Are Not Essential for Rodent Fibroblast Transformation and PI3K/Akt Activation. J. Virol. 77: 7924-7935.
  • Liu S.-L., F. M. Duh, M. I. Lerman, and A. D. Miller. 2003. Role of Virus Receptor Hyal2 in Oncogenic Transformation of Rodent Fibroblasts by Sheep Betaretrovirus Env Proteins. J. Virol., 77: 2850-2858.
  • Danilkovitch-Miagkova A, F. M. Duh, I. Ikuzmin, D. Angeloni, S.-L. Liu, A. D. Miller, and M. I. Lerman MI. 2003.  Candidate Tumor Suppressor HYAL2 Is a Negative Regulator of RON Receptor Tyrosine Kinase and Mediates Transformation of Epithelial Cells by Jaagsiekte Sheep Retrovirus. Proc. Natl. Acad. Sci.  USA. 100: 4580-4585.
  • Liu S.-L., J. M. Mittler, D. C. Nickle, T. Mulvania, D. Shriner, A.G. Rodrigo, B. Kosloff, X. He, L. Corey, and J. I. Mullins. 2002. Selection for Human Immunodeficiency Virus Type 1 Recombinants in A Patient with Rapid Progression to AIDS. J. Virol., 76: 10674-10684.
  • Frenkel, L., J. I. Mullins, G. H. Learn, L. Manns-Arcuino, B. L. Herring, M. L. Kalish, R. W. Steketee, D. M. Thea, J. E. Nichols, S.-L. Liu, A. Harmache, X. He, D. Muthui, A. Madan, L. Hood, A. T. Haase, M. Zupancic, K. Staskus, S. M. Wolinsky, P. Krogstad, J. Zhao, I. Chen, R. Koup, D. D. Ho, B. T. Korber, R. J. Apple, R. W. Coombs, S. Pahwa and N. J. Roberts, Jr. 1998. Genetic Evaluation of Suspected Cases of Transient HIV-1 Infection of Infants. Science, 280:1073-1077.
  • Liu, S.-L., T. Schacker, L. Musey, D. Shriner, M. J. McElrath, L. Corey, and J. I. Mullins. 1997. Divergent Patterns of Progression to AIDS After Infection from the Same Source: HIV-1 Evolution and Antiviral Responses. J. Virol. 71: 4284- 4295.
  • Liu, S.-L., A. G. Rodrigo, R. Shankarappa, G. H. Learn, L. Hsu, O. Davidov, L.-P. Zhao, and J. I. Mullins. 1996. HIV Quasispecies and Resampling. Science. 273: 415-416.
Areas of Expertise
  • Molecular Virology
  • Virus-host interaction
  • Innate Immunity
  • Cell Signaling
Education
  • M.D., Zhengzhou University School of Medicine, 1989
  • Ph.D., University of Washington School of Medicine, 2003
  • PostDoctoral Fellow, University of Washington and Fred Hutchinson Cancer Research Center, 2004

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Phone:
614-292-8690