Acute-phase Responses Vary with Pathogen Identity in House Sparrows (Passer domesticus)

Document Type

Article

Publication Date

2011

Keywords

inflammation, fever, lipopolysaccharide, PolyI:C, sickness behavior, zymosan

Digital Object Identifier (DOI)

https://doi.org/10.1152/ajpregu.00187.2010

Abstract

Pathogens may induce different immune responses in hosts contingent on pathogen characteristics, host characteristics, or interactions between the two. We investigated whether the broadly effective acute-phase response (APR), a whole body immune response that occurs in response to constitutive immune receptor activation and includes fever, secretion of immune peptides, and sickness behaviors such as anorexia and lethargy, varies with pathogen identity in the house sparrow (Passer domesticus). Birds were challenged with a subcutaneous injection of either a glucan at 0.7 mg/kg (to simulate fungal infection), a synthetic double-stranded RNA at 25 mg/kg (to simulate viral infection), or LPS at 1 mg/kg (to simulate a gram-negative bacterial infection), and then body mass, core body temperature changes, sickness behaviors, and secretion of an acute-phase protein, haptoglobin, were compared. Despite using what are moderate-to-high pyrogen doses for other vertebrates, only house sparrows challenged with LPS showed measurable APRs. Febrile, behavioral, and physiological responses to fungal and viral mimetics had minimal effects.

animals often discriminate self from nonself via conserved molecular patterns of pathogens [i.e., pathogen-associated molecular patterns (PAMPs)]. For example, many viruses express double-stranded RNA (dsRNA) sometime during replication, whereas normal animal cells do not. Vertebrate hosts recognize PAMPs through the use of pattern recognition receptors (21, 36), such as the Toll-like receptors (TLRs) (17, 30, 31). Once activated, transmembrane portions of TLRs initiate intracellular signaling cascades that can initiate a whole organism immune response known as an acute-phase response (APR) (17). An APR is an inflammatory process characterized by heterothermia (most often hyperthermia, fever), expression of pro- and anti-inflammatory cytokines, release of glucocorticoids and liver-derived antimicrobial proteins (including haptoglobin), and sickness behaviors, which include anorexia, lethargy, anhedonia, and hyperalgesia (21, 27). Together, these APR components are thought to limit pathogen burden and increase the likelihood of host survival after infection by 1) impairing pathogen survival or replication (e.g., via high temperatures, complement-induced cell lysis); 2) limiting resources available to the pathogen (e.g., iron via heme scavenging); and/or 3) diverting resources from other physiological processes such as digestion, reproduction, and physical activity (e.g., foraging, territorial display) for use in an immune reaction (27, 36).

Although invaluable for combating infections, APRs are expensive in terms of energy demand and protein turnover (49). Moreover, APRs can impart serious fitness consequences to the host including collateral tissue damage, lost opportunities to breed and forage associated with lethargy and reduced libido, and decreased growth and reproductive output (12, 27, 42, 61). Subsequently, APRs are thought to be major progenitors of trade-offs among immunity, growth, and reproduction (44, 52) and thus should vary in predictable ways contingent on context [e.g., with resource availability; pathogen identity; host sex, age, and condition; and ontogenic experience (4, 52)].

Because APRs are more rapid and more broadly effective at pathogen control than other immune options (e.g., the generation of antibodies, which requires 7–10 days to provide protection), one might predict host variability (both within and among species) in APRs to be minimal (53). On the other hand, the high costs of APRs might constrain their magnitude in some contexts. Indeed, inflammatory processes, including APRs, are immunological double-edged swords: for the same reasons that these processes are broadly and rapidly protective, they can also be detrimental (36). Many defensive elements of APRs (e.g., release of reactive oxygen and nitrogen species) harm pathogens, but absent strong compensatory responses in hosts (e.g., antioxidants), the same defensive elements can also harm host tissues. Therefore, maximal inflammatory responses to all pathogen challenges may be maladaptive. In this light, APRs might be better understood as anti-parasite emergency life history stages entered into only when parasite clearance is favored over other life processes (62). Because individual fitness can be maximized in multiple ways, when, if, and how hosts respond to pathogens should be determined by the value of pathogen resistance vs. other costly life history processes, such as breeding, growth, and territorial defense (69, 79).

The present study was designed to test whether APRs would be similar regardless of pathogen identity, as would be expected if hosts are selected to mount maximal responses to parasites or whether APRs are variable, as would be expected if hosts evolve optimal immunity (1, 40, 52, 79). We compared aspects of APRs, namely fever, sickness behaviors, and haptoglobin induction among groups of house sparrows (Passer domesticus) challenged with different pathogen components. To instigate APRs, we used three well-known PAMPs that act predominantly through three different immune receptors: zymosan (a fungal glucan) through TLR-2, polyinosinic:polycytidylic acid (PolyI:C; a synthetic dsRNA) through TLR-3, and LPS (a component of gram-negative bacteria cell walls) through TLR-4. We used wild animals because studies of domesticated, inbred animals would be difficult to interpret from an ecological and evolutionary perspective (14). We chose the house sparrow for our study because 1) much is known of its natural history, ecology, and physiology (5); 2) its immune system (12, 13, 42, 49), and passerine immune systems generally (61, 62), have been studied extensively already, giving context to our results; and 3) it is the current focal species in our lab.

While molecular mediators of APRs are highly conserved across vertebrates (6, 9) and the actions of APRs tend to be stereotypical (27, 36), some variation in duration and magnitude exists among mammals, chickens, and songbirds (reviewed in Ref. 62). In general, however, passerines have similar APRs compared with both chickens and mammals, including acute-phase protein secretion, anorexia and body mass loss, activation of the hypothalamic-pituitary-adrenal axis, inhibition of the hypothalamic-pituitary-gonadal axis, and generally decreased activity and aggression levels (35, 62), regardless of immune challenge type (LPS, sheep red blood cells, vaccine, etc.) (36). One notable exception is that some small passerines engage hypothermia, as opposed to fever, possibly because the high thermal set point and high surface area-to-volume ratio of passerines makes hyperthermia metabolically unfeasible (62). We predicted that all three pyrogens would induce measurable yet variable APRs in our house sparrows, as nearly all passerine species to date, including house sparrows, have shown at least partially stereotypical APRs in response to immune challenges (3, 12, 42, 47, 62). However, because two PAMPs (zymosan and PolyI:C) had never been used in wild bird species before and had been used minimally in domestic fowl, we did not make specific predictions about APR differences among pyrogens.

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Citation / Publisher Attribution

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, v. 300, issue 6, p. R1418-R1425

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