University of Missouri School of Medicine MU Health School of Medicine

Shan Lu Liu

Shan-Lu Liu, Ph.D

Associate Professor
Phone: (573) 882-4770

Fields of Interest:

  • Viral membrane fusion and entry
  • Innate immunity to viral infections


  • Ph.D. 2003, University of Washington

Research Statement:

  • 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.

Selected Publications

Lab Members:

Liu Lab Members - 2013

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