About
Glenn C. Randall, PhD, is a Professor of Microbiology at the University of Chicago, where he also serves as the Committee Chair of the Committee on Microbiology. His research investigates the roles of virus-host interactions in the replication and pathogenesis of RNA viruses, including hepatitis C virus, dengue virus, Zika virus, and noroviruses. These viruses are medically significant, causing conditions such as cirrhosis, liver cancer, hemorrhagic fever, birth defects, and severe gastrointestinal disease. Dr. Randall's laboratory has identified approximately 100 host cofactors involved in viral replication and studies their importance across various stages of the viral life cycle, including entry, translation regulation, RNA replication, modulation of lipid metabolism, formation of replication complexes, virus secretion, and immune system control of infection. His work has contributed to understanding the molecular mechanisms of viral infection and potential therapeutic targets.
Research topics
- Biology
- Virology
- Medicine
- Biochemistry
- Immunology
- Chemistry
- Cell biology
- Internal medicine
- Genetics
- Pharmacology
- Computational biology
- Bioinformatics
- Microbiology
- Pathology
Selected publications
Proceedings of the National Academy of Sciences · 2025-03-05 · 2 citations
articleOpen accessSenior authorCorrespondingPositive-sense single-stranded RNA [(+)RNA] viruses constitute more than one-third of all virus genera, including numerous pathogens of clinical significance. All (+)RNA viruses reorganize cellular membranes from organelles to establish replication compartments (RCs). These RCs are thought to form a platform for membrane-associated replicases, in addition to protecting the viral RNAs from cytosolic innate immune signaling and RNA-degradation machinery. Previous work demonstrated that three families of (+)RNA viruses, namely Bromoviridae , Picornaviridae , and Flaviviridae , commonly induce the accumulation of phosphatidylcholine (PC) at their RCs. This phenomenon suggests a potential avenue for a broad-spectrum antiviral strategy targeting PC metabolism. Our study elucidates three key observations: i) hepatitis C virus (HCV) infection prompts the relocalization of CCTα, the rate-limiting enzyme in PC synthesis, to the RCs; ii) the enhancement of PC synthesis is contingent upon the protease activity of the NS3/4A protein; and iii) utilizing click chemistry, we demonstrate that HCV infection stimulates de novo PC synthesis at the viral replication site through the Kennedy pathway. These findings provide significant insights into the manipulation of lipid metabolism by HCV during RC formation, a mechanism likely conserved across various (+)RNA virus families.
iScience · 2025-09-17
articleOpen access. AbLM outperformed other language models in predicting IgGs with low variant susceptibility. Our work advances artificial intelligence-based antibody discovery by synergizing data-driven language models and Kriging with physics-driven docking and design.
bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-04 · 1 citations
preprintOpen accessAbstract Therapeutic antibodies have become one of the most influential therapeutics in modern medicine to fight against infectious pathogens, cancer, and many other diseases. However, experimental screening for highly efficacious targeting antibodies is labor-intensive and of high cost, which is exacerbated by evolving antigen targets under selective pressure such as fast-mutating viral variants. As a proof-of-concept, we developed a machine learning-assisted antibody generation pipeline AbGen that greatly accelerates the screening and re-design of immunoglobulins G (IgGs) against a broad spectrum of SARS-CoV-2 coronavirus variant strains. Our AbGen centers around a novel antibody language model (AbLM) that is pretrained on 12 million generic protein domain sequences and fine-tuned on 4,000+ paired VH-VL sequences, with IgG-specific CDR-masking and VH-VL cross-attention. AbLM provides a latent space of IgG sequence embeddings for AbGen, including (a) landscapes of IgGs’ activities in neutralizing the wild-type virus are analyzed through structure prediction for IgG and IgG-antigen (viral protein spike’s receptor binding domain, RBD) interactions; and (b) landscapes of IgGs’ susceptibility in neutralizing variant viruses are predicted through Gaussian process regression, despite that as few as 14 clinical antibodies’ responses to variants of concern are available. The AbGen pipeline was applied to over 1300 IgG sequences we collected from RBD-binding B cells of convalescent patients. With experimental validations, AbGen efficiently prioritized IgG candidates against a broad spectrum of viral variants (wildtype, Delta, and Omicron), preventing the infection of host cells in vitro and hACE2 transgenic mice in vivo . Compared to other existing protein language models that require 10-100 times more model parameters, AbLM improved the precision from around 50% to 75% to predict IgGs with low variant susceptibility. Furthermore, AbGen enables structure-based computational protein redesign for selected IgG clones with single amino acid substitutions at the RBD-binding interface that doubled the IgG blockade efficacy for one of the severe, therapy-resistant strains - Delta (B.1.617). Our work expedites applications of artificial intelligence in antibody screen and re- design combining data-driven protein language models and Kriging for antibody sequence analysis and activity prediction, in synergy with physics-driven protein docking and design for antibody-antigen interface analyses and functional optimization.
Peptide Science · 2024-07-22 · 3 citations
articleOpen accessThe COVID-19 pandemic drove a uniquely fervent pursuit to explore the potential of peptide, antibody, protein, and small-molecule based antiviral agents against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The interaction between the SARS-CoV2 spike protein with the angiotensin-converting enzyme 2 (ACE2) receptor that mediates viral cell entry was a particularly interesting target given its well described protein-protein interaction (PPI). This PPI is mediated by an α-helical portion of ACE2 binding to the receptor binding domain (RBD) of the spike protein and thought to be susceptible to blockade through molecular mimicry. Small numbers of hydrocarbon-stapled synthetic peptides designed to disrupt or block this interaction were tested individually and were found to have variable efficacy despite having related or overlapping sequences and similarly increased α-helicity. Reasons for these differences are unclear and reported pre-clinical successes have been limited. The current study sought to better understand reasons for these differences through evaluation of a comprehensive collection of hydrocarbon stapled peptides, designed based on four distinct principles: stapling position, number of staples, amino acid sequence, and primary sequence length. Surprisingly, we observed that the helicity and amino acid sequence iterations of hydrocarbon-stapled peptides did not correlate with their bioactivity. Our results highlight the importance of iterative and combinatorial testing of these compounds to determine a configuration that best mimics natural binding and allows for chain flexibility while sacrificing structural helicity.
Cells · 2024-01-23 · 7 citations
articleOpen accessSevere acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) utilizes angiotensin-converting enzyme 2 (ACE2) as its main receptor for cell entry. We bioengineered a soluble ACE2 protein termed ACE2 618-DDC-ABD that has increased binding to SARS-CoV-2 and prolonged duration of action. Here, we investigated the protective effect of this protein when administered intranasally to k18-hACE2 mice infected with the aggressive SARS-CoV-2 Delta variant. k18-hACE2 mice were infected with the SARS-CoV-2 Delta variant by inoculation of a lethal dose (2 × 104 PFU). ACE2 618-DDC-ABD (10 mg/kg) or PBS was administered intranasally six hours prior and 24 and 48 h post-viral inoculation. All animals in the PBS control group succumbed to the disease on day seven post-infection (0% survival), whereas, in contrast, there was only one casualty in the group that received ACE2 618-DDC-ABD (90% survival). Mice in the ACE2 618-DDC-ABD group had minimal disease as assessed using a clinical score and stable weight, and both brain and lung viral titers were markedly reduced. These findings demonstrate the efficacy of a bioengineered soluble ACE2 decoy with an extended duration of action in protecting against the aggressive Delta SARS-CoV-2 variant. Together with previous work, these findings underline the universal protective potential against current and future emerging SARS-CoV-2 variants.
CAPRIN1 Is Required for Control of Viral Replication Complexes by Interferon Gamma
mBio · 2023-04-13 · 7 citations
articleOpen accessSenior authorReplication complexes provide a microenvironment important for (+) RNA virus replication and shield it from host immune response. Previously we have shown that interferon gamma (IFNG) disrupts the RC of MNV via evolutionarily conserved autophagy proteins and IFN-inducible GTPases. Elucidating the mechanism of targeting of viral RC by ATG16L1 and IFN-induced GTPase will pave the way for development of therapeutics targeting the viral replication complexes. Here, we have identified GBP1 as the sole GBP targeting viral RC and uncovered the novel role of CAPRIN1 in recruiting ATG16L1 to the viral RC.
Preprints.org · 2023-12-25 · 1 citations
preprintOpen accessSevere acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) utilizes Angiotensin Converting Enzyme 2 (ACE2) as its main receptor for cell entry. We have bioengineered a soluble ACE2 protein termed ACE2 618-DDC-ABD that has increased binding to SARS-CoV-2 and prolonged duration of action. Here we investigated the protective effect of this protein when administered intranasally to k18-hACE2 mice infected with the aggressive SARS-CoV-2 delta variant. k18-hACE2 mice were infected with the SARS-CoV-2 delta variant by inoculation of a lethal dose (2x104 PFU) and followed for up to 14 days. ACE2-618-DDC-ABD (10mg/kg) or PBS was administered intranasally six hours prior and 24 and 48 hours post viral inoculation. All animals in the PBS-control group had succumbed to the disease on day 7 post infection (0% survival) whereas, by contrast, there was only one casualty in the group that received ACE2-618-DDC-ABD (90% survival). Mice in the ACE2-618-DDC-ABD group had minimal disease as assessed by a clinical score and stable weight and both brain and lung viral titers were markedly reduced. These findings demonstrate the efficacy of a bioengineered soluble ACE2 decoy with extended duration of action in protecting against the aggressive delta SARS-CoV-2 variant. Together with previous work these findings demonstrate the universal protective potential against current and future emerging SARS-CoV-2 variants.
PLoS Pathogens · 2023-12-29 · 9 citations
articleOpen accessSenior authorCorrespondingThe multi-step process of hepatitis C virus (HCV) entry is facilitated by various host factors, including epidermal growth factor receptor (EGFR) and the tight junction proteins claudin-1 (CLDN1) and occludin (OCLN), which are thought to function at later stages of the HCV entry process. Using single particle imaging of HCV infection of polarized hepatoma spheroids, we observed that EGFR performs multiple functions in HCV entry, both phosphorylation-dependent and -independent. We previously observed, and in this study confirmed, that EGFR is not required for HCV migration to the tight junction. EGFR is required for the recruitment of clathrin to HCV in a phosphorylation-independent manner. EGFR phosphorylation is required for virion internalization at a stage following the recruitment of clathrin. HCV entry activates the RAF-MEK-ERK signaling pathway downstream of EGFR phosphorylation. This signaling pathway regulates the sorting and maturation of internalized HCV into APPL1- and EEA1-associated early endosomes, which form the site of virion uncoating. The tight junction proteins, CLDN1 and OCLN, function at two distinct stages of HCV entry. Despite its appreciated function as a "late receptor" in HCV entry, CLDN1 is required for efficient HCV virion accumulation at the tight junction. Huh-7.5 cells lacking CLDN1 accumulate HCV virions primarily at the initial basolateral surface. OCLN is required for the late stages of virion internalization. This study produced further insight into the unusually complex HCV endocytic process.
Intranasal soluble ACE2 improves survival and prevents brain SARS-CoV-2 infection
Life Science Alliance · 2023-04-11 · 12 citations
articleOpen accessA soluble ACE2 protein bioengineered for long duration of action and high affinity to SARS-CoV-2 was administered either intranasally (IN) or intraperitoneally (IP) to SARS-CoV-2-inoculated k18hACE2 mice. This decoy protein (ACE2 618-DDC-ABD) was given either IN or IP, pre- and post-inoculation, or IN, IP, or IN + IP but only post-inoculation. Survival by day 5 was 0% in untreated mice, 40% in the IP-pre, and 90% in the IN-pre group. In the IN-pre group, brain histopathology was essentially normal and lung histopathology significantly improved. Consistent with this, brain SARS-CoV-2 titers were undetectable and lung titers reduced in the IN-pre group. When ACE2 618-DDC-ABD was administered only post-inoculation, survival was 30% in the IN + IP, 20% in the IN, and 20% in the IP group. We conclude that ACE2 618-DDC-ABD results in markedly improved survival and provides organ protection when given intranasally as compared with when given either systemically or after viral inoculation, and that lowering brain titers is a critical determinant of survival and organ protection.
Nature Biotechnology · 2022 · 196 citations
- Computational biology
- Biology
- Virology
Recent grants
Hepatitis C Virus Trafficking in Hepatocytes
NIH · $2.7M · 2026–2031
HEPATOCYTE REMODELING BY HEPATITIS C VIRUS
NIH · $1.4M · 2015–2020
Elucidating How Tri-phosphatase DUSP11 Controls HCV Infection and Hepatocyte Inflammation
NIH · $1.8M · 2018–2023
Novel antiviral activity of interferon-gamma against viral replication complex
NIH · $1.6M · 2017–2022
Hepatitits C Virus Trafficking in Infected Hepatocytes
NIH · $777k · 2017–2018
Frequent coauthors
- 48 shared
Vlad Nicolaescu
University of Chicago
- 28 shared
Haley Gula
University of Chicago
- 22 shared
R. Jedrzejczak
Argonne National Laboratory
- 20 shared
A. Joachimiak
University of Chicago
- 17 shared
Jan Wysocki
Northwestern University
- 16 shared
Daniel Batlle
Hypertension Institute
- 16 shared
N. Maltseva
University of Chicago
- 15 shared
Nicholas S. Heaton
Labs
Education
- 1993
B.S., Microbiology
University of Illinois
- 1999
Ph.D., Virology
The University of Chicago
- 2005
Other, Virology
Rockefeller University
Awards & honors
- Investigator in the Pathogenesis of Infectious Disease Final…
- Research Scholar American Cancer Society (2010 - 2014)
- Career Development Award NIH GLRCE (2008 - 2011)
- Career Development Award Schweppe Foundation (2007 - 2009)
- Herman Lopata Hepatitis C Liver Scholar American Liver Found…
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