The fungus Ceratocystis fagacearum (Bretz) Hunt causes the vascular disease of oak wilt and has been decimating live oaks (Quercus virginiana Mill. and Quercus fusiformis Small.) and red oaks (Quercus texana Small and Quercus marilandica Muenchh.) in Texas. The purpose of this research was to test the hypotheses that live oaks have heritable tolerance to oak wilt, and that allozyme markers are associated with this tolerance. One-year-old half-sib and two-year-old clonal progeny of live oaks (Q. fusiformis) were grown from acorns and ramets from a disease center and then challenged with C. fagacearum. Allozyme analyses were used to compare the pre- and post-epidemic populations in two natural disease centers to search for alleles associated with survivability and decreased crown loss. Half-sib and clonal challenge tests supported the hypothesis that heritable tolerance to the pathogen occurs in live oaks. The progeny tolerances seen in half-sib and clonal groups did not correlate with parental tree performance. This finding suggests that the tolerance of one-year-old seedlings in the greenhouse setting is not a good predictor of how mature trees will do in a natural setting. Seedlings may not be a good model for testing tolerance to a pathogen. The ability to survive this vascular pathogen is containment, and seedlings may be too small to test this type of tolerance. The clonal groups from post-epidemic trees performed better than the seedlings. They may have an increased resistance because they are mature or they may have a postdisease immunity. No significant allele frequencies between pre- and post-epidemic trees were consistent among sites or with previous research. The different disease sites had remarkably similar allele frequencies which indicate high levels of gene flow among sites. Both sites were found to contain significant numbers of clones, but the Izoro site had significantly larger clonal groups. Sites were in Hardy-Weinberg equilibrium which indicates substantial sexual reproduction and not just clonal reproduction is taking place. Several cases of linkage disequilibrium occurred at the Izoro site, but population structure was responsible in all but one case.

Emerging infectious diseases can exert strong selection on hosts to evolve resistance or tolerance to infection. However, it remains unknown whether the evolution of specific defense strategies against a novel pathogen influences host immune phenotypes more broadly, potentially affecting their ability to respond to other pathogens. In 1994 the bacterial pathogen, Mycoplasma gallisepticum (MG) jumped from poultry into house finches, causing severe conjunctivitis and reducing host survival. MG then spread across the continental United States, exerting strong selection on host populations and creating geographic variation in the degree of population co-evolutionary history with the pathogen. Prior work found that populations of house finches with longer histories of MG endemism have evolved tolerance and resistance to MG, and this evolution is associated with several immunological differences including reductions in pro-inflammatory immune responses. However, it remains unknown whether these immunological changes are limited to MG-specific defenses or whether broader immune responses differ between populations with distinct coevolutionary histories with MG. To examine possible effects of the evolution of host responses to MG, we used five immune assays to challenge house finches from four populations, ranging from no history of MG endemism to 20+ years of MG endemism. When challenged with phytohemagglutinin (PHA), populations differed significantly in the strength of wing web swelling, with populations with longer MG exposure (and thus the highest MG tolerance) on average exhibiting the weakest swelling response when mass differences were controlled for. However, detected population differences in wing web swelling were small, and population differences were absent for responses to four other immune assays that spanned components of the innate and adaptive immune system. Future work should examine whether the local inflammation that underlies swelling responses to PHA shares common immunological mechanisms with local inflammatory responses to MG, which may explain why populations with evolved tolerance to MG show slightly lower swelling responses in response to PHA. Overall, these results suggest that the evolution of MG tolerance may have minor downstream consequences for responses to certain antigens, with the potential to influence a host's ability to respond to novel pathogen challenges, but most components of the host immune system appear largely unaffected. / Master of Science / Emerging infectious diseases can have devasting effects on new host species. To reduce the cost of these pathogens, host species can evolve ways to eliminate infection (resistance) or reduce damage during infection (tolerance), which is often caused by the host's immune system itself. As populations evolve these disease strategies, it is likely that other aspects of the immune system will also be affected, potentially compromising the ability of hosts to respond to pathogens other than the ones they evolved defenses against. We examined what sort of trade-offs might arise as house finches evolved resistance and tolerance to a new deadly pathogen, Mycoplasma gallisepticum (MG). House finch populations in the mid-Atlantic were first exposed to the disease in 1994, and as the disease spread across the continental United States, different populations have been exposed for different periods of time. This created a gradient in whether certain populations have had long enough time with MG to evolve disease strategies. Populations that have been exposed to MG for longer appear to have evolved both resistance and tolerance, and tolerant populations show lower levels of inflammatory immune markers that can be associated with self-damage. Using house finches from four different populations (ranging from 25 years of exposure history to zero years of MG exposure history), we tested a variety of immune system components to examine what areas of the immune system might have been broadly affected by the evolution of resistance and tolerance. We hypothesized that birds from populations with evolved MG tolerance would also have a reduced inflammation response when stimulated with substances that mimic infection by something other than MG. Only one assay supported this hypothesis. Birds from populations that had been exposed to MG for a longer period of time (and thus had evolved MG tolerance) had a reduced swelling response following injection with a plant protein called phytohemagglutinin. However, there were no population differences observed with the other four assays, suggesting that evolving defenses against MG did not result in widespread immunological effects. This suggests that the evolution of host defenses against an emerging pathogen may not compromise that host's ability to respond effectively to other types of pathogens that they encounter in nature.

Health is often defined in terms of absence of disease or pathological processes, but this is a definition of exclusion and incomplete. For example, SARS-CoV-2 viral load does not reliably predict disease severity, and so individuals must vary in their ability to control inflammation and maintain normal tissue homeostasis. This host defense strategy is called disease tolerance, and better understanding of disease tolerance mechanisms could change the way that we treat disease and work to maintain health. The first project presented in this dissertation found that after accounting for effects of age and sex, innate lymphoid cells (ILCs), but not T cells, were lower in adults and children sick with COVID-19 or MIS-C, independent of lymphopenia. Furthermore, abundance of ILCs, but not of T cells, correlated inversely with disease severity. These blood ILCs were shown to produce amphiregulin, a protein implicated in disease tolerance and tissue homeostasis, and the percentage of amphiregulin-producing ILCs was lower in males. These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance accounts for increased COVID-19 severity with age and in males. The second project describes a novel mouse model of epigenetic inheritance wherein paternal influenza A virus (IAV) infection results in less severe influenza disease in IAV infected offspring. This offspring phenotype was not attributable to differences in viral load, indicating a possible difference in disease tolerance. Paternal caloric deprivation decreased, and influenza B virus infection increased, offspring influenza disease severity, and in vitro fertilization demonstrated sperm are sufficient to transfer IAV-associated epigenetic inheritance phenotypes. These findings represent a foundation for further work that, by continuing to elucidate the mechanisms of disease tolerance and epigenetic inheritance, could provide novel therapeutic interventions to help promote and maintain health.