Photoperiodic regulation of behavioral responses to bacterial and viral mimetics: a test of the winter immunoenhancement hypothesis

Siberian hamsters (Phodopus sungorus) exhibit changes in immune function following adaptation to short photoperiods, including a marked attenuation of energetically expensive thermoregulatory and behavioral responses to gram-negative bacterial infections. Whether this seasonal attenuation of the immune response is idiosyncratic to gram-negative infections or is representative of innate immune responses in general is not known. If seasonal attenuation of responsiveness to infection is indeed driven primarily by anticipation of energetic constraints, then one would predict that responsiveness to all pathogens would be diminished during short days. If, on the other hand, seasonal changes in responsiveness to infection reflect anticipation of specific pathogens that are common at different phases of the annual cycle, then one would expect short photoperiods to attenuate responsiveness to some pathogens and long photoperiods to attenuate responsiveness to others. To resolve this issue, we exposed male Siberian hamsters to either long or short photoperiods for 11 weeks, then examined their behavioral sickness responses to compounds that represent the minimally immunogenic components of gram-negative bacterial (lipopolysaccharide), gram-positive bacterial (muramyl dipeptide), and viral (polyinosinepolycytidylic acid) organisms. Hamsters exhibited anorexic, anhedonic, ponderal, and/or thermoregulatory sickness behaviors to all 3 pathogen mimetics, but in all cases in which sickness responses were evident, they were attenuated in short days. Energetically costly behavioral responses to several distinct classes of infectious organisms are attenuated in anticipation of winter. The data are not consistent with a pathogen-specific seasonal modulation of innate immune responses.     

Gonadal hormone-dependent and -independent regulation of immune function by photoperiod in Siberian hamsters

Siberian hamsters (Phodopus sungorus) exhibit changes in reproductive and immune function in response to seasonal variations in day length. Exposure to short days induces gonadal regression and inhibits testosterone secretion. In parallel, short days enhance immune function: increasing leukocyte numbers and attenuating cytokine and behavioral responses to infection. We examined whether photoperiodic changes in leukocyte phenotypes and sickness behaviors are dependent on concurrent photoperiodic changes in gonadal function. Male hamsters were gonadectomized or sham-gonadectomized and either exposed to short days (9 h light/day; SD) or kept in their natal long-day (15 h light/day; LD) photoperiod for 10-13 wk. Blood samples were obtained for leukocyte enumeration, and hamsters were challenged with bacterial LPS, which induced behavioral (anorexia, reductions in nest building) and somatic (weight loss) sickness responses. Among gonad-intact hamsters, exposure to SD increased total and CD62L+ lymphocytes and CD3+ T lymphocytes in blood and significantly attenuated LPS-induced sickness responses. Independent of photoperiod, castration alone increased total and CD62L+ lymphocyte and CD3+ T lymphocyte numbers and attenuated somatic and anorexic sickness responses. Among castrated hamsters, SD exposure increased lymphocyte numbers and suppressed sickness behaviors. In castrated hamsters, the magnitude of most immunological effects of SD were diminished relative to those evident in gonad-intact hamsters. The SD phenotype in several measures of immunity can be instated via elimination of gonadal hormones alone; however, photoperiodic effects on immune function persist even in castrated hamsters. Thus, photoperiod affects the immune system and neural-immune interactions underlying sickness behaviors via gonadal hormone-dependent and -independent mechanisms.     

Stimulation of innate immune responses by CpG oligodeoxynucleotide in newborn lambs can reduce bovine herpesvirus-1 shedding

Stimulation of the innate immune system is potentially very important in neonates who have an immature adaptive immune system and vaccination cannot be used to reduce the risk of infection. CpG oligodeoxynucleotide (ODN) can stimulate innate immune responses in newborn chickens and mice, but similar studies are lacking in other mammalian species. We have shown previously that CpG ODN can both stimulate an acute-phase immune response and induce the antiviral effector molecule, 2'5'-A synthetase, in adult sheep. Therefore, the immunostimulatory activity of A class and B class CpG ODN was evaluated in newborn lambs, and the capacity of CpG ODN-induced responses to reduce viral shedding was evaluated following aerosol challenge with the respiratory pathogen, bovine herpesvirus-1 (BHV-1). In vitro CpG ODN stimulation of peripheral blood mononuclear cells (PBMC) isolated from newborn lambs (3-5 days old) and adult sheep induced equivalent CpG-specific proliferative responses and interferon-alpha (IFN-alpha) secretion. CpG ODN-induced IFN-alpha secretion by neonatal PBMCs was, however, significantly (p < 0.01) enhanced 6 days after subcutaneous (s.c.) injection of 100 microg/kg CpG ODN 2007. Newborn lambs injected s.c. with B class CpG ODN 2007 or the inverted GpC control ODN formulated in 30% Emulsigen (MVP Laboratories, Ralston, NE) displayed CpG ODN-specific increases in body temperature (p < 0.0001), serum 2'5'-A synthetase activity (p = 0.0015), and serum haptoglobin (p = 0.07). CpG ODN-treated lambs also displayed a transient reduction in viral shedding on day 2 postinfection (p < 0.05), which correlated (p < 0.03) with serum 2'5'-A synthetase levels on the day of viral challenge. These observations confirmed that CpG ODNs effectively activate innate immune responses in newborn lambs and CpG ODN-induced antiviral responses correlated with a reduction in viral shedding.     

Augmentation of protective immune responses against viral infection by oral administration of schizophyllan

An oral administration of fungal polysaccharide schizophyllan has augmented protective immune responses to Sendai virus infection in mice and the rodshaped DNA virus of Penaeus japonicus (RV-PJ) infection in Kuruma shrimps. When schizophyllan was administered orally at a dose of 50 or 100 mg/kg body weight per day, the survival rates after virus challenge were significantly higher than those of the control groups. High phagocytic activities were observed in the haemocytes of the schizophyllan-fed shrimps.These results suggest that schizophyllan confers effective protection against viral infection by increasing antiviral immune responses, and that it could be used to boost immunity to virus infection in animals or in invertebrates.     

Pineal-dependent and -independent effects of photoperiod on immune function in Siberian hamsters (Phodopus sungorus)

Siberian hamsters (Phodopus sungorus) exhibit reproductive and immunological responses to photoperiod. Short (<10-h light/day) days induce gonadal atrophy, increase leukocyte concentrations, and attenuate thermoregulatory and behavioral responses to infection. Whereas hamster reproductive responses to photoperiod are dependent on pineal melatonin secretion, the role of the pineal in short-day induced changes in immune function is not fully understood. To examine this, adult hamsters were pinealectomized (PINx) or sham-PINx, and transferred to short days (9-h light/day; SD) or kept in their natal long-day (15-h light/day; LD) photoperiod. Intact and PINx hamsters housed in LD maintained large testes over the next 12 weeks; sham-PINx hamsters exhibited gonadal regression in SD, and PINx abolished this effect. Among pineal-intact hamsters, blood samples revealed increases in leukocyte, lymphocyte, CD62L+ lymphocyte, and T cell counts in SD relative to LD; PINx did not affect leukocyte numbers in LD hamsters, but abolished the SD increase in these measures. Hamsters were then treated with bacterial lipopolysaccharide (LPS), which induced thermoregulatory (fever), behavioral (anorexia, reductions in nest building), and somatic (weight loss) sickness responses in all groups. Among pineal-intact hamsters, febrile and behavioral responses to LPS were attenuated in SD relative to LD. PINx did not affect sickness responses to LPS in LD hamsters, but abolished the ameliorating effects of SD on behavioral responses to LPS. Surprisingly, PINx failed to abolish the effect of SD on fever. In common with the reproductive system, PINx induces the LD phenotype in most aspects of the immune system. The pineal gland is required for photoperiodic regulation of circulating leukocytes and neural-immune interactions that mediate select aspects of sickness behaviors.     

CCK(2) receptor nullification attenuates lipopolysaccharide-induced sickness behavior

Systemic infection produces a highly regulated set of responses such as fever, anorexia, adipsia, inactivity, and cachexia, collectively referred to as sickness behavior. Although the expression of sickness behavior requires immune-brain communication, the mechanisms by which peripheral cytokines signal the brain are unclear. Several mechanisms have been proposed for neuroimmune communication, including the interaction of cytokines with peripheral nerves. A critical role has been ascribed to the vagus nerve in mediating sickness behavior after intraperitoneally delivered immune activation, and converging evidence suggests that this communication may involve neurochemical intermediaries afferent and/or efferent to this nerve. Mice lacking functional CCK(2/gastrin) receptors (CCK(2)KO) and wild-type (WT) controls were administered LPS (50, 500, or 2,500 microg/kg; serotype 0111:B4; ip). Results indicate a role for CCK(2) receptor activation in the initiation and maintenance of LPS-induced sickness behavior. Compared with WT controls, CCK(2)KO mice were significantly less affected by LPS on measures of body temperature, activity, body weight, and food intake, with the magnitude of effects increasing with increasing LPS dose. Although activation of CCK(2) receptors at the level of the vagus nerve cannot be excluded, a possible role for these receptors in nonvagal routes of immune-brain communication is suggested.     

Silicon Deprivation Does Not Significantly Modify the Acute White Blood Cell Response but Does Modify Tissue Mineral Distribution Response to an Endotoxin Challenge

An experiment with rats was conducted to determine whether silicon deprivation affects the acute-phase immune response to an endotoxin challenge. Weanling female rats were assigned to two weight-matched groups of 24; one group was fed a basal diet containing about 1.9 µg Si/kg; the other group was fed the basal diet supplemented with 35 µg Si/kg as arginine silicate inositol complex. After being fed their respective diets for 8 weeks, 12 rats in each group were injected subcutaneously with 1 mg lipopolysaccharide (LPS)/kg body weight; the other 12 rats in each group were injected with deionized water. Two hours after injection, the rats were anesthetized with ether for collection of blood (for plasma), liver and femurs, and then euthanized by decapitation. LPS injection decreased total white blood cell, lymphocyte, monocyte, eosinophil, and basophil counts by 80–90%, but did not affect neutrophil counts. LPS injection also increased plasma tumor necrosis factor-α and osteopontin and decreased plasma hyaluronic acid. Silicon deprivation did not significantly affect any of these responses to LPS. Silicon in liver and silicon, iron, and zinc in femur were increased by LPS injection only in silicon-deprived rats. Silicon deprivation also increased monocyte counts and osteopontin and decreased femur zinc in rats not injected with LPS. The findings indicate that silicon deprivation does not affect the acute-immune phase decrease in inflammatory cell numbers and increase in inflammatory cytokines in response to an endotoxin challenge. Silicon deprivation, however, apparently causes slight chronic inflammation and might influence inflammatory cell proliferation in the chronic-phase inflammatory response.     

Zinc Prevents Sickness Behavior Induced by Lipopolysaccharides after a Stress Challenge in Rats

Sickness behavior is considered part of the specific beneficial adaptive behavioral and neuroimmune changes that occur in individuals in response to infectious/inflammatory processes. However, in dangerous and stressful situations, sickness behavior should be momentarily abrogated to prioritize survival behaviors, such as fight or flight. Taking this assumption into account, we experimentally induced sickness behavior in rats using lipopolysaccharides (LPS), an endotoxin that mimics infection by gram-negative bacteria, and then exposed these rats to a restraint stress challenge. Zinc has been shown to play a regulatory role in the immune and nervous systems. Therefore, the objective of this study was to examine the effects of zinc treatment on the sickness response of stress-challenged rats. We evaluated 22-kHz ultrasonic vocalizations, open-field behavior, tumor necrosis factor α (TNF-α), corticosterone, and brain-derived neurotrophic factor (BDNF) plasma levels. LPS administration induced sickness behavior in rats compared to controls, i.e., decreases in the distance traveled, average velocity, rearing frequency, self-grooming, and number of vocalizations, as well as an increase in the plasma levels of TNF-α, compared with controls after a stressor challenge. LPS also decreased BDNF expression but did not influence anxiety parameters. Zinc treatment was able to prevent sickness behavior in LPS-exposed rats after the stress challenge, restoring exploratory/motor behaviors, communication, and TNF-α levels similar to those of the control group. Thus, zinc treatment appears to be beneficial for sick animals when they are facing risky/stressful situations.     

Peripubertal immune challenges attenuate reproductive development in male Siberian hamsters (Phodopus sungorus)

Differential allocation of energy to reproduction versus host defense is assumed to drive the seasonal antiphase relation between peak reproductive function and immunocompetence; however, evidence supporting this assumption is only correlational. These experiments tested whether photoperiod affects immune responses to antigens in peripubertal Siberian hamsters, whether such activation of the immune system exacts energetic and reproductive costs, and whether such costs vary seasonally. Male Siberian hamsters were raised from birth in long (LD) or short days (SD), which respectively initiate or inhibit the onset of puberty. To elicit a specific immune response, hamsters were injected with a novel antigen (keyhole limpet hemocyanin [KLH]) as juveniles. Reproductive development was attenuated and body temperature was elevated in LD hamsters relative to saline-injected control animals. In contrast, KLH treatments affected neither thermoregulation nor reproductive development in photoinhibited SD hamsters. In experiment 2, juvenile male hamsters were challenged with bacterial lipopolysaccharide (LPS) in order to elicit an innate immune response. Febrile and anorexic responses to LPS were greater in reproductively stimulated LD hamsters relative to reproductively inhibited SD hamsters. LPS treatments attenuated somatic and testicular development in LD hamsters, but did not significantly affect circulating testosterone concentrations. In contrast, LPS treatments were without effect on somatic and reproductive development in SD hamsters. These experiments indicate that photoperiod affects antigen-specific antibody production, febrile responses to LPS, and sickness behaviors in juvenile Siberian hamsters, and that peripubertal activation of the immune system exacts energetic and metabolic costs that can diminish the magnitude of somatic and reproductive maturation in LD. The data also underscore the importance of seasonally dependent life history factors in assessing physiological tradeoffs.     

Differential effect of chronic antidepressant treatments on lipopolysaccharide-induced depressive-like behavioural symptoms in the rat

In the present study we observed that lipopolysaccharide (LPS) administration provoked a characteristic reduction in body weight gain, food consumption, saccharin (but not water) consumption and nocturnal locomotor activity. It has been previously suggested that the ability of LPS to suppress the consumption of, and preference for, a palatable solution such as saccharin without altering water consumption, may represent an anhedonic response. The results of the present study demonstrate that chronic treatment with the tricyclic antidepressant (TCA) desipramine (7.5 mg/kg; i.p.) prevented LPS-induced anorexia, loss of body weight, the antidipsogenic effect and hypoactivity. In contrast, chronic treatment with the antidepressants paroxetine (7.5 mg/kg; i.p.) and venlafaxine (10 mg/kg; i.p.) failed to alter any of the LPS-induced behavioural responses. Furthermore, chronic treatment with desipramine (and to a lesser extent paroxetine) reduced the consumption of, and preference for, saccharin suggesting that these antidepressant treatments induce an "anhedonic" response in their own right. In conclusion, chronic desipramine treatment attenuated LPS-induced depressive-like behavioural symptoms in the rat. However, chronic treatment with paroxetine and venlafaxine did not significantly alter LPS-induced behavioural responses. The results of the present study support the hypothesis that TCA's may exert part of their anti-depressive efficacy through their effects on the immune system. However, this property does not appear to be shared by newer antidepressants which possess a better side effect profile than the TCA's. The suppressive effect of TCA's on proinflammatory cytokine secretion is discussed as a mechanism by which these agents alter LPS-induced behavioural responses.     

Lipopolysaccharide administration in the dominant mouse destabilizes social hierarchy

Sickness behavior is a set of behavioral changes that are part of an adaptive strategy to overcome infection. Mice that interact with conspecifics displaying sickness behavior also show relevant behavioral changes. In this work we sought to determine the role of sickness behavior display by a dominant mouse as a promoter of hierarchy instability. We treated the dominant mouse within a dyad with lipopolysaccharide (LPS) (400 μg/kg, i.p.) for three consecutive days and assessed social dominance behavior. Since elder animals display increased inflammatory responses and the behaviors toward conspecifics are influenced by kinship we also assessed whether kinship and age, might influence sickness related hierarchy instability. Our results show that administration of LPS in the dominant mouse promotes social instability within a dyad, and indicates that this instability could be influenced by kinship and age.     

Lipopolysaccharide injection induces rapid decrease of hypothalamic GnRH mRNA and peptide, but does not affect GnIH in zebra finches

Lipopolysaccharide (LPS) is frequently used experimentally to mimic acute infection. Through activation of the host's immune response, an LPS injection has profound effects on the adrenocortical response to stress and on behaviors including reduction in activity, water and food intake, and libido. These behavioral changes occurring during infection are collectively called "sickness behavior." It is thought that adoption of sickness behavior reallocates energy from other fitness-enhancing activities, such as reproduction, for use in the immune response. Although the behavioral effects of LPS treatment are well-known, less information is available regarding the effects of LPS on the brain in terms of controlling reproductive behavior, specifically concerning a newly discovered neuropeptide, gonadotropin-inhibitory hormone (GnIH). This study investigated the effects of an LPS injection on the behavior and the hypothalamic neuropeptides controlling reproduction [GnIH and gonadotropin-releasing hormone (GnRH)] of zebra finches (Taeniopygia guttata). Overall, there was a decrease in activity in birds injected with LPS. The number of GnRH-immunoreactive neurons was significantly reduced in birds injected with LPS when compared to controls, while the number of GnIH-releasing neurons remained unchanged. At the level of gene expression, a similar pattern was found: there was reduced expression of GnRH mRNA in LPS-injected animals, whereas GnIH expression remained unchanged. Plasma testosterone did not change significantly in LPS-injected animals, nor did plasma corticosterone. Taken together, these results indicate a rapid (within 3h) inhibition of the reproductive axis during an immune challenge mimicking an infection, specifically acting on the GnRH system. The present study expands our knowledge on the interaction between the immune system and the reproductive system.     

Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-kappaB activation

Host defence against infection requires a range of innate and adaptive immune responses that may lead to tissue damage. Such immune-mediated pathologies can be controlled with appropriate T regulatory (Treg) activity. The aim of the present study was to determine the influence of gut microbiota composition on Treg cellular activity and NF-kappaB activation associated with infection. Mice consumed the commensal microbe Bifidobacterium infantis 35624 followed by infection with Salmonella typhimurium or injection with LPS. In vivo NF-kappaB activation was quantified using biophotonic imaging. CD4+CD25+Foxp3+ T cell phenotypes and cytokine levels were assessed using flow cytometry while CD4+ T cells were isolated using magnetic beads for adoptive transfer to na?ve animals. In vivo imaging revealed profound inhibition of infection and LPS induced NF-kappaB activity that preceded a reduction in S. typhimurium numbers and murine sickness behaviour scores in B. infantis-fed mice. In addition, pro-inflammatory cytokine secretion, T cell proliferation, and dendritic cell co-stimulatory molecule expression were significantly reduced. In contrast, CD4+CD25+Foxp3+ T cell numbers were significantly increased in the mucosa and spleen of mice fed B. infantis. Adoptive transfer of CD4+CD25+ T cells transferred the NF-kappaB inhibitory activity. Consumption of a single commensal micro-organism drives the generation and function of Treg cells which control excessive NF-kappaB activation in vivo. These cellular interactions provide the basis for a more complete understanding of the commensal-host-pathogen trilogue that contribute to host homeostatic mechanisms underpinning protection against aberrant activation of the innate immune system in response to a translocating pathogen or systemic LPS.     

Postnatal programming of the innate immune response

A host's defensive response to a pathogen is a phylogenetically ancient reaction that consists of a CNS-mediated series of autonomic, hormonal and behavioral responses that combine to combat infection. The absence of such defense results in greater morbidity and mortality and thus, these responses are essential for survival. The postnatal period represents a malleable phase in which the long-term behavior and physiology of the developing organism, including its immune responses, can be influenced. Postnatal challenge of the immune system by introduction of live replicating infections, or administration of bacterial and viral mimetics, can result in a multidomain alteration to the defenses of the adult host. Findings from our laboratory and others' indicate that the postnatal administration of lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (PolyI:C), which mimic bacterial and viral infections respectively, can influence the neuroimmune response (generation of fever and production of cytokines) to a second challenge to the immune system in adulthood. This long-lasting alteration in the innate immune response is associated with myriad other effects on the animal's physiology and appears to be primarily mediated by a sensitized hypothalamic-pituitary-adrenal axis. Thus, a transient immunological perturbation to a developing animal may program the organism for subsequent health complications as an adult. In this review we discuss some of the potential mechanisms for these phenomena.     

Fungal Chitin Dampens Inflammation through IL-10 Induction Mediated by NOD2 and TLR9 Activation

Chitin is an essential structural polysaccharide of fungal pathogens and parasites, but its role in human immune responses remains largely unknown. It is the second most abundant polysaccharide in nature after cellulose and its derivatives today are widely used for medical and industrial purposes. We analysed the immunological properties of purified chitin particles derived from the opportunistic human fungal pathogen Candida albicans, which led to the selective secretion of the anti-inflammatory cytokine IL-10. We identified NOD2, TLR9 and the mannose receptor as essential fungal chitin-recognition receptors for the induction of this response. Chitin reduced LPS-induced inflammation in vivo and may therefore contribute to the resolution of the immune response once the pathogen has been defeated. Fungal chitin also induced eosinophilia in vivo, underpinning its ability to induce asthma. Polymorphisms in the identified chitin receptors, NOD2 and TLR9, predispose individuals to inflammatory conditions and dysregulated expression of chitinases and chitinase-like binding proteins, whose activity is essential to generate IL-10-inducing fungal chitin particles in vitro, have also been linked to inflammatory conditions and asthma. Chitin recognition is therefore critical for immune homeostasis and is likely to have a significant role in infectious and allergic disease.

Authors Summary

Chitin is the second most abundant polysaccharide in nature after cellulose and an essential component of the cell wall of all fungal pathogens. The discovery of human chitinases and chitinase-like binding proteins indicates that fungal chitin is recognised by cells of the human immune system, shaping the immune response towards the invading pathogen. We show that three immune cell receptors– the mannose receptor, NOD2 and TLR9 recognise chitin and act together to mediate an anti-inflammatory response via secretion of the cytokine IL-10. This mechanism may prevent inflammation-based damage during fungal infection and restore immune balance after an infection has been cleared. By increasing the chitin content in the cell wall pathogenic fungi may influence the immune system in their favour, by down-regulating protective inflammatory immune responses. Furthermore, gene mutations and dysregulated enzyme activity in the described chitin recognition pathway are implicated in inflammatory conditions such as Crohn''s Disease and asthma, highlighting the importance of the discovered mechanism in human health.     

Body‐mass‐dependent trade‐off between immune response and uropygial gland size in house sparrows Passer domesticus

Parasites greatly impact host fitness. The immune system is fundamental to combat endoparasites, and survival increases with greater investment in immunity. Some ectoparasites, by contrast, are reportedly combated by the use of the uropygial gland, an organ exclusive to birds, which secretes an oily substance (preen oil) that is spread on plumage. However, both mounting an immune response against a parasite and producing uropygial gland secretion depend on the same resources, a situation which may induce trade‐offs between the two antiparasitic functions. In this study, I experimentally test whether immune response is traded off against uropygial gland size in the house sparrow Passer domesticus. In the experiment, a group of sparrows were injected with an antigen (lipopolysaccharide, LPS), which stimulates the immune system, while the other group received a sham injection. The uropygial gland of LPS‐treated birds decreased significantly more than that of the control birds after treatment. Nevertheless, the effect of the treatment was limited to house sparrows with low body mass, suggesting that heavy house sparrows were able to produce an immune response while maintaining a relatively large uropygial gland. Given that uropygial gland size is strongly related to production of preen oil, these results suggest that preen oil production declines in birds in poor body condition when resources are preferentially diverted to other demanding functions, such as the immune system. Considering that the uropygial gland is involved in several fitness‐related processes in birds, the trade‐off between immune response and uropygial gland size may have important consequences for bird life histories.     

Photoperiodic adjustments in immune function protect Siberian hamsters from lethal endotoxemia

Seasonal changes in day length enhance or suppress components of immune function in individuals of several mammalian species. Siberian hamsters (Phodopus sungorus) exhibit multiple changes in neuroendocrine, reproductive, and immune function after exposure to short days. The manner in which these changes are integrated into the host response to pathogens is not well understood. The present experiments tested the hypothesis that short-day changes in immune function alter the pathogenesis of septic shock and survival after challenge with endotoxin. Male and female Siberian hamsters raised in long-day photoperiods were transferred as adults to short days or remained in their natal photoperiod. Six to 8 weeks later, hamsters were injected i.p. with 0, 1, 2.5, 10, 25, or 50 mg/kg bacterial lipopolysaccharide (LPS) (the biologically active constituent of endotoxin), and survival was monitored for 96 h. Short days significantly improved survival of male hamsters treated with 10 or 25 mg/kg LPS and improved survival in females treated with 50 mg/kg LPS. Transfer from long to short days shifted the LD50 in males by approximately 90%, from 5.3 to 9.9 mg/kg, and in females from 11.1 to 15.0 mg/kg (+35%). Long-day females were more resistant than were males to lethal endotoxemia. In vitro production of the proinflammatory cytokine TNFalpha in response to LPS stimulation was significantly lower in macrophages extracted from short-day relative to long-day hamsters, as were circulating concentrations of TNFalpha in vivo after i.p. administration of LPS, suggesting that diminished cytokine responses to LPS in short days may mitigate the lethality of endotoxemia. Adaptation to short days induces changes in immune parameters that affect survival in the face of immune challenges.     

Characterization of calves exhibiting a novel inheritable TNF-alpha hyperresponsiveness to endotoxin: associations with increased pathophysiological complications.

A subpopulation of calves, herein termed "hyperresponders" (HPR), was identified and defined by the patterns of plasma TNF-alpha concentrations that developed following two challenges with endotoxin (LPS, 0.8 mug Escherichia coli 055:B5 LPS/kg(0.75) live body wt) separated by 5 days. The principle characteristic of HPR calves was a failure to develop tolerance to repeated LPS challenge that was evident in the magnitude of the TNF-alpha concentrations and prolonged severity of pathological sequellae. Whereas calves failing to develop LPS tolerance were identified on the basis of their excessive in vivo plasma TNF-alpha concentration responses, in vitro TNF-alpha responses of peripheral blood mononuclear cells isolated from each calf and challenged with LPS or PMA did not correlate or predict the magnitude of in vivo plasma TNF response of the calf. Intentional breeding to obtain calves from bulls and/or cows documented as HPR resulted in offspring displaying the HPR character when similar progeny calves were tested with LPS in vivo, with extensive controls in place to account for sources of variability in the general TNF-alpha response to LPS that might compromise interpretation of the data. Feed intake, clinical serology and hematology profiles, and acute-phase protein responses of HPR calves following LPS were significantly different from those of calves displaying tolerance. These results suggest that the pattern of plasma TNF-alpha changes that evolve from a low-level double LPS challenge effectively reveal the presence of a genetic potential for animals to display excessive or prolonged pathological response to LPS-related stress and compromised prognosis for recovery.