When animals become infected, they can employ two broad categories of defense: resistance, which kills off the invading pathogens, or disease tolerance, which minimizes harm from the infection without necessarily clearing the pathogens. Although resistance has been well-studied, much has remained unclear about the evolution, underlying mechanisms, and consequences of disease tolerance in animals?a critical gap in understanding how variation in responses to infection can impact disease dynamics and co-evolution of hosts and pathogens.

Using a recently emerged bacterial pathogen, Mycoplasma gallisepticum, which causes severe conjunctivitis (similar to pink eye) and reduces survival in its songbird host, the house finch (Haemorhous mexicanus), this project asked:

1) How rapidly can disease tolerance evolve in a new host species?

2) Which immune responses might play a role in disease tolerance?

3) Does disease tolerance of a given animal enhance or inhibit pathogen spread?

We answered these questions by comparing house finches from seven populations spanning the pathogen?s invasion path across the United States, each with a different number of years since pathogen invasion, and thus, a different amount of time in which to evolve in response to the pathogen. From these populations, we brought juvenile individuals into the laboratory, ensured that each had not been previously exposed to the pathogen in the wild, and experimentally exposed animals to either the earliest known pathogen strain collected from wild birds, or a more recently collected strain, the latter of which is known to cause more severe disease in birds. By measuring the severity of conjunctivitis and amount of pathogen present in the eye (pathogen load), we determined that populations with a longer time since pathogen invasion showed higher disease tolerance. That is, populations with the longest time  since pathogen invasion (20-25 years) showed milder conjunctivitis for a given pathogen load than did populations with 10-20 years since pathogen invasion or no history of pathogen presence.

To assess potential immune responses important for disease tolerance, we used ?next generation? sequencing methods to measure gene expression in an immune tissue located near the eye, the Harderian gland. Overall, we found more differentially expressed genes (those producing different levels of gene expression in infected vs. uninfected animals) among birds from less-tolerant than more-tolerant populations. Moreover, in less-tolerant populations, those genes tended to be associated with inflammatory immune processes. These results suggest that a down-regulation of inflammatory responses, which can incur significant damage to a host?s own tissues, contribute to the disease tolerance observed in populations with a longer history of pathogen presence.

To determine how disease tolerance impacts disease spread in this system, we paired infected birds from less- and more-tolerant populations with uninfected individuals from a third population and assessed the likelihood of spread. We found that less-tolerant individuals were more likely to spread the disease to their partner than were more-tolerant individuals. Prior work has shown that less-tolerant birds shed more pathogen onto surfaces, a likely transmission mechanism in this system. As such, we conclude that in systems where very inflamed tissues?like conjunctivitis?lead to more pathogen shedding, disease tolerance (i.e., less swollen conjunctiva) in animals can impede spread.

In addition, this project helped train one postdoctoral scholar, three graduate students, and 23 undergraduates, many of whom were first-generation university students and/or members of underrepresented groups in STEM. Moreover, we led a monthly speaker series, Nerd Nite, to engage the public in science through entertaining, informative talks on topics ranging from avian disease to the physiological feasibility of comic book characters and the art and science of audio synthesizers. Thus far, the project has resulted in seven peer-reviewed publications, with three additional papers under review. We have also given over twenty presentations of this work at colleges, universities, and scientific meetings.

Overall, this project made significant strides in our understanding of disease tolerance, a critical, yet understudied response to infection in animals. Specifically, we show that disease tolerance can arise within 20 years (roughly 15 host generations) of disease emergence in a species; reduced expression of genes involved in inflammatory immune responses is associated with higher disease tolerance; and higher tolerance impedes the spread of pathogen to susceptible hosts. These advances leave us poised to answer new and critical questions about how disease tolerance influences the co-evolution of pathogens, especially their ability to cause harm in naive hosts.

Last Modified: 05/02/2023
Modified by: James Adelman