Our funding sources

The Laboratory of Functional Viromics is supported by multiple sources of funding. Below, are each of the individual grants that support our various projects.

R01 – Functional Viromics of betacoronavirus entry (R01AI179720)

November 2023 – October 2028

Collaborators: (1) Barbara Han @ Cary Institute,

No-cost collaborators: (2) Bonnie Gunn @ WSU, (3) Pamela Bjorkman @ Caltech

ABSTRACT After the severe acute respiratory coronavirus (SARS-CoV) emerged in China in 2002, the virus was traced back to animal markets and several genetically related viruses were identified in bats. This early work into coronavirus zoonosis and the concomitant rise of next generation sequencing technologies in the early 2000’s helped initiate global research efforts to identify viruses circulating in wildlife. The genomes for tens of thousands of novel animal viruses have now been sequenced and deposited in online repositories. Coronaviruses are abundant in mammals and birds and comprise approximately 25% of all bat viruses discovered to date. The highly pathogenic human coronaviruses, SARS-CoV, and middle east respiratory syndrome coronavirus (MERS-CoV) are only representative members of their respective sarbeco- and merbeco- subgenera, which encompass hundreds of related viruses found in bats and other wildlife, worldwide. Unfortunately, because there are few tools available for researchers to study uncharacterized animal viruses, virus discovery studies rarely isolate viruses under laboratory conditions or perform experiments beyond genetic sequencing, leaving some of the most essential questions about these viruses – including if they have the potential to infect humans – unanswered. An improved understanding for what species these viruses can infect and how they invade the cells of their hosts is essential for future pandemic preparedness.

The most significant species barrier for the coronaviruses that have transmitted to humans is at the level of cell entry and studies have shown that overcoming this barrier allows for coronaviruses to replicate in cells from diverse species. To invade cells, the “spike” glycoprotein on the surface of viral particles binds to host cell receptor molecules. The receptor binding domain (RBD) is a small region on the distal tip of the spike protein, capable of folding independently of spike and contains all amino acids that contact the host receptor. We previously developed “SarbecoType” – a BSL2-compatible, viral pseudotype-based platform to functionally screen the cell entry properties of the RBD from any sarbecovirus. This approach is highly cost-efficient and scalable, requiring synthesis of only a small portion of the spike gene, and has allowed us to characterize the cell entry phenotypes of approximately 95% of all published sarbecoviruses. This dataset identified multiple clades of sarbecovirus RBDs that vary in their zoonotic properties for humans, and has formed a foundational basis for ongoing universal sarbecovirus design. Therefore, we hypothesize uncharacterized coronaviruses pose a threat to humans. Here we propose to functionally screen the much larger and diverse group of merbecoviruses with similar methods (I.e., “MerbecoType”) and use this entry data to predict the entry capabilities of novel sarbeco- and merbeco-virus sequences.

PRESS RELEASE

R21 – Assessing the interferome of novel, purpose-driven bat-derived cells (1R21AI169527)

February 2022 – February 2024

Collaborators: Arinjay Banerjee @ VIDO Canada, University of Saskatchewan

ABSTRACT Over the last decade, bats have emerged as intriguing mammalian reservoirs of emerging high impact viruses that cause severe disease in humans and agricultural animals. However, bats that are naturally or experimentally infected with these viruses do not develop clinical signs of disease. Thus, understanding how bats tolerate virus infections may allow us to develop novel drugs or identify new drug targets for alternate mammalian species, such as humans. In spite of recent advances in bat immunology, studies have largely relied on cell culture models from selected bat species, limiting our understanding of this diverse mammalian order. The order Chiroptera is made up of over 1420 species of bats, and data from a handful of bats do not represent evolutionary adaptations in all bats. In addition, these reagents are not available on public repositories making it hard for the research community to pursue this intriguing and growing field of research. For our proposal, we propose to develop novel bat reagents, including primary and immortalized cells from five major bat species, Rousettus aegyptiacus, Pteropus alecto, Eptesicus fuscus, Artibeus jamaicensis, and Carollia perspicillata, representing bats that currently exist in research colonies, making future in vivo translational studies feasible and logical. Data from selected bats, such as Rousettus, Pteropus and Eptesicus bats suggest that bat cells have evolved adaptations in their cytokine responses to better tolerate virus infections relative to humans. Type I interferon (IFN) responses are the first line of mammalian antiviral defense, and although type I IFNs and their downstream effects have been studied in selected bat cells, global cellular responses and the full range of IFN-mediated antiviral effects or the ‘interferome’ remain elusive. For this project, we shall use our diverse bat cell types, derived from multiple bat species, to identify and delineate evolutionarily conserved and unique bat-specific IFN responses. Results from our study will shed light on intriguing questions around the ability of bats to control infection with zoonotic RNA viruses, along with making important discoveries on evolutionary adaptations in the mammalian type I IFN pathway. Importantly, our research will generate critical bat reagents, such as primary cells, cell lines, recombinant cytokines and molecular assays that will facilitate the development of larger collaborative projects to study bat immunology.

Ecology and Evolution of Infectious Diseases (EEID) – The future of SARS-CoV-2 in ecological communities

August 2023 – August 2028

Collaborators: (1) Barbara Han @ Cary Institute, (2) Andrew Kramer @ University of South Florida

ABSTRACT It now appears certain that SARS-CoV-2 will persist in animals as long as it is prevalent in humans. The virus causes persistent, long-term infections in numerous mammal species and can lead to fatal disease, including in several threatened and endangered species. In addition to its impressive host range, new variants with differential host specificity continue to appear. The diversity of potential hosts and variants presents a vast combinatorial space that is further complicated when we consider that viral transmission dynamics are driven by contact patterns among interacting hosts, with patterns depending fundamentally on host ecology. To understand the future of SARS-CoV-2 in natural systems we will advance predictive capacity for potential hosts, novel variants, and their interaction in ecological communities. We integrate leading edge advances in artificial intelligence (AI), virology, and ecological theory in four specific aims: In Aim 1 we will make predictions about future zoonotic variants of SARS-CoV-2 and their evolutionary trajectories by advancing methods in controlled generative AI. In Aim 2, we will make predictions about which particular mammalian species are suitable hosts for existing and future zoonotic variants, extending predictions even to species for which host cell receptor (ACE2) sequences are still unknown. We will do this by harnessing foundational modeling in AI trained on a wider universe of biological relationships in existing databases. In Aim 3 we will conduct high throughput empirical validations of predictions made in Aims 1 and 2, safely testing cell entry in a pseudotyped virus platform for a subset of zoonotic variants and animal cell receptors. These empirical validations will feed back to tune predictive models, completing the loop between modeling and empirical validations to improve model accuracy. In Aim 4 we will advance transmission theory for ecological communities by building a framework that accounts for species distributions, their interactions (such as predation and competition), and finer scale contact patterns among individuals that together enable spatially explicit predictions about SARS-CoV-2 dynamics in ecological communities. We will instantiate this model for the northeastern forest community using 30 years of data for multiple mammal species and current surveillance data on SARS-CoV-2 in this community.

PRESS RELEASE