Glenn Randall, Ph.D.


  • Associate Professor, Department of Microbiology, Committee on Immunology, Committee on Microbiology


Ph.D., The University of Chicago
B.S., University of Illinois, 


The University of Chicago 
920 East 58th Street 
Chicago, Illinois 60637

Phone:  (773) 702-5673


Virus-Host Interactions

Research Interests

Our laboratory investigates the roles of virus-host interactions in replication and pathogenesis. We study viruses of theFlaviviridae, including hepatitis C virus (HCV) and dengue virus (DENV). These are clinically important viruses: over 130 million people are chronically infected with HCV, while an estimated 50-100 million DENV infections occur annually. The most severe pathologies are HCV-associated liver cancer and dengue hemorrhagic fever.

We have applied RNAi interference to identify ~85 host cofactors of viral replication. We now study the importance of these cellular genes in diverse steps of the viral life cycle, including entry, the regulation of viral protein translation and RNA replication, modulation of cellular lipid metabolism, the establishment of viral replication complexes, the secretion of infectious virus, and control of infection by the innate immune system. Additionally, the identification of cellular cofactors of HCV and DENV infection greatly expands the pool of potential targets for drug design. Three major project areas are:

1. HCV trafficking in infected hepatocytes.

Virus Entry

HCV entry is an unusually complex process. We combined an RNA interference analysis of HCV endocytosis with the development of single particle tracking of HCV virions to dissect the sequential steps of HCV infection. We next developed approaches to image entry into three dimensional hepatocyte organoids that produce a polarized architecture similar to the liver. This approach has defined a model for HCV entry wherein HCV virions associate with a set of “early receptors”, including CD81, SR-BI and EGFR. The virus-receptor complex migrates to the tight junction by an unknown mechanism. Once at the tight junction, the virus localizes with “late receptors” CLDN and OCLN. EGFR is activated at the tight junction, which then recruits the clathrin endocytic machinery to internalize the virus-receptor complex, which subsequently uncoats from endosomes.  We are currently investigating how HCV traffics to the tight junction and the mechanism of virion internalization.

Virus Release

Conceptually similar studies into HCV release and spread have been recently completed. We combined an RNAi analysis of host factors that are required for infectious HCV secretion with live cell imaging of HCV core trafficking. Using this approach, we identified numerous components of the secretory pathway that are both required for infectious HCV release and co-traffic with HCV core. The dynamics of HCV core trafficking, both in terms of frequency of transport, particle velocity, and the corresponding run lengths were quantified. We observe that dynamic core movements in the periphery require NS2, a viral protein required for virion assembly. Core co-traffics with multiple components of the secretory pathway, including the Golgi, recycling endosome, microtubules, VAMP1 secretory vesicles, and ApoE. This study identifies new molecular determinants of HCV secretion and describes the dynamics of their movements with HCV core in real time. We are currently studying a secondary release pathway that directs the virus to spread from cell to cell without extra-cellular release.

2. Viral replication complex formation and cellular remodeling: viral modulation of host lipid metabolism and signaling.

Viruses intimately interact with their host cell to promote infection. This involves two major strategies: (i) mechanisms for circumventing host antiviral surveillance and (ii) usurping host pathways to redirect their function for the benefit of the virus.  Many viruses have evolved a mechanism to remodel intra-cellular membranes to form protected sites of replication.  In essence, these are unique virus-induced mini-organelles whose sole purpose is to facilitate the production of large amounts of viral genomes in a way that minimizes alerting cellular antiviral responses.  Understanding how these structures form is of fundamental importance, with the added potential of uncovering targets for antiviral therapies.

For most viruses, we know very little about how membrane remodeling occurs. We have analyzed how HCV and DENV remodel membranes using a combinatorial approach, involving cellular and viral genetics, drug inhibitors, cell biology, and biochemical approaches. This analysis revealed that both viruses share a common theme: co-opting a cellular enzyme(s) in lipid signaling or synthesis. However, the mechanisms are quite different. While HCV manipulates lipid signaling to redirect cellular vesicle trafficking, DENV usurps a cellular lipid synthesis pathway. HCV NS5A activates the cellular PI4 kinase IIIa at sites of replication, while the DENV protein NS3 binds to FASN, a major cellular enzyme in lipid biosynthesis, recruits it to sites of viral replication, and activates it. Both interactions are required for viral replication complex formation. We have also defined a new role for autophagy in viral replication: the regulation of lipid metabolism. DENV induces autophagy to specifically deplete cellular lipid stores and increases their oxidation for energy production.

Of particular interest, approved drugs exist which inhibit fatty acid biosynthesis for obesity therapy. Additionally, this pathway is required for the replication of many other medically relevant viruses, suggesting the possibility of broad-spectrum antivirals. We have also found that an important HCV drug class, approved for therapy, targets the NS5A-PI4K interaction. Our lab is currently investigating the mechanism by which the viruses hijack these cellular pathways and the outcome on cellular remodeling and innate immune detection of viral infection, in addition to exploring the therapeutic potential of targeting these virus-host interactions as therapeutics.


Shulla, A. and G. Randall (2015). "Spatiotemporal analysis of hepatitis C virus infection." PLoS Pathog 11(3): e1004758.

Chukkapalli, V., K. L. Berger, S. M. Kelly, M. Thomas, A. Deiters and G. Randall (2015). "Daclatasvir inhibits hepatitis C virus NS5A motility and hyper-accumulation of phosphoinositides." Virology 476: 168-179.

Chukkapalli, V. and G. Randall (2014). "Hepatitis C virus replication compartment formation: mechanism and drug target." Gastroenterology 146(5): 1164-1167.

Oakland, T. E., K. J. Haselton and G. Randall (2013). "EWSR1 binds the hepatitis C virus cis-acting replication element and is required for efficient viral replication." J Virol 87(12): 6625-6634.

Shulla, A. and G. Randall (2012). "Hepatitis C virus-host interactions, replication, and viral assembly." Curr Opin Virol 2(6): 725-732.