Neuroimmunomodulation in poultry

Neuroimmunomodulation is the scientific study of the two-way relations among the central nervous system (CNS), endocrine system and the immune system. It is a multidisciplinary field that integrates knowledge in the form of networks in which neurons and immune cells interact, modulating the responses of animals and humans (Ader, Reference ADER2000; Costa-Pinto and Palermo-Neto, Reference COSTA-PINTO and PALERMO-NETO2010; Karrow, Reference KARROW2006). The CNS, endocrine system and the immune system share a common set of ligands and receptors, i.e. neurotransmitters, neuropeptides, growth factors, neuroendocrine hormones and cytokines, that connect these three systems (Marsh and Scanes, Reference MARSH and SCANES1994; Kaiser et al., Reference KAISER, WU, ROTHWELL, FIFE, GIBSON, POH, SHINI, BRYDEN and SHINI2009).

In general, the concepts of neuroendocrine-immune interactions observed in mammals can be applied to birds. The action of the CNS on the immune system has been linked mainly to the activities of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (Ziegler and Herman, Reference ZIEGLER and HERMAN2002). The activation of the HPA axis releases corticosterone, the key hormone in stress situations, and the sympathetic nervous system releases catecholamines epinephrine and norepinephrine. Corticosterone was reported to modulate some performance indexes and immunological parameters of chickens (Kaiser et al., Reference KAISER, WU, ROTHWELL, FIFE, GIBSON, POH, SHINI, BRYDEN and SHINI2009). It is known that catecholamines alter cytokine production, decreasing inflammatory responses (interleukin [IL]-12, tumour necrosis factor α, interferon γ) and increasing anti-inflammatory responses (IL-10 and transforming growth factor β) (Johnson et al., Reference JOHNSON, CAMPISI, SHARKEY, KENNEDY, NICKERSON, GREENWOOD and FLESHNER2005; Licinio and Frost, Reference LICINIO and FROST2000).

In the other hand, other systems are involved in neuroimmune connections, for example the parasympatic nervous system, hypothalamic-pituitary-gonadal axis and hypothalamic-pituitary-thyroid axis (Glick, Reference GLICK1984; Bédécarrats et al., Reference BÉDÉCARRATS, BAXTER and SPARLING2016). The parasympatic nervous system is important for the transmission of visceral afferent stimuli, in particular those coming from the intestines, with possible activation via the negative feedback of the HPA axis (Calefi et al., Reference CALEFI, FONSECA, COHN, HONDA, COSTOLA-DE-SOUZA, TSUGIYAMA, QUINTEIRO-FILHO, FERREIRA and PALERMO-NETO2016a; Nance and Sanders, Reference NANCE and SANDERS2007). Moreover, the hormones thyroxine, triiodothyronine, thyrotropin-releasing hormone and thyroid-stimulating hormone stimulate the cells of the immune system in chickens (Mashaly et al., Reference MASHALY, TROUT, HENDRICKS III, AL-DOKHI and GEHAD1998); and IL-1 proinflammatory cytokines suppress the release of the thyroid-stimulating hormone, while IL-2 stimulates the activation of the HPA axis (Chandratilleke et al., Reference CHANDRATILLEKE, HÀLA and MARSH1996). Furthermore, bird reproduction is controlled by the hypothalamic-pituitary-gonadal axis and is directly influenced by the environment, for example lighting cycle (Bédécarrats et al., Reference BÉDÉCARRATS, BAXTER and SPARLING2016). Indeed, changes in the cycle and intensity of light could modulate the immune system and performance of chickens (Ryu et al., Reference RYU, PARK, BANG, KANG and HWANGBO2016). The pineal gland and the melatonin release are involved in this process, regulating the hypothalamic-pituitary-gonadal and HPA axis (Markowska et al., Reference MARKOWSKA, MAJEWSKI and SKWARŁO-SOŃTA2017).

Neuroimmune interactions in health and disease are unequivocal. Most of our knowledge of neuroendocrine-immune responses are based on mammals; however, over the last decade the neuroimmune studies in birds has been increasing (Kaiser et al., Reference KAISER, WU, ROTHWELL, FIFE, GIBSON, POH, SHINI, BRYDEN and SHINI2009; Shini et al., Reference SHINI, HUFF, SHINI and KAISER2010; Shini and Kaiser, Reference SHINI and KAISER2009).

Until recently, most studies have focused only on aspects of neurology and immunology in birds, including the use of isolated approaches or free neuroimmune interpretations, similar to studies in humans. One of the first studies to examine the issue of neuroimmunomodulation in birds was reported by Marsh and Scanes (Reference MARSH and SCANES1994). In this review, the authors emphasised the discussion of existing neuroendocrine relations between thyroid hormones, growth hormones and hormone mediators, as well as between gonadal steroids and adrenocortical steroids with the immune system. A related mechanism linked with aging was presented by Ottinger (2007). However, one of the pioneering works involving the study of neuroimmune relations in birds was the study by Glick in 1984.

Similar to what occurs in mammals, thyroid hormones, growth hormones, corticosteroids, prolactin, gonadal steroids and their mediators, among others, modulate the immune system of birds (Deviche and Cortez, Reference DEVICHE and CORTEZ2005; Duffy et al., Reference DUFFY, BENTLEY, DRAZEN and BALL2000; Haddad and Mashaly, Reference HADDAD and MASHALY1991; Skwarlo-Sonta, Reference SKWARLO-SONTA1992; Trout and Mashaly, Reference TROUT and MASHALY1995; Kang et al., Reference KANG, BÉDÉCARRATS and ZADWORNY2007). Under stressful conditions, birds release corticosterone by a mechanism similar to that described in mammals, with some populations of lymphocytes being retained in the spleen, which produces the so-called stress leukogram (Mashaly et al., Reference MASHALY, TROUT, HENDRICKS III, AL-DOKHI and GEHAD1998; Reference MASHALY, TROUT and HENDRICKS III1993).

Hendricks et al. (1991; 1998) showed that stimulation of ex vivo spleen lymphocytes through the release of adrenocorticotropic hormone (ACTH) resulted in corticotropin-releasing hormone (CRH) production by these cells. These studies showed that the culture supernatant was capable of stimulating in vitro adrenal cells to release ACTH. Identical results were obtained by stimulating macrophages in birds using CRH (Hendricks and Mashaly, Reference HENDRICKS and MASHALY1998).

The nervous and immune systems of birds are directly related; in fact, a classic study showed that a lesion produced in the hypothalamus of young birds compromised immune parameters, such as the production of T and B lymphocytes (Glick, Reference GLICK1984). A poultry bursectomy generated an increase in the weight of the adrenal glands and testes (Glick, Reference GLICK1984). Furthermore, it was shown that the thymus and bursa of Fabricius were influenced by corticosteroids, with thymic growth also being associated with thyroid hormones. Taken together, these results show the existence of a complex neuroendocrine-immune relationship in birds (Glick, Reference GLICK1984).

It was observed that the use of corticosteroids causes changes in the immune system in birds. Thus, treatment with dexamethasone altered the activity of peripheral NK cells in ducks, which was possibly associated with the modulation of eicosanoid production by monocytes (Fowles et al., Reference FOWLES, FAIRBROTHER, FIX, SCHILLER and KERKVLIET1993). A decrease in humoral immunity has been associated with the application of dexamethasone in birds (Fowles et al., Reference FOWLES, FAIRBROTHER, FIX, SCHILLER and KERKVLIET1993). Furthermore, it was shown that dexamethasone modulates populations of CD4+CD25+ lymphocytes and macrophages when a bird is challenged by Eimeria spp. (Calefi et al., Reference CALEFI, QUINTEIRO-FILHO, FUKUSHIMA, CRUZ, SIQUEIRA, SALVAGNI, NAMAZU, MASSOCO, PIANTINO-FERREIRA and PALERMO NETO2016b).

Corticosterone in doses that mimicked stressful situations modulated the performance, immune system and cellular structure of chickens. Specifically, Shini and Kaiser (Reference SHINI and KAISER2009) observed that cortiscoterone in drinking water alter the ultrastructure of heterophils and lymphocytes, i.e. heterophil size, shape, and granulation, and lymphocyte cytoplasmic characteristics. The same laboratory has showed a reduction of egg production, body weight gain and relative weight of the spleen and bursa in chickens treated with corticosterone (Shini et al., Reference SHINI, KAISER, SHINI and BRYDEN2008; Reference SHINI, SHINI and HUFF2009). In addition, the acute treatment with corticosterone upregulated mRNA expression levels of proinflammatory interleukins (such as IL-1β, IL-6, IL-18) and the proinflammatory chemokines of chicken`s lymphocytes and heterophils (Shini et al., Reference SHINI, HUFF, SHINI and KAISER2010; Reference SHINI, SHINI and HUFF2009; Shini and Kaiser, Reference SHINI and KAISER2009). However, a chronic treatment (one week exposure) with corticosterone downregulated several proinflammatory cytokines and chemokines in the same cells, suggesting that the delayed effects of chronic stress could suppress the immune response (Shini et al., Reference SHINI, HUFF, SHINI and KAISER2010; Reference SHINI, SHINI and HUFF2009; Shini and Kaiser, Reference SHINI and KAISER2009). Indeed, injection of corticosterone decreases antibody production against sheep red blood cells and impaired bronchitis vaccine response in chickens (Post et al., Reference POST, REBEL and TER HUURNE2003).

Exogenous administration of hormones from other species in birds has demonstrated the conservation of some neuroimmune mechanisms at the phylogenetic scale. Thus, the application of human growth hormone in chickens with dwarfism increased the size of the bursa of Fabricius and humoral tissues. It was shown that the application of human thyroid hormones increased the weight of the thymus of birds (Marsh et al., Reference MARSH, LAUTERIO and SCANES1984). Other studies have shown that providing human thyroid hormones in the diet increased the weight of the bursa and spleen and the number of splenic leucocytes and receptors for IL-2 on splenocytes (Chandratilleke et al., Reference CHANDRATILLEKE, HÀLA and MARSH1996; Haddad and Mashaly, Reference HADDAD and MASHALY1990).

The bursa of Fabricius plays an important role in the immune system of birds, mainly in the maturation of B lymphocytes. In recent years, its interaction with the neuroendocrine system has been the subject of much study (Glick, Reference GLICK1991; Pintea et al., Reference PINTEA, CONSTANTINESCU and RADU1967; Zentel et al., Reference ZENTEL, NOHR, ALBRECHT, JEURISSEN, VAINIO and WEIHE1991; Zentel and Weihe, Reference ZENTEL and WEIHE1991). Bursectomy of birds at one day of life decreases the in vitro responses of adrenal ACTH. Another effect associated with bursectomy was a decrease in testosterone production by Leydig cells (El-Far et al., Reference EL-FAR, MASHALY and KAMAR1994; Haddad and Mashaly, Reference HADDAD and MASHALY1990).

Gehad et al. (Reference GEHAD, LILLEHOJ, HENDRICKS III and MASHALY2002) showed that the application of lipopolysaccharide in sexually immature male birds resulted in an increase in corticosterone levels and a decrease of circulating triiodothyronine. However, this finding was not observed when a T-dependent antigen (bovine serum albumin) was previously applied; that is, it was shown that the effects were directly linked to humoral response. As revised by Karrow (Reference KARROW2006), the inflammatory process can also modulate the HPA and the autonomic nervous system, influencing the immune response against different antigens. The lipopolysaccharide-induced inflammation may stimulate the HPA axis direct or indirectly, binding in circumventricular organs in the CNS or stimulation the release of cytokines and other inflammatory mediators.

Since the first analysis of the innervation of lymphoid organs, the notion of a close relationship between the nervous system and immune system of birds have been reinforced (Cordier, Reference CORDIER1969; Pintea et al., Reference PINTEA, CONSTANTINESCU and RADU1967). The bursa of Fabricius has peptidergic innervation; peptides related to the calcitonin gene and tachykinin neuropeptide Y were found in close proximity to vessels that maintained the bursa. This demonstrated the presence of sympathetic innervation of the arteries located near the follicles (Zentel et al., Reference ZENTEL, NOHR, ALBRECHT, JEURISSEN, VAINIO and WEIHE1991). Ciriaco et al. (Reference CIRIACO, RICCI, BRONZETTI, MAMMOLA, GERMANA and VEGA1995), using immunohistochemical techniques, identified noradrenergic fibres that were reactive to acetylcholinesterase in the perivascular region of the bursa neurons. Although these authors have not reported the presence of autonomic nerve fibres in the medulla of the follicles, the bursa showed the presence of such dendritic cells and other cells responsive to the acetylcholinesterase follicular region (Ciriaco et al., Reference CIRIACO, RICCI, BRONZETTI, MAMMOLA, GERMANA and VEGA1995). Thus, the autonomic nervous system was shown to be involved in the functions of the bursa of Fabricius.

The development and involution of the thymus and bursa are related to the production of peptides derived from pro-opielomelocortin, a precursor protein of pituitary ACTH and β-endorphin (Franchini and Ottaviani, Reference FRANCHINI and OTTAVIANI1999). These peptides and cytokines can be identified in the thymus of birds from the 4th day of life. The concentrations of these substances increase with advancing age of the bird, and this is related to changes in populations of endothelial cells and the interdigitating thymus. The same process occurs with the follicle cells of the bursa. In this case, the process of involution becomes more apparent from the second month of life, with the substitution of the constituent bursa cells by fibrous tissue (Franchini and Ottaviani, Reference FRANCHINI and OTTAVIANI1999; Hendricks and Mashaly, Reference HENDRICKS and MASHALY1998).

The avian denervation in ovo employing 6-hydroxydopamine, a neurotoxin that destroys noradrenergic terminals, was able to enhance the primary immune response in poultry against challenges with sheep red blood cells. The application of in ovo 6-hydroxydopamine also decreased cytokine expression in an in vitro splenic lymphocyte proliferation assay as well as decreasing the responsiveness of splenic CD8+ lymphocytes to norepinephrine injection in birds (Motobu et al., Reference MOTOBU, EL-ABASY, NA, VAINIO, TOIVANEN and HIROTA2003). It was shown that the norepinephrine levels were increased in pre-immunised chicks with sheep red blood cells in ovo (Brown-Borg and Edens, Reference BROWN-BORG and EDENS1992). This evidence confirmed that sympathetic innervation of lymphoid organs is able to modulate the activity of the immune system in birds.

In vitro migration of circulating white blood cells and the production of antibodies showed that monoamines (dopamine, serotonin and norepinephrine) stimulate the production of immunoglobulins and the migration of immune cells (Denno et al., Reference DENNO, MCCORKLE and TAYLOR1994; Lukas et al., Reference LUKAS, MCCORKLE and TAYLOR1987; McCorkle et al., Reference MCCORKLE, TAYLOR, DENNO and JABE1990; McCorkle and Taylor, Reference MCCORKLE and TAYLOR1994; Motobu et al., Reference MOTOBU, EL-ABASY, NA, VAINIO, TOIVANEN and HIROTA2003).

In this context, it is clear that intensive farming systems of both broilers and laying hens generates stressful stimuli, and this can account for the occurrence of various endocrine deregulations in animals and, in consequence, a sharp decrease in production rates (Heckert et al., Reference HECKERT, ESTEVEZ, RUSSEK-COHEN and PETTIT-RILEY2002; Mashaly et al., Reference MASHALY, HENDRICKS III, KALAMA, GEHAD, ABBAS and PATTERSON2004).

Neuroimmunomodulation and heat stress

Both an increase and decrease of ambient temperatures, outside the optimal comfort level, may be considered stressors for production animals. High ambient temperature stressor could be related in pre-hatching (incubation) and post-hatching situations (Piestun et al., Reference PIESTUN, DRUYAN, BRAKE and YAHAV2013; Yahav and Brake, Reference YAHAV and BRAKE2014).

Heat stress increases the release of steroids in the stools of the animals and the increase in temperature is directly related to the mortality rate (Trout and Mashaly, Reference TROUT and MASHALY1994). Indeed, it has been observed that this stressor reduces productive parameters such as feed conversion, weight gain, the number and quality of eggs and carcass quality. These findings have been shown to have a direct impact relative to the magnitude of the increase in ambient temperature above the limits of thermal comfort (Mashaly et al., Reference MASHALY, HENDRICKS III, KALAMA, GEHAD, ABBAS and PATTERSON2004; Quinteiro-Filho et al., Reference QUINTEIRO-FILHO, RODRIGUES, RIBEIRO, FERRAZ-DE-PAULA, PINHEIRO, SA, FERREIRA and PALERMO-NETO2012b; Rozenboim et al., Reference ROZENBOIM, TAKO, GAL-GARBER, PROUDMAN and UNI2007; Soleimani et al., Reference SOLEIMANI, ZULKIFLI, OMAR and RAHA2011). According to some authors, in current breeding broiler systems, the ambient temperature variations are more important for productive gain of birds when the density in which animals live (Dawkins et al., Reference DAWKINS, CHRISTL and TRACEY2004) is maintained. Still, overpopulation is a stressor that has significant effects on homeostasis and particularly on immunity in birds (Gomes et al., Reference GOMES, QUINTEIRO-FILHO, RIBEIRO, FERRAZ-DE-PAULA, PINHEIRO, BASKEVILLE, AKAMINE, ASTOLFI-FERREIRA, FERREIRA and PALERMO-NETO2014).

Relative humidity is another important factor impacting the thermal variations, since the higher the relative humidity is, the lower the evaporative heat loss by the birds (Menezes et al., Reference MENEZES, NÄÄS and BARACHO2010). On the other hand, when combining low relative humidity and high-temperature environments, the animals tend to dehydrate very quickly. It is unquestionable that the association of relative humidity to the ambient temperature changes the thermal sensation of animals (Moura et al., Reference MOURA, VERCELLINO, SANTOS and VALE2015). Younger birds and females show the greatest discomfort to stressful conditions imposed by variations in the apparent temperature and environmental humidity (Moura et al., Reference MOURA, VERCELLINO, SANTOS and VALE2015).

With decreasing evaporative losses, more non-evaporative mechanisms are required to control the temperature of the birds, such as breathing, increased peripheral blood flow and heat loss by conduction wattles, the crest, footpad and breast contact with the floor. The compensatory hyperventilation triggers biochemical changes that may be reflected in other systems. Thus, increased circulating concentrations of CO2 and blood alkalosis side effects are induced by hyperventilation (Gleeson and Brackenbury, Reference GLEESON and BRACKENBURY1984).

The maintenance of homeothermy is regulated through a sophisticated central integration mechanism in the hypothalamus (Baarendse et al., Reference BAARENDSE, DEBONNE, DECUYPERE, KEMP and VAN DEN BRAND2007). The preoptic area of the anterior hypothalamus is the centre of body temperature control and is regulated by afferent information related to temperature (Seebacher, Reference SEEBACHER2009). The integrated information of temperature receptors present in the nerve pathways, and even in the hypothalamus, determine the compensatory temperature control mechanisms (Baarendse et al., Reference BAARENDSE, DEBONNE, DECUYPERE, KEMP and VAN DEN BRAND2007). It is known that the central temperature receptors are up to ten times more sensitive than the peripheral temperature variations, although the peripheral receivers inform the hypothalamus of environmental and all visceral organs/systems thermal fluctuations (Baarendse et al., Reference BAARENDSE, DEBONNE, DECUYPERE, KEMP and VAN DEN BRAND2007; Seebacher, Reference SEEBACHER2009). When the behavioural response does not meet the requirements imposed by the rise in temperature, physiological mechanisms are activated to compensate for the thermal imbalance (Baarendse et al., Reference BAARENDSE, DEBONNE, DECUYPERE, KEMP and VAN DEN BRAND2007; Etches et al., Reference ETCHES, JOHN and GIBBINS2008). In general, the response to a thermal stimulus is proportional to the number of receptors activated and the stimulated CNS area, i.e., the number and location of these receptors (Seebacher, Reference SEEBACHER2009). As already mentioned, the activation of central temperature receptors surpasses the stimuli from the periphery. This initiates all compensatory mechanisms, regardless of the stimulation of peripheral receptors (Bicego et al., Reference BICEGO, BARROS and BRANCO2007).

Although heat stress reduces food intake to lower the heat increment, the animal's gut increases its absorptive capacity of glucose in the intestinal lumen (Garriga et al., Reference GARRIGA, HUNTER, AMAT, PLANAS, MITCHELL and MORETO2006). It has been shown that heat stress, especially a hyperthermic state, changes the intestinal permeability (Dokladny et al., Reference DOKLADNY, POPE and THOMAS2006), facilitating the transport of bacterial toxins into the body and promoting an electrolyte imbalance (Lambert et al., Reference LAMBERT, GISOLFI, BERG, MOSELEY, OBERLEY and KREGEL2002).

The metabolic balance can be set by mechanisms of the HPA axis. The CRH peptides related to CRH and CRH receptors have been included in the list of mechanisms that modulate energy metabolism (Gillies et al., Reference GILLIES, LINTON and LOWRY1982). It has been shown that nerve pathways that contain these peptides directly influence the heat balance and are also deregulated in heat stress (Chen et al., Reference CHEN, CHRISTINE, DANIEL and CHIEN2012; Hillhouse and Grammatopoulos, Reference HILLHOUSE and GRAMMATOPOULOS2006; Richard et al., Reference RICHARD, QIN and TIMOFEEVA2002). Reports have indicated that hyperthermia produces cellular oxidative damage, a fact that exacerbates the effects of heat stress and increases the chances of infection or injury by microorganisms (Oliver et al., Reference OLIVER, PHILLIPS, NOVOSAD, BAKOS, TALBERT and CLANTON2012).

Star et al. (Reference STAR, NIEUWLAND, KEMP and PARMENTIER2007) showed that a heat stressor (32ºC for 23 days), when applied to layers of pure strains, produces a stimulating effect on the specific immune response. Indeed, Varasteh et al. (Reference VARASTEH, BRABER, AKBARI, GARSSEN and FINK-GREMMELS2015) observed that six days exposure to heat stress increased the RNA expression of IL-6, IL-8, toll-like receptor 4 and different tight junction markers in jejunum and ileum of broiler chickens.

Honda et al. (Reference HONDA, CALEFI, COSTOLA-DE-SOUZA, QUINTEIRO-FILHO, DA SILVA FONSECA, DE PAULA and PALERMO-NETO2015) demonstrated a reduction of B lymphocytes in the circulation after the application of heat stress and Newcastle vaccination. Calefi et al. (Reference CALEFI, HONDA, COSTOLA-DE-SOUZA, DE SIQUEIRA, NAMAZU, QUINTEIRO-FILHO, FONSECA, ALOIA and PALERMO-NETO2014) found that heat stress in the long term reduced intestinal injury produced by infection with C. perfringens. In turn, Calefi et al. (Reference CALEFI, SIQUEIRA, NAMAZU, COSTOLA-DE-SOUZA, HONDA, FERREIRA, QUINTEIRO-FILHO, DA SILVA FONSECA and PALERMO-NETO2016c) confirmed the existence of heterophilic reducing inflammation and intestinal injury in animals stressed by heat in a model of avian necrotic enteritis. These authors characterised the means of fluid thioglycolate and/or infection by C. perfringens, which is able to modulate the brain-gut axis of broilers.

Tsiouris et al. (Reference TSIOURIS, GEORGOPOULOU, BATZIOS, PAPPAIOANNOU, DUCATELLE and FORTOMARIS2015a; Reference TSIOURIS, GEORGOPOULOU, BATZIOS, PAPPAIOANNOU, DUCATELLE and FORTOMARIS2015b), in an experimental model of avian necrotic enteritis, found that employing co-infection by C. perfringens and Eimeria spp., cold stress and high density predisposed the development of the disease. In fact, the number of colony-forming units increased in the caecum of these stressed animals. Additionally, these authors observed the occurrence of biochemical changes in the intestinal environment of the birds when they were stressed by cold or were maintained in overpopulated conditions. Similarly, Gomes et al. (Reference GOMES, QUINTEIRO-FILHO, RIBEIRO, FERRAZ-DE-PAULA, PINHEIRO, BASKEVILLE, AKAMINE, ASTOLFI-FERREIRA, FERREIRA and PALERMO-NETO2014) found a high population density decreased phagocytic capacity of macrophages and increased infection by Salmonella spp. in broiler chickens. They showed that heat stress decreased macrophage activity and increased the severity of a Salmonella enteritidis infection in broilers (Quinteiro-Filho et al., Reference QUINTEIRO-FILHO, RIBEIRO, FERRAZ-DE-PAULA, PINHEIRO, SAKAI, SA, FERREIRA and PALERMO-NETO2010; Reference QUINTEIRO-FILHO, GOMES, PINHEIRO, RIBEIRO, FERRAZ-DE-PAULA, ASTOLFI-FERREIRA, FERREIRA and PALERMO-NETO2012a). In addition, it was observed that there was a greater migration of these bacteria to lymphoid organs of stressed animals, a decrease of cytokine and avian defensins RNA expression, and decrease of plasmatic immunoglobulin A and interferon γ levels (Quinteiro-Filho et al., Reference QUINTEIRO-FILHO, CALEFI, CRUZ, ALOIA, ZAGER, ASTOLFI-FERREIRA, FERREIRA and PALERMO-NETO2017). Furthermore, heat stress induced the breakdown of intestinal barriers, leading to an impairment of the intestinal mucosal barrier and increasing chicken susceptibility to the invasion of different organs by Salmonella enteritidis (Quinteiro-Filho et al., Reference QUINTEIRO-FILHO, GOMES, PINHEIRO, RIBEIRO, FERRAZ-DE-PAULA, ASTOLFI-FERREIRA, FERREIRA and PALERMO-NETO2012a; Reference QUINTEIRO-FILHO, CALEFI, CRUZ, ALOIA, ZAGER, ASTOLFI-FERREIRA, FERREIRA and PALERMO-NETO2017).

According to Banfield et al. (Reference BANFIELD, TEN DOESCHATE and FORBES1998), chronic heat stress in broilers reduces the elimination of oocysts Eimeira spp. This suggested that the heat stress applied intermittently or continuously produces a response similar to chronic stress. Variations in infections were related to a standard cytokine imbalance; i.e., Th1/Th2 ratio, which assists the organic response to Eimeria spp. and even favours the erratic behaviour of the strains used. However, it is noteworthy that stress increased the number of colony-forming units of C. perfringens in the caecum of broiler chickens, indicating a favouring of the avian necrotic enteritis development (Tsiouris et al., Reference TSIOURIS, GEORGOPOULOU, BATZIOS, PAPPAIOANNOU, DUCATELLE and FORTOMARIS2015a; Reference TSIOURIS, GEORGOPOULOU, BATZIOS, PAPPAIOANNOU, DUCATELLE and FORTOMARIS2015b).

Various studies indicate that heat stress can modulate both CNS activity and infectious processes. Similarly, an infectious process can modulate CNS activity and the behaviour of animals. However, differences in the etiological agents and the type, intensity and duration of stressors can produce different responses in the HPA-gut axis and neuroimmune system of birds and the intensity and severity of infection.

Acknowledgements

This study was supported by São Paulo Research Foundation (FAPESP), São Paulo, Brazil, under grant numbers 2009/51886-3, 2012/03103-2, 2013/17408-2, and by the National Counsel of Technological and Scientific Development (CNPq), Brazil, under grant number 474690/2013-0 and 434848/2016-6.