Jason Nomburg did his undergraduate degree at the University of California, Santa Barbara where he studied the interplay between measles virus and proteins involved in histone methylation. He received his PhD in Virology from Harvard in 2022. As a PhD student he conducted research in the labs of James DeCaprio and Matthew Meyerson, where he led studies on diverse topics, including the role of oral bacteria in esophageal cancers, viral discovery efforts in human cancers, and the transcriptional dynamics of SARS-CoV-2 and polyomaviruses. Jason went on to do a postdoctoral fellowship in the lab of Jennifer Doudna at the Gladstone Institutes in San Francisco. As a postdoc, Jason Nomburg used AI-guided structure prediction to investigate the function and evolution of viral proteins. As part of this work, Jason discovered a pan-viral mechanism of immune antagonism shared by viruses that infect animals and those that infect bacteria.

His research group at AITHYRA will lead efforts to systematically understand the function of proteins in the virome. Jason’s lab pairs computational and experimental methods to study viruses, with a special emphasis on (1) using protein structure to understand viral protein function and evolution, (2) understanding the interplay between viral proteins and cellular immunity, and (3) using functional genomics to explore the behavior of viral proteins.

Orchid number: https://orcid.org/0000-0001-7807-8658
LinkedIn: https://www.linkedin.com/in/jason-nomburg/

Viruses evolve more rapidly than any other biological entity, leading to the emergence of hundreds of millions of viral proteins with no known function. Understanding the function of these proteins is essential to understanding how viruses infect and cause disease in their hosts.

The Nomburg Lab combines computational inference, high-throughput experimental methods, and artificial intelligence to understand what viral proteins do and how they work. Their overall goal is to use this knowledge to uncover how viruses cause disease, how viral proteins evolve, and how divergent viruses use common strategies to overcome cellular immunity.

Principles of immune antagonism: Cells encode immune sensors responsible for detecting and initiating a response to viral infection. Viruses in turn encode immune antagonists that shut down these cellular pathways, enabling infection. Understanding the strategies viruses use to shut down cellular immunity is essential for the development of anti-viral countermeasures. Furthermore, many cellular immune sensing pathways are conserved across the tree of life. This means that the strategies and principles of viral immune antagonism are broadly applicable across viruses and relevant to immune regulation by other types of pathogens.

The laboratory of Jason Nomburg is interested in questions that include:

• How do viruses subvert cellular immunity?
• How widespread are these strategies, and how do they evolve?
• What conserved mechanisms of immune regulation exist between viruses, other pathogens, and cells themselves?
• How do viral immune antagonists evolve in the context of viral spillover?

Structure and evolution of viral proteins: Proteins are often compared at the sequence level, where sequence similarity can be used to learn about their function and evolution. However, the speed of viral evolution leads to sequence divergence that can make sequence comparisons challenging. Protein structure is one way to address this limitation, as structure is often constrained to preserve protein function. The Nomburg group uses protein structure prediction and sensitive structural alignments to explore viral protein function and evolution.

• What proteins are shared by divergent viruses across the tree of life, and how have these proteins evolved?
• What are the patterns of gene transfer throughout viral and cellular species?
• How do proteins and protein domains cooperate to mediate complex functions?

Functional genomics of viral protein behavior: Protein sequence plays a substantial role in how proteins behave. For example, protein-protein interactions and subcellular localization are often driven by short, disordered amino acid motifs. Understanding how protein sequences contribute to protein function is essential for understanding the function of viral proteins. The lab of Jason Nomburg develops functional genomics assays to understand the contribution of protein sequence to protein function, with an initial focus on the sequence determinants of viral protein localization.

• What sequence motifs target viral proteins to distinct compartments of the cell?
• How does this behavior contribute to viral infection?
• How do host factors control these behaviors?

Publication Highlights

Nomburg J, Doherty EE, Price N, Bellieny-Rabelo D, Zhu YK, Doudna JA. Birth of protein folds and functions in the virome. Nature. 2024 Sep 19;633(8030):710-7. https://www.nature.com/articles/s41586-024-07809-y

Hobbs SJ, Nomburg J, Doudna JA, Kranzusch PJ. Animal and bacterial viruses share conserved mechanisms of immune evasion. Cell. 2024 Oct 3;187(20):5530-9. https://www.cell.com/cell/abstract/S0092-8674(24)00889-4

Nomburg J, Zou W, Frost TC, Datta C, Vasudevan S, Starrett GJ, Imperiale MJ, Meyerson M, DeCaprio JA. Long-read sequencing reveals complex patterns of wraparound transcription in polyomaviruses. PLoS pathogens. 2022 Apr 1;18(4):e1010401. https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010401