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ABSTRACT An animal's immune function is vital for survival but is potentially metabolically expensive. Some pathogens can manipulate their hosts' immune and metabolic responses. One example is Mycoplasma gallisepticum (MG), which infects both the respiratory system and conjunctiva of the eye in house finches (Haemorhous mexicanus). MG has been shown to exhibit immune- and metabolic-suppressive properties, but the physiological mechanisms are still unknown. Recent studies demonstrated that mitochondria could serve as powerhouses for both ATP production and immunity, notably inflammatory processes, by regulating complex II and its metabolites. Consequently, in this study, we investigate the short-term (3 days post-inoculation) and long-term (34 days post-inoculation) effects of MG infection on the hepatic mitochondrial respiration of house finches from two populations infected with two different MG isolates. After short-term infection, MG-infected birds had significantly lower state 2 and state 4 respiration, but only when using complex II substrates. After long-term infection, MG-infected birds exhibited lower state 3 respiration with both complex I and II substrates, resulting in a lower respiratory control ratio compared with uninfected controls, which aligned with the hypothesized metabolic-suppressive properties of MG. Interestingly, there were limited differences in mitochondrial respiration regardless of house finch population of origin, MG isolate and whether birds recovered from infection or not. We propose that MG targets mitochondrial complex II for its immune-suppressive properties during the early stages of infection and inhibits mitochondrial respiration for its metabolic-suppressive properties at a later stage of infection, both of which should delay recovery of the host and extend infectious periods. 

Abstract Immunopathology, or the harm caused to an organism's own tissues during the activation of its immune system, carries substantial costs. Moreover, avoiding this self-harm may be an important mechanism underlying tolerance of infection, helping to reducing fitness costs without necessarily clearing parasites. Despite the apparent benefits of minimizing immunopathology, such damage persists across a range of host species. Prior work has explored a trade-off with resistance during a single infection as a potential driver of this persistence, with some collateral damage being unavoidable when killing parasites. Here, we present an additional trade-off that could favor the continued presence of immunopathology: robust immune responses during initial infection (e.g., innate immunity in vertebrates) can induce stronger memory (adaptive immunity), offering protection from future infections. We explore this possibility in an adaptive dynamics framework, using theoretical models parameterized from an ecologically relevant host-parasite system, house finches (Haemorhous mexicanus) infected with the bacterial pathogen, Mycoplasma gallisepticum. We find that some degree of immunopathology is often favored when immunopathology during first infection either reduces susceptibility to or enhances recovery from second infection. Further, interactions among factors like transmission rate, recovery rate, background mortality and pathogen virulence also shape these evolutionary dynamics. Most notably, the evolutionary stability of investment in immunopathology is highly dependent upon the mechanism by which hosts achieve secondary protection (susceptibility vs. recovery), with the potential for abrupt evolutionary shifts between high and low investment under certain conditions. These results highlight the potential for immune memory to play an important role in the evolutionary persistence of immunopathology and the need for future empirical research to reveal the links between immunopathology during initial infections and longer-term immune protection. 

Acute infections can alter foraging and movement behaviors relevant to sociality and pathogen spread. However, few studies have directly examined how acute infections caused by directly transmitted pathogens influence host social preferences. While infected hosts often express sickness behaviors (e.g., lethargy) that can reduce social associations with conspecifics, enhanced sociality during infection might be favored in some systems if social grouping improves host survival of infection. Directly assaying social preferences of infected hosts is needed to elucidate potential changes in social preferences that may act as a form of behavioral tolerance (defined as using behavior to minimize fitness costs of infection). We tested how infection alters sociality in juvenile house finches (Haemorhous mexicanus), which are both highly gregarious and particularly susceptible to infection by the bacterial pathogenMycoplasma gallisepticum(MG). We inoculated 33 wild‐caught but captive‐held juvenile house finches with MG or media (sham control). At peak infection, birds were given a choice assay to assess preference for associating near a flock versus an empty cage. We then repeated this assay after all birds had recovered from infection. Infected birds were significantly more likely than controls to spend time associating with, and specifically foraging near, the flock. However, after infected birds had recovered from MG infection, there were no significant differences in the amount of time birds in each treatment spent with the flock. These results indicate augmented social preferences during active infection, potentially as a form of behavioral tolerance. Notably, infected birds showed strong social preferences regardless of variation in disease severity or pathogen loads, with 14/19 harboring high loads (5–6 log₁₀copies of MG) at the time of the assay. Overall, our results show that infection with a directly transmitted pathogen can augment social preferences, with important implications for MG spread in natural populations. 

Pathogen adaptations during host-pathogen co-evolution can cause the host balance between immunity and immunopathology to rapidly shift. However, little is known in natural disease systems about the immunological pathways optimised through the trade-off between immunity and self-damage. The evolutionary interaction between the conjunctival bacterial infectionMycoplasma gallisepticum(MG) and its avian host, the house finch (Haemorhous mexicanus), can provide insights into such adaptations in immune regulation. Here we use experimental infections to reveal immune variation in conjunctival tissue for house finches captured from four distinct populations differing in the length of their co-evolutionary histories with MG and their disease tolerance (defined as disease severity per pathogen load) in controlled infection studies. To differentiate contributions of host versus pathogen evolution, we compared house finch responses to one of two MG isolates: the original VA1994 isolate and a more evolutionarily derived one, VA2013. To identify differential gene expression involved in initiation of the immune response to MG, we performed 3’-end transcriptomic sequencing (QuantSeq) of samples from the infection site, conjunctiva, collected 3-days post-infection. In response to MG, we observed an increase in general pro-inflammatory signalling, as well as T-cell activation and IL17 pathway differentiation, associated with a decrease in the IL12/IL23 pathway signalling. The immune response was stronger in response to the evolutionarily derived MG isolate compared to the original one, consistent with known increases in MG virulence over time. The host populations differed namely in pre-activation immune gene expression, suggesting population-specific adaptations. Compared to other populations, finches from Virginia, which have the longest co-evolutionary history with MG, showed significantly higher expression of anti-inflammatory genes and Th1 mediators. This may explain the evolution of disease tolerance to MG infection in VA birds. We also show a potential modulating role of BCL10, a positive B- and T-cell regulator activating the NFKB signalling. Our results illuminate potential mechanisms of house finch adaptation to MG-induced immunopathology, contributing to understanding of the host evolutionary responses to pathogen-driven shifts in immunity-immunopathology trade-offs. 

Animal hosts can adapt to emerging infectious disease through both disease resistance, which decreases pathogen numbers, and disease tolerance, which limits damage during infection without limiting pathogen replication. Both resistance and tolerance mechanisms can drive pathogen transmission dynamics. However, it is not well understood how quickly host tolerance evolves in response to novel pathogens or what physiological mechanisms underlie this defense. Using natural populations of house finches ( Haemorhous mexicanus ) across the temporal invasion gradient of a recently emerged bacterial pathogen ( Mycoplasma gallisepticum ), we find rapid evolution of tolerance (<25 years). In particular, populations with a longer history of MG endemism have less pathology but similar pathogen loads compared with populations with a shorter history of MG endemism. Further, gene expression data reveal that more-targeted immune responses early in infection are associated with tolerance. These results suggest an important role for tolerance in host adaptation to emerging infectious diseases, a phenomenon with broad implications for pathogen spread and evolution. 

How directly transmitted pathogens benefit from harming hosts is key to understanding virulence evolution. It is recognized that pathogens benefit from high within-host loads, often associated with virulence. However, high virulence may also directly augment spread of a given amount of pathogen, here termed ‘spreadability’. We used house finches and the conjunctival pathogen Mycoplasma gallisepticum to test whether two components of virulence—the severity of conjunctival inflammation and behavioural morbidity produced—predict pathogen spreadability. We applied ultraviolet powder around the conjunctiva of finches that were inoculated with pathogen treatments of distinct virulence and measured within-flock powder spread, our proxy for ‘spreadability’. When compared to uninfected controls, birds infected with a high-virulence, but not low-virulence, pathogen strain, spread significantly more powder to flockmates. Relative to controls, high-virulence treatment birds both had more severe conjunctival inflammation—which potentially facilitated powder shedding—and longer bouts on feeders, which serve as fomites. However, food peck rates and displacements with flockmates were lowest in high-virulence treatment birds relative to controls, suggesting inflammatory rather than behavioural mechanisms likely drive augmented spreadability at high virulence. Our results suggest that inflammation associated with virulence can facilitate pathogen spread to conspecifics, potentially favouring virulence evolution in this system and others. 

Individuals can express a range of disease phenotypes during infection, with important implications for epidemics. Tolerance, in particular, is a host response that minimizes the per-pathogen fitness costs of infection. Because tolerant hosts show milder clinical signs and higher survival, despite similar pathogen burdens, their potential for prolonged pathogen shedding may facilitate the spread of pathogens. To test this, we simulated outbreaks of mycoplasmal conjunctivitis in house finches, asking how the speed of transmission varied with tissue-specific and behavioural components of tolerance, milder conjunctivitis and anorexia for a given pathogen load, respectively. Because tissue-specific tolerance hinders pathogen deposition onto bird feeders, important transmission hubs, we predicted it would slow transmission. Because behavioural tolerance should increase interactions with bird feeders, we predicted it would speed transmission. Our findings supported these predictions, suggesting that variation in tolerance could help identify individuals most likely to transmit pathogens. 

Since its introduction to North America in 1999, the West Nile virus (WNV) has resulted in over 50,000 human cases and 2400 deaths. WNV transmission is maintained via mosquito vectors and avian reservoir hosts, yet mosquito and avian infections are not uniform across ecological landscapes. As a result, it remains unclear whether the ecological communities of the vectors or reservoir hosts are more predictive of zoonotic risk at the microhabitat level. We examined this question in central Iowa, representative of the midwestern United States, across a land use gradient consisting of suburban interfaces with natural and agricultural habitats. At eight sites, we captured mosquito abundance data using New Jersey light traps and monitored bird communities using visual and auditory point count surveys. We found that the mosquito minimum infection rate (MIR) was better predicted by metrics of the mosquito community than metrics of the bird community, where sites with higher proportions of Culex pipiens group mosquitoes during late summer (after late July) showed higher MIRs. Bird community metrics did not significantly influence mosquito MIRs across sites. Together, these data suggest that the microhabitat suitability of Culex vector species is of greater importance than avian community composition in driving WNV infection dynamics at the urban and agricultural interface.