Immune memory evolved to protect hosts from reinfection, but incomplete responses that allow future reinfection may inadvertently select for more-harmful pathogens. We present empirical and modeling evidence that incomplete immunity promotes the evolution of higher virulence in a natural host-pathogen system. We performed sequential infections of house finches with strains of various levels of virulence. Virulent bacterial strains generated stronger host protection against reinfection than less virulent strains and thus excluded less virulent strains from infecting previously exposed hosts. In a two-strain model, the resulting fitness advantage selected for an almost twofold increase in pathogen virulence. Thus, the same immune systems that protect hosts from infection can concomitantly drive the evolution of more-harmful pathogens in nature.

In December 2019, a novel coronavirus of likely zoonotic origin, SARS-CoV-2, was discovered following detection of an outbreak of acute respiratory disease in people from Wuhan, China (Zhou et al., 2020). The virus has since spread across the world and in early March 2020 the WHO declared COVID-19, the disease caused by the virus, a pandemic (https://www.who.int/dg/speec hes/detai l/who-direc tor-gener al-s-openi ng-remar ks-at-the-media -brief ing-on-covid -19---11-march -2020). As of November 2020, worldwide mortality from COVID-19 was over 1,360,000 deaths (https://coron avirus.jhu.edu/map.html; Accessed November 20, 2020).Coronaviruses have large (~30 kb), positive-sense, RNA genomes and are known to infect a variety of mammals and birds. Their genomes are also known to have a high propensity for recombination with other coronaviruses. Coronaviruses are classified as alpha-, beta-, gamma-or deltacoronaviruses. Both alpha-and betacoronaviruses infect mammals, and while worldwide bats are known to be infected by both types of viruses (Decaro & Larusso, 2020; Falcon et al., 2011), only alphacoronaviruses have been found to date in North American bats (Olival et al., 2020).

Hosts in free-living populations can experience substantial variation in the frequency and dose of pathogen exposure, which can alter disease progression and protection from future exposures. In the house finch-Mycoplasma gallisepticum (MG) system, the pathogen is primarily transmitted via bird feeders, and some birds may be exposed to frequent low doses of MG while foraging. Here we experimentally determined how low-dose, repeated exposures of house finches to MG influence host responses and protection from secondary high-dose challenge. MG-naive house finches were given priming exposures that varied in dose and total number. After quantifying host responses to priming exposures, all birds were given a secondary high-dose challenge to assess immunological protection. Dose, but not the number of exposures, significantly predicted both infection and disease severity following priming exposure. Furthermore, individuals given higher priming doses showed stronger protection upon secondary, high-dose challenge. However, even single low-dose exposures to MG, a proxy for what some birds likely experience in the wild while feeding, provided significant protection against a high dose challenge. Our results suggest that bird feeders, which serve as sources of infection in the wild, may in some cases act as “immunizers”, with important consequences for disease dynamics.

Tissue factor (TF) is a transmembrane receptor that serves as the major cofactor for factor VIIa-catalyzed proteolytic activation of factors IX and X. In response to bacterial lipopolysaccharide (LPS), monocytes transcribe, synthesize, and express TF on their surface, thereby conveying to activated monocytes the ability to initiate the blood coagulation protease cascades. Agents that elevate cellular cyclic AMP (cAMP) inhibit the functional expression of TF by LPS-stimulated monocytes. In this study, we investigated the mechanism of this suppression. Northern blot analysis of total RNA from LPS-stimulated monocytes showed a concentration-dependent decrease in TF messenger RNA (mRNA) levels in response to dibutyryl-cAMP (dBt-cAMP). TF mRNA and procoagulant activity were inhibited as early as 1 hour after the addition of dBt-cAMP and the inhibition persisted through 4 hours. Suppression of specific mRNA abundance was also observed with agents, including forskolin and iso-butyl-methyl-xanthine (IBMX), that increase cAMP levels by independent mechanisms. Flow immunocytometric analysis confirmed that cell-surface TF protein levels declined in parallel with TF functional activity. The rate of decay of TF mRNA after the arrest of transcription by actinomycin D was not altered by the addition of dBt-cAMP, IBMX, or forskolin, thus excluding effects on TF mRNA stability. We conclude that elevated cAMP levels suppress TF mRNA by reducing the rate of TF gene transcription.