Changes in corticosterone concentrations and behavior during Mycoplasma gallisepticum infection in house finches (Haemorhous mexicanus)
Introduction
Individuals vary considerably in their behavioral and hormonal responses to infectious agents, although the underlying causes of this variation are not always clear. When organisms are exposed to a chronic stressor, hormonal mediators of the stress response (e.g., glucocorticoids) can modify immune function (Sapolsky et al., 2000, Dhabhar, 2002, Dhabhar, 2009, Martin, 2009) and decrease disease resistance (Brown and Zwilling, 1994). Despite the often-suppressive effects of stress hormones on immune function, infections also incite the production of stress hormones (Webster et al., 2002, Webster and Sternberg, 2004, Weidenfeld et al., 1995, Turnbull and Rivier, 1996, McEwen et al., 1997, Adamo, 2010). While this seems paradoxical, it is thought that glucocorticoid concentrations might rise following infection to help maintain homeostasis by minimizing overactive immune responses (Elenkov and Chrousos, 2006, Webster and Sternberg, 2004). Overall, given that glucocorticoids can both influence and respond to pathogen infection, examining changes in glucocorticoids over the course of experimental infection can help elucidate mechanisms underlying individual responses to infection.
Corticosterone (CORT), the main glucocorticoid in birds, is involved in the regulation of energy and is an integral part of the stress response. CORT enables animals to respond to changing energy demands by suppressing unnecessary physiological processes and redistributing energy to processes that promote immediate survival (Wingfield et al., 1998, Sapolsky et al., 2000, Angelier and Wingfield, 2013). While glucocorticoids may mediate energetic demands of immune responses, stress hormones also interact directly with components of the immune system, making these hormones a likely mechanism underlying variation in host responses to pathogens. One component of the immune system known to interact with stress hormones during infection is the acute phase response, an innate, non-specific defense against pathogens early in infection (Besedovsky and del Rey, 1996). When an organism is challenged with a bacterial or viral pathogen, activated leukocytes release inflammatory cytokines that induce fever and sickness behaviors, increase other non-specific defenses such as the production of free-radicals, and often elevate glucocorticoid concentrations via activation of the hypothalamic-pituitary-adrenal (HPA) axis (Dantzer, 2004, Webster et al., 2002, Webster and Sternberg, 2004). It has been hypothesized that high concentrations of glucocorticoids may help prevent acute phase responses from progressing to harmful levels, acting as a brake on a costly innate immune component by, for example, suppressing inflammatory immune responses (Dantzer, 2004, Elenkov and Chrousos, 2006, Webster and Sternberg, 2004). This brake is important because inflammatory defenses are non-specific and can cause damage to host cells in addition to pathogen cells, resulting in immunopathology (Graham et al., 2005, Sears et al., 2011). Thus, CORT-mediated suppression of inflammation may be a crucial factor in limiting immunopathology during infection. Indeed, the inhibition of glucocorticoid release during experimental infections can result in increased disease severity and mortality, demonstrating that an intact HPA-axis and glucocorticoid release are crucial to surviving infection (Webster and Sternberg, 2004).
Behavioral responses to infection have also been linked to changes in CORT concentrations (Pezeshki et al., 1996, Propes and Johnson, 1997). Sickness behaviors, including the lethargy and anorexia typically observed in vertebrates early in infection, are hypothesized to improve the ability of organisms to cope with infection by conserving energy needed for immune activation (Hart, 1988). However, sickness behaviors also come at significant costs (Adelman and Martin, 2009), which can include reduced caloric intake and lost reproductive opportunities (Lochmiller and Deerenberg, 2000, Konsman et al., 2002, Aubert et al., 1997). Although some studies suggest that a rise in glucocorticoids following exposure to a stressor may prolong sickness behavior during an acute phase response (Chijiwa et al., 2015), other studies indicate that glucocorticoids can suppress sickness behaviors through negative feedback on cytokine release (Goujon et al., 1995, Pezeshki et al., 1996, Propes and Johnson, 1997, Willette et al., 2007). The latter data support the hypothesis that glucocorticoids can act as a brake on the acute phase response by preventing severe behavioral disruptions caused by infection. Because glucocorticoids like CORT can have variable effects on sickness behavior, CORT may contribute to individual variation in behavioral as well as immunological responses to infection.
An excellent host-pathogen system for examining how CORT interacts with the acute phase response is the naturally-occurring infection of house finches (Haemorhous mexicanus) with the bacterium Mycoplasma gallisepticum (MG). Since MG first appeared in free-living house finches in the mid-1990s, it has caused annual epidemics of Mycoplasmal conjunctivitis (Dhondt et al., 1998) and has been related to significant declines in eastern North American populations of house finches (Hochachka and Dhondt, 2000). Outbreaks of Mycoplasmal conjunctivitis are most common during winter and at the beginning of the breeding season when birds feed together in flocks (Altizer et al., 2004), periods generally associated with higher baseline CORT concentrations (Lindström et al., 2005). This study system is unique because the clinical signs of this inflammatory disease can be visually and non-invasively scored. There are also potentially high costs of inflammation associated with MG infection, which may underlie the increased mortality rates in diseased birds (Faustino et al., 2004). These include the production of pro-inflammatory cytokines, infiltration of lymphocytes and heterophils, and fever, all of which have the potential to damage host tissue (Adelman et al., 2013b, Luttrell et al., 1998, Hawley et al., 2012). The inflammatory eye lesions associated with Mycoplasmal conjunctivitis may also impair vision, reducing the ability to evade predators or find food. Finally, infected house finches also exhibit sickness behavior during infection (Kollias et al., 2004), decreasing activity levels to points that could incur additional fitness costs.
While this host-pathogen system is well studied, little is known about the physiological factors underlying individual variation in house finch responses to MG infection. Work on free-living house finches found that birds with clinical signs of Mycoplasmal conjunctivitis had higher stress-induced CORT concentrations than uninfected birds, but could not determine whether the increased CORT concentrations were a cause or consequence of infection (Lindström et al., 2005). Recent work by Adelman et al. (2015) on male house finches found that pre-infection baseline CORT concentrations were negatively associated with the extent of conjunctival swelling and sickness behavior during infection, but the detected association between CORT and inflammation may have been confounded by population differences, making interpretation difficult. Together these studies suggest that CORT concentrations may be linked to individual variation in MG response in house finches. However, no studies to date have investigated how CORT concentrations change throughout the course of experimental MG infection, or whether post-infection CORT concentrations are linked to variation in individual responses to infection. In this study, we hypothesized that baseline CORT concentrations vary during the course of MG infection and are linked to individual variation in the acute phase response. Specifically, we predicted that 1) CORT concentrations would increase early in infection and 2) CORT concentrations during infection would be positively correlated with the severity of conjunctival inflammation and sickness behaviors. We also predicted that, consistent with prior work, pre-infection CORT concentrations would negatively correlate with the extent of eye inflammation. Ultimately, this study aimed to enhance our understanding of the endocrine mechanisms that underlie variation in host immune responses and shed light on how CORT-immune interactions could impact disease dynamics in an ecologically relevant host-pathogen system.
Section snippets
Bird capture and housing
Thirty-four house finches (24 female, 10 male) were captured using cage traps in Auburn, Alabama, in September 2010, then transported to the Virginia Polytechnic Institute and State University campus in Blacksburg, Virginia. All birds were housed individually in cages on a 12 L:12 D light cycle. Cages had two wooden perches, a water dish, and a cylindrical feeder in which birds were fed an ad libitum pelleted diet (Roudybush Maintenance Diet). Birds were housed in four rooms and treatments (MG
Treatment differences
Experimental infection with MG influenced baseline plasma CORT concentrations, but the extent of this effect varied across the sampling intervals (infection timing*treatment: F4,108 = 5.01; p = 0.001; Table S1). Plasma CORT concentrations of MG-infected birds were similar to that of control birds prior to (t = −1.67; Adj p = 0.81) and immediately following infection (6 h: t = 0.86, Adj p = 0.98; 24 h; t = 0.74; Adj p = 0.99), but were significantly higher than control birds on day 5 (t = −3.61; Adj p = 0.016)
Discussion
Here we examined how baseline CORT concentrations in house finches both predict and respond to experimental infection with a naturally-occurring bacterial pathogen. Consistent with our predictions, CORT concentrations significantly increased following experimental infection with MG, but this increase was not yet detectable at 24 h post-inoculation. Due to the inability to repeatedly blood-sample small birds at finer temporal intervals, we were unable to pinpoint in this study when plasma CORT
Conclusions
By investigating relationships between CORT concentrations and MG infection in house finches, this study demonstrates the importance of examining CORT-infection interactions at multiple time points. Overall, our results suggest that the house finch glucocorticoid stress response may both influence and respond to MG infection, potentially in sex-specific ways. Moreover, the fact that CORT concentrations are linked to conjunctival inflammation during MG infection could have important implications
Acknowledgments
We thank Laila Kirkpatrick and William Mills for their assistance with data collection and G. Hill for assistance with bird capture. This work was supported by a National Science Foundation Research Experiences for Undergraduates supplement (Grant EF-0622705 to André Dhondt under the NSF-NIH Ecology of Infectious Diseases Program), NSF Grant IOS-1054675 to D.M.H., NSF Grant IOS-1145625 to I.T.M., Virginia Tech’s Organismal Biology and Ecology (OBE) Interdisciplinary Grant to A.C.L., and
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2019, Comparative Biochemistry and Physiology -Part A : Molecular and Integrative PhysiologyCitation Excerpt :Furthermore, it is likely that changes in Cort are context-specific, meaning that the type of chronic stress an animal experiences might alter the function and regulation of the HPA axis differently. Although it is generally accepted that chronic stress—no matter its origin—causes broad physiological and behavioral consequences including immunosuppression (Dhabhar and McEwen, 1997; Martin, 2009), reduced reproductive success (Cyr and Romero, 2007; Dickens and Bentley, 2014), and altered behavior (Gormally et al., 2018; Love et al., 2016), it remains unclear whether Cort is the proximal mechanism for these responses. The broader field of stress physiology is in need of a more integrative and consistent biomarker of chronic stress (Romero et al., 2015).
- 1
Present address: Department of Integrative Biology, Oklahoma State University, Stillwater, OK 74078, USA.
- 2
Present address: Department of Biology, Radford University, Radford, VA 24142, USA.
- 3
Present address: Department of Natural Resource Ecology and Management, Iowa State University, Ames, IA 50011, USA.