Omenn Award Winners: Anne Demongines and Matthew Barber

ISEMPH - Omenn Prize lectures

“Evolution of zoonosis: Exploring receptor-binding as a viral host range barrier”
Anne Demogines
Scientist for Regulated Products at BioFire Diagnostics, LLC
Omenn Award Winner
 
In wild rodent populations, arenaviruses and the retrovirus MMTV both utilize the host Transferrin Receptor 1 (TfR1) for cellular entry. We show that the physical interactions between the surface glycoproteins of these viruses and TfR1 has been highly dynamic over time, leading to an evolutionary arms race that has shaped the protein sequences of both TfR1 and virus glycoproteins for millions of years. Evolutionary analysis of only eight rodent TFR1 gene sequences allowed us to quickly identify specific residues in TfR1 that mediate patterns of viral host range. We also gained additional insight into the host ranges and origins of these viruses. Based on our analyses, we predicted that MMTV-like retroviruses, which are restricted to rodents of the genus Mus, once circulated widely among rodent genera. We verified this through identification of endogenous MMTV-like genomes “fossilized” in the genome of a former host. This evolutionary approach can theoretically be applied to the study of any host-virus interaction. As such, this is a scalable framework for understanding the host range of viruses emerging from wildlife reservoirs.
 
 
“Evolutionary conflicts shape host nutritional immunity”
Matthew Barber 
Postdocotral Fellow, Elde Lab
University of Utah School of Medicine 
 

The sequestration of essential metals by host proteins provides an innate immune defense termed nutritional immunity. Microbial pathogens in turn meet their metabolic requirements by stealing these nutrients from the host. Recently we discovered that the primate bloodstream iron transporter, transferrin, has been engaged in a longstanding evolutionary conflict with transferrin binding protein A (TbpA), a major virulence factor in Gram-negative bacteria that scavenges iron from transferrin. Single mutations at rapidly evolving sites in transferrin and TbpA are sufficient to dictate this protein-protein interaction, providing a direct link between signatures of positive selection and pathogen receptor function. Moreover, we find that an abundant transferrin human polymorphism confers resistance to binding by H. influenzae TbpA, suggesting functional implications for transferrin evolution in modern humans. Together this work establishes the “battle for iron” as a critical node of host-pathogen evolutionary conflict, on par with those involving canonical host immunity factors. More recently we have identified new evidence for positive selection involving primate nutritional immunity factors beyond
transferrin. We are continuing to investigate the genetic and biochemical basis of these host-pathogen conflicts as well as implications for human disease.