Molecular Microbiology & Immunology
Fields of Interest
- Viral membrane fusion and entry
- Innate immunity to viral infections
- Ph.D. 2003, University of Washington
- Host restriction of viral infections and viral countermeasures
- Retrovirus (HIV) entry and cell-to-cell transmission
- IFN response to HCV infection and viral pathogenesis
- Ebolavirus fusion and entry
IFITM restriction of viral infections
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 have recently been shown to 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-1.
Recent work from our lab have shown that IFITM proteins inhibit cell-cell fusion, most strongly prior to hemifusion induced 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 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 also virus dependent. Currently, we use a variety of biophysical, biochemical, forward genetics, as well as molecular approaches to dissect the mechanisms of IFITM restriction of viral entry as well as virus countermeasures. The model viruses applied to this project include IAV, retroviruses, EBOV and HIV.
Results from these investigations will lead to better understanding of the mechanisms of IFITM restriction and may provide new clues for development of antivirals.
Retrovirus (including HIV) entry and cell-to-cell transmission
Entry is the first step of viral replication and essential for viral pathogenesis. For enveloped viruses, membrane fusion is necessary for release of viral genetic materials into cytosol and initiation of replication. 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 retroviruses, particularly HIV-1 and Jaagsiekte sheep retrovirus (JSRV). 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. Because cell-to-cell transmission has been shown to be more efficient (~100-1000 fold) than the cell-free virus infection of HIV-1, we are also currently investigating viral and cellular factors that regulate HIV-1 cell-to-cell transmission.
IFN response to HCV infection and viral pathogenesis
Hepatitis C virus (HCV) is a serious human pathogen worldwide, and is notoriously successful in establishing persistent infection closely associated with cirrhosis and hepatocelluar carcinoma. The mechanisms underlying HCV persistency and its associated pathogenesis are currently not well understood. Upon HCV infection, type I interferon (IFN-α/β) is rapidly produced in virus-infected cells, which stimulates cells to establish antiviral states by inducing hundreds of IFN-stimulated genes (ISGs). Interestingly, only a very small fraction of ISGs, i.e, ISG56, PKR, ISG20, GBP1, and viperin, have been shown to have direct anti-HCV effects. Importantly, HCV has evolved various strategies to evade the host innate immunity, including the IFN-mediated antiviral response, and this may explain, at least in part, its persistent infection.
Although loss of IFN-α/β and ISGs induction has been reported in the hepatocytes of patients with chronic HCV infection, elevated levels of ISGs expression are evident in many chronic HCV-infected humans and chimpanzees and no further ISGs can be induced by IFN in these individuals. Hence, despite the presence of ISGs, HCV infection still persists in the liver of these individuals, suggesting that HCV may block the effector functions of ISGs at the post-transcriptional levels. The goal of this project is to use shRNA screen to identify and characterize novel cellular factors, including new ISGs, which are involved in HCV replication and pathogenesis.
Ebolavirus fusion and entry
Ebolavirus (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. GP is synthesized as a precursor (GP0), which is further cleaved into GP1 and GP2; GP1 is responsible for interacting with cellular receptors or cofactors, while GP2 is directly involved in fusion with target cell membranes. 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. Recent data from several groups have shown or suggested that NPC1, low pH, and perhaps the reducing environment of endosome participate in EBOV GP-mediated fusion; however, whether or not these are the authentic triggers of EBOV GP-mediated fusion currently remain debatable.
The goal of this project is to elucidate how EBOV GP is trigged to induce membrane fusion and mediate entry, with an ultimate goal of developing novel fusion inhibitors against EBOV and other highly pathogenic human viruses.
- 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. Bio. Chem. 290 (7): 4248-4259.
- 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.
- 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.
- Zhao, R, X. Liang, M. Zhao, S.-L. Liu, T. Croxton, the TLRC Investigators, and H.-L. Ji. 2014. Correlations of Apical Fluid-Regulating Channel Proteins with Lung Functionality of COPD. PLoS One. 9(10):e109725.
- 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.
- Li, M, Ablan, S, Miao, C, Zheng, Y-M, Fuller, MS, Rennert, PD, Maury, W, Johnson, M, Freed, EO, and S-L Liu. 2014 TIM-Family Proteins Inhibit HIV-1 Release. PNAS USA. In Press.
- Ding, S, Pan, Q, Liu, S-L, and C Liang. 2014. HIV-1 mutates to escape IFITM1 restriction. Virology 454-455: 11-24.
- Jia R, Xu F, Qian J, Yao Y, Miao C, Zheng YM, Liu SL, Guo F, Geng Y, Qiao W, and C Liang. 2014. Identification of an endocytic signal essential for the antiviral action of IFITM3. Cell Microbiol. 2014 Jan 20. doi: 10.1111/cmi.12262. [Epub ahead of print]
- Li K, Markosyan, RM, Zheng, Y-M, Golfetto, O, Bungart, B, Li, M, Ding, S, He, Y, Liang, C, Lee, JC, Gratton, E, Cohen, FS, and S-L Liu. 2013. IFITM proteins restrict viral membrane hemifusion. PLoS Pathogens 9 (3) e1003232.
- Jia R, Pan, Ding, QS, Rong, L, Liu, S-L, Geng, Y, Qiao, W and C. Liang.. 2012. The N-terminal region of IFITM3 modulates its antiviral activity through regulating IFITM3 cellular location. J Virol. 2012 Oct 10. [Epub ahead of print]
- Côté M, Zheng, Y-M, 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.
- Côté M, Zheng, Y-M, Li, K, Xiang, S-H, Albritton, LM 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
- Ndongwe TP, Adedeji, AO, Michailidis E, Ong, YT, Hachiya, A, Marchand, B, Ryan, EM, Rai, DK, Kirby, KA, Whatley, AS, Burke, DH, Johnson, M, Ding, S, Zheng, Y-M, Liu, S-L, Kodama, E, Delviks-Frankenberry KA, Pathak, VK, Mitsuya, H, Parniak, MA, Singh, K, and SG Sarafianos. 2012. Biochemical, inhibition and inhibitor resistance studies of xenotropic murine leukemia virus-related virus reverse transcriptase. Nucleic Acids Res. 40(1):345-59.
- Côté M, Zheng, YM 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. In revision.
- Lu JQ, Pan Q, Rong L, S-L Liu, and C Liang. 2011. The IFITM proteins inhibit HIV-1 infection. J. Virol. 85: 2126-2137.
- Côté M, Zheng YM and S-L Liu. “Receptor binding and low pH coactivate oncogenic retrovirus envelope-mediated fusion.” J Virol. 2009 Nov; 83(22): 11447-55.
- Côté M, Kucharski TJ, and S-L Liu. “Enzootic Nasal Tumor Virus Envelope Requires a Very Acidic pH for Fusion Activation and Infection.” J Virol. 2008 Sept; 82(18):9023-34.
- Côté M, Zheng YM, Albritton LM, and SL Liu. “Fusogenicity of Jaagsiekte sheep retrovirus envelope protein is dependent on low pH and is enhanced by cytoplasmic tail truncations.” J Virol. 2008 Mar;82(5):2543-54.
- Bertrand P, Côté M, Zheng YM, Albritton LM, and SL Liu. “Jaagsiekte sheep retrovirus utilizes a pH-dependent endocytosis pathway for entry.” J Virol. 2008 Mar;82(5):2555-9.
- Côté M, Miller AD, and SL Liu. “Human RON receptor tyrosine kinase induces complete epithelial-to-mesenchymal transition but causes cellular senescence.” Biochem Biophys Res Commun. 2007 Aug 17;360(1):219-25.
- Liu SL and AD Miller. “Oncogenic transformation by the jaagsiekte sheep retrovirus envelope protein.” Oncogene. 2007 Feb 8;26(6):789-801.
- Liu SL, and AD Miller. “Transformation of Madin-Darby canine kidney epithelial cells by sheep retrovirus env proteins.” J. Virol. 2005. 79: 927-933.
- Miller AD, Van Hoeven NS, and SL Liu. “Transformation and scattering activities of the receptor tyrosine kinase RON/Stk in rodent fibroblasts and lack of regulation by the jaagsiekte sheep retrovirus receptor, Hyal2.” journal date and rest.
- Liu SL, Halbert CL, and AD Miller. “Jaagsiekte sheep retrovirus envelope efficiently pseudotypes human immunodeficiency virus type 1-based lentiviral vectors.” J Virol. 2004 Mar;78(5):2642-7.
- Liu SL, Lerman MI, and AD Miller. “Putative phosphatidylinositol 3-kinase (PI3K) binding motifs in ovine betaretrovirus Env proteins are not essential for rodent fibroblast transformation and PI3K/Akt activation.” J Virol. 2003 Jul;77(14):7924-35.
- Danilkovitch-Miagkova A, Duh FM, Kuzmin I, Angeloni D, Liu SL, Miller AD, and MI Lerman. “Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus.” Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4580-5. Epub 2003 Apr 03.
- Liu SL, Duh FM, Lerman MI, and AD Miller. “Role of virus receptor Hyal2 in oncogenic transformation of rodent fibroblasts by sheep betaretrovirus env proteins.” J Virol. 2003 Mar;77(5):2850-8.
- Liu SL, Mittler JE, Nickle DC, Mulvania TM, Shriner D, Rodrigo AG, Kosloff B, He X, Corey L, and JI Mullins. “Selection for human immunodeficiency virus type 1 recombinants in a patient with rapid progression to AIDS.” J Virol. 2002 Nov;76(21):10674-84.