Clinical and Welfare Aspects of Immunosuppression in Poultry Farming

Abstract

Immunosuppression refers to a condition in which the body’s immune system becomes weakened or suppressed, making them more susceptible to infections, diseases and other health problems. Immunosuppression in poultry can be caused by a variety of factors, including infectious activity (viruses, bacteria, parasites, and fungi), environmental stress, malnutrition, and poor management. Viruses have the most dominant immunosuppressive effect on the poultry population, especially infectious bursitis virus, infectious anemia virus and Marek’s disease virus. Immunosuppression in poultry can have significant consequences on their health, welfare, and overall productivity. The biggest losses in poultry production are reflected in reduced growth and performance of individuals, reduced egg production and shell quality, increased morbidity and mortality rates, and greater susceptibility of immunocompromised individuals to secondary infections. Effective management strategies are key to minimizing the impact of immunosuppression in poultry. Biosecurity measures, strict hygiene protocols, immunoprophylaxis, control, and reduced transport of poultry and people, adequate diet, and correct husbandry and housing conditions are some of the factors that result in prevention and/or solvation of this problem.

1. Introduction

Animal welfare stands as a cornerstone principle across a multitude of domains, with particular significance in agricultural operations and food production systems [1]. At its core, ensuring the well-being of animals not only resonates with ethical imperatives but also serves as a linchpin for sustaining the health and productivity of livestock populations. Within the intricate tapestry of agricultural landscapes, where animals are raised to supply meat, dairy, and other essential products, maintaining optimal welfare conditions emerges as a linchpin for success [2]. These conditions foster an environment conducive to heightened animal health, diminished stress levels, and accelerated growth rates, culminating in more robust and resilient livestock populations. Furthermore, the promotion of poultry welfare assumes a critical role in mitigating the risk of immunosuppression within poultry populations. Optimal welfare conditions, characterized by spacious living environments, adequate nutrition, and minimal stressors, are paramount for maintaining robust immune function in poultry [3]. By prioritizing poultry welfare, farmers can bolster the resilience of their flocks against immunosuppressive factors, thereby reducing the incidence of infectious diseases and enhancing overall flock health. Additionally, promoting poultry welfare aligns with broader societal values regarding ethical animal treatment and sustainable food production. Consumers increasingly expect poultry products to be sourced from farms that prioritize animal welfare, underscoring the interconnectedness between animal welfare, immune health, and consumer preferences. Ultimately, by prioritizing both poultry welfare and immune health, agricultural practitioners not only safeguard the well-being of their flocks but also meet the expectations of conscientious consumers and uphold the integrity of the poultry industry [4]. Consumers are increasingly attuned to the conditions under which their food is produced, demanding transparency, accountability, and adherence to humane standards. By prioritizing animal welfare in agricultural practices and food production, producers not only align with evolving consumer preferences but also fortify the ethical foundation of their operations [5]. In essence, the pursuit of animal welfare in agricultural contexts transcends mere industry norms; it embodies a collective commitment to ethical stewardship, sustainable husbandry, and societal well-being. By championing the welfare of animals and elevating standards of care, agricultural stakeholders not only honor their moral obligation to sentient beings but also fortify the resilience and viability of our food systems. In doing so, they forge a path toward a future where compassion, sustainability, and societal values converge, ensuring the welfare and prosperity of both animals and consumers alike [6].

In poultry farming, the control of infectious diseases stands as a paramount concern in ensuring the production of healthy poultry flocks. This objective is typically achieved through comprehensive vaccination programs complemented by effective management practices, including rigorous biosecurity measures aimed at minimizing the risk of infection. The efficacy of vaccination programs hinges upon the birds’ capacity to mount a robust immune response, underscoring the foundational importance of immune function in poultry health. However, beyond the intrinsic capability of individual birds to initiate an immune response to natural antigens or those introduced via vaccination, numerous external factors exert influence over the level of immunity conferred [7]. It is the delicate interplay of these myriad factors, whether in excess or deficiency, that can precipitate the onset of immunosuppression.

The term ‘immunosuppression’ was first defined by Dohms and Saif as ‘a state of temporary or permanent dysfunction of the immune response resulting from an insult to the immune system and resulting in increased susceptibility to disease’ [8]. Lutticken further elaborated on this definition, suggesting that immunosuppression often manifests as a suboptimal antibody response, to which we add ‘suboptimal innate and cell-mediated responses’ [9]. In essence, poultry immunosuppression denotes a condition wherein the avian immune system becomes weakened or suppressed, rendering birds more susceptible to infections, diseases, and other health complications. This phenomenon holds profound significance within both the poultry industry and wild bird populations, as it can precipitate substantial economic losses and harbor detrimental biological and ecological ramifications. Avian immunosuppression can arise from a myriad of sources, including infectious agents, environmental stressors, malnutrition, and suboptimal management practices. Understanding the mechanisms underlying immunosuppression in birds, as well as its attendant consequences, is paramount for the formulation and implementation of effective prevention and control strategies [10]. Viral infections such as infectious bursal disease virus (IBDV), chicken infectious anemia virus (CIAV), and Marek’s disease virus (MDV) exemplify prominent immunosuppressive agents. These viruses exhibit a pronounced tropism toward the avian immune system, targeting the lymphoid tissue/cells and impeding the normal development and function of immune cells. Consequently, the bird’s capacity to mount an effective immune response against pathogens becomes compromised, heightening susceptibility to infections [11]. Environmental stressors, such as temperature fluctuations, overcrowding, poor ventilation, and hygiene deficiencies, also contribute significantly to the manifestation of immunosuppression in birds. Additionally, malnutrition, particularly deficiencies in essential vitamins and minerals, can compromise immune function by impairing cellular and humoral immunity [10]. The repercussions of impaired immune function in birds extend beyond mere health implications; they encompass reduced production efficiency, elevated mortality rates in commercial settings, and heightened antibiotic usage. While antibiotics may offer therapeutic benefits, their excessive use can engender antibiotic resistance, posing a formidable challenge to public health. Immunosuppression in wild bird populations can engender ecological ramifications, influencing disease dynamics and population dynamics within ecosystems [12]. A weakened immune system renders birds more susceptible to infections, resulting in elevated disease prevalence and severity, potential population declines, and altered interspecies interactions. Addressing avian immunosuppression necessitates a comprehensive and multifaceted approach encompassing robust biosecurity measures, enhanced management practices, and optimized nutrition to bolster immune function. Key interventions include ensuring optimal housing conditions, implementing stringent biosecurity protocols, and adhering to the ‘all in, all out’ principle in poultry production [13]. The recognition of the causes and consequences of immunosuppression in domestic poultry and wild birds is paramount to the implementation of proactive measures aimed at promoting bird health, welfare, and sustainable production practices. Resolving the issue of immunosuppression confers myriad benefits, ranging from the preservation of indigenous poultry and wild bird species to the mitigation of economic losses attributable to disease outbreaks. By fostering a deeper understanding of immunosuppression and its implications, stakeholders can work collaboratively to safeguard the well-being of birds across diverse environments. The aim of this book chapter is to elucidate the mechanisms of poultry immunosuppression and its profound implications for both poultry welfare and production.

2. Avian immune system

The evolution of birds and mammals from a common reptilian ancestor over 250 million years ago has resulted in distinct immune system adaptations reflecting their divergent ecological niches. While sharing fundamental immune protection mechanisms, avian and mammalian immune systems exhibit notable differences crucial for understanding avian immunology [14]. Mammals possess discrete lymphoid organs such as the thymus, spleen, and lymph nodes, facilitating adaptive immune responses. In contrast, birds lack distinct lymph nodes, with lymphoid tissue distributed peripherally and associated with mucosal surfaces, such as the conjunctiva and gastrointestinal tract [15]. In mammals, bone marrow serves as the primary site for B cell production, whereas birds rely on the bursa of Fabricius for B cell maturation, akin to mammalian bone marrow [16]. Birds exhibit a broader repertoire of antimicrobial peptides (AMPs) compared to mammals, including species-specific defensins that aid in pathogen neutralization [17]. Additionally, variations in the complement system, such as unique complement proteins in birds, contribute to pathogen recognition and elimination [18]. Birds produce IgY antibodies in the bursa of Fabricius, providing passive immunity to offspring through the yolk. Unlike mammals, birds lack IgA and IgE isotypes but possess γδ T cells instead of CD⁴⁺ T cells [19]. Birds exhibit cellular memory primarily mediated by γδ T cells and NK cells, ensuring rapid immune responses upon reinfection. However, humoral memory in birds is less pronounced compared to mammals [20]. Birds maintain higher body temperatures than mammals, creating less favorable conditions for pathogen growth and enhancing immune responses. The unique adaptations of avian immune systems reflect their specialized physiological and ecological requirements. Understanding these differences is pivotal for advancing knowledge in immunology and disease management across avian species [21].

3. Immunosuppression in poultry

3.1 Mechanisms of immunosuppression

Immunosuppression poses a significant challenge in the poultry industry, yet quantifying its prevalence remains elusive due to the complex interplay of various factors spanning physiological, environmental, and managerial stressors. Both acute and chronic stressors, including transportation, handling procedures, crowding, and abrupt environmental changes, disrupt the delicate equilibrium of the avian immune system, thereby impeding its ability to mount effective immune responses against pathogens and impacting the profitability of broiler flocks [22]. Similarly, pathogen-induced immunosuppression can occur independently of clinical disease, emphasizing the need for focused investigation into subclinical infections [22]. Infectious diseases constitute another pivotal determinant of immunosuppression in poultry. Pathogens such as viruses, bacteria, fungi, and parasites possess mechanisms to directly target and compromise immune cells, thereby impairing their functionality and rendering birds more susceptible to secondary infections [13]. Chronic infections exacerbate immunosuppression by perpetuating persistent inflammatory responses and depleting the host’s immune resources. Environmental variables, encompassing temperature fluctuations, inadequate ventilation, high humidity, and exposure to pollutants, significantly impact poultry immune competence. Suboptimal environmental conditions impose physiological stress on birds, disrupt metabolic homeostasis, and compromise immune function. For instance, extremes of temperature elevate metabolic demands, predisposing birds to thermal stress and concomitant immunosuppression [10]. Management practices exert a profound influence on the immunological integrity of poultry flocks. Poor nutrition, suboptimal vaccination strategies, inadequate biosecurity measures, and overcrowding contribute to immunosuppression. Nutritional deficiencies impede the synthesis of vital immune mediators, such as antibodies and cytokines, while substandard vaccination regimens leave birds vulnerable to preventable diseases. Furthermore, overcrowded housing conditions foster pathogen transmission and exacerbate stressors, exacerbating immunosuppression. Some of the key viral pathogens implicated in immunosuppression include Marek’s disease virus (MDV), although their immunosuppressive effects may be confounded by interactions with other pathogens such as Chicken Infectious Anemia Virus (CIAV) [7]. For instance, while CIAV primarily causes clinical disease in young chickens, its subclinical effects can result in profound immunosuppression, compromising the host’s ability to mount effective immune responses [7]. Infectious bursal disease virus (IBDV) also poses a threat by damaging immune tissues, particularly the bursa of Fabricius and associated lymphocytes, thereby impairing subsequent immunity [7]. However, caution is warranted when interpreting immunosuppressive effects attributed to certain viruses, as older studies may not delineate primary immunosuppression from synergistic effects with other pathogens [7]. For instance, early observations of hematopoietic system destruction in chickens with Marek’s disease were later found to be influenced by concurrent CIAV infection [23]. The exploration of immunosuppressive mechanisms has traditionally focused on well-documented factors such as stress-induced elevation of corticosteroids, programmed cell death pathways including apoptosis, necrosis, and pyroptosis, and alterations in immune response regulation mediated by viral infections. However, despite significant advancements, the intricate molecular interactions between viral proteins and host cells remain inadequately characterized in current scientific literature. This subchapter delves into the complexities of these mechanisms, shedding light on their nuanced roles in immunosuppression.

3.1.1 Immunosuppression induced by corticosteroids

Stress, whether acute or chronic, triggers a complex cascade of physiological and immunological responses aimed at adapting to challenging conditions and ensuring survival. In mammals, this response involves neuroendocrine signaling pathways, including the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system, resulting in the secretion of glucocorticoids such as corticosterone [24]. These hormones modulate immune cell activities and cytokine production, influencing immune function [25]. However, the avian stress response differs due to unique immune system characteristics, including the absence of lymph nodes and a distinct repertoire of cytokines and chemokines [26]. In chickens, stress induces increased plasma corticosterone levels, impacting immune function through alterations in immune organ mass and cellular activity [27]. While stress is often associated with immunosuppression, some instances, particularly acute stress, may enhance immune functions, resulting in improved resistance to certain pathogens [28, 29]. Therefore, experiments with exogenous corticosterone administration in chickens reveal dynamic immune responses, including leukocyte redistribution and altered cytokine expression [30]. These observations underscore the intricate interplay between stress, corticosterone, and immune function in poultry, highlighting the need for further investigation into the nuanced effects of stress on avian immunity.

3.1.2 Apoptosis, necrosis, and pyroptosis

Viral infections often trigger programmed cell death (PCD), which can either benefit or harm the host depending on the timing of cell death relative to the viral replication cycle [31]. In lymphoid cells, such as those infected with infectious bursal disease virus (IBDV), chicken infectious anemia virus (CIAV), or Marek’s disease virus (MDV), viral replication-induced PCD can lead to (sub)clinical immunosuppression. PCD encompasses three main mechanisms: apoptosis, necroptosis, and pyroptosis, each with distinct characteristics [32]. Apoptosis, the best-understood form of PCD, can be initiated via intrinsic or extrinsic pathways, resulting in controlled cell death. While necroptosis and pyroptosis are inflammatory processes triggered by external and internal stimuli, they differ in their cellular and molecular mechanisms [32]. Although necroptosis and pyroptosis have not yet been identified as primary mechanisms of viral insult in avian infections, apoptosis induced by viral replication remains a significant contributor to cell death in avian viral infections, as observed in studies of IBDV and chicken infectious anemia virus [33, 34]. Understanding the intricacies of viral-induced PCD is crucial for deciphering the pathogenesis of avian viral infections and developing targeted therapeutic interventions [35].

3.2 Causes of immunosuppression in poultry farming

Immunosuppression in poultry farming arises from a complex interplay of factors spanning management practices, environmental conditions, infectious agents, and physiological stressors [36]. These causes, individually and collectively, contribute to the impairment of the avian immune system’s function, thereby impacting the health and welfare of poultry populations. Suboptimal management practices, including overcrowding, inadequate ventilation, and lapses in biosecurity, create stressful conditions within poultry production systems. Overcrowding fosters social stress and competition for resources, while poor ventilation facilitates the accumulation of airborne pathogens and pollutants. Inadequate biosecurity measures heighten the risk of introducing infectious agents into the flock, further compromising immune health [37]. Poor nutrition is a significant contributor to immunosuppression in poultry. Diets lacking essential nutrients, such as vitamins, minerals, and amino acids, impair immune function and compromise the birds’ ability to mount effective immune responses against pathogens. Imbalances or deficiencies in the diet exacerbate the susceptibility of poultry to infectious diseases [38]. Poultry are susceptible to a wide array of infectious agents, including viruses, bacteria, fungi, and parasites, which directly target immune cells, compromising their function and resulting in immunosuppression. Disease outbreaks within flocks can significantly impact immune health and productivity [22]. Environmental stressors, such as temperature fluctuations, high humidity, and exposure to toxins, induce physiological stress in poultry. Chronic stress alters hormone levels and cytokine production, suppressing immune function and increasing susceptibility to infections. Environmental stressors exacerbate the impact of infectious diseases on poultry health [37]. Inappropriate vaccination protocols can compromise immune function in poultry [36]. Failure to administer vaccines effectively or the use of vaccines with limited efficacy leaves birds vulnerable to infections. Conversely, over-vaccination or vaccination during periods of stress can induce immunosuppression and compromise immune responses. Genetic selection for traits such as rapid growth and high productivity can inadvertently impact immune function in poultry. Birds bred for these traits may exhibit compromised immune systems, increasing their susceptibility to infections and immunosuppression [36].

3.2.1 Heat stress

Heat stress poses a significant challenge in the poultry industry, exerting profound effects on both the health and reproductive performance of poultry [39]. With annual economic losses ranging from 128 to 165 million dollars since 2003, exacerbated by escalating global temperatures, its impact is poised to escalate further [40]. Defined as the inability of chickens to maintain thermal equilibrium amidst environmental heat loads, heat stress arises from a complex interplay of factors including ambient temperature, humidity, heat radiation, and air velocity, with elevated ambient temperature playing a pivotal role [41]. Chickens exhibit optimal growth within a thermoneutral temperature range of 18–21°C, with any ambient temperature surpassing 25°C inducing heat stress [42]. Beyond compromising immune function, heat stress disrupts various physiological processes, manifesting in increased feed intake coupled with reduced growth rates and egg production [43]. In addition, heat stress triggers the activation of the sympathetic pituitary-adrenal axis, resulting in elevated plasma corticosterone levels via the hypothalamic-pituitary-adrenal (HPA) axis [41, 43]. Immune suppression due to thermal stress primarily manifests as regression in immune organs such as the spleen, thymus, and lymphatic tissues. This decline is evident in reduced total white blood cell (WBC) counts and antibody levels, along with elevated heterophils to lymphocytes ratio (H/L) in immunocompromised poultry [44].

3.2.2 Oxidative stress

Oxidative stress arises from an imbalance between the production and elimination of reactive oxygen species (ROS), which are free radicals and peroxides generated within cells during routine metabolism. While ROS plays vital roles in cellular functions like cytokine transcription, immunomodulation, and ion transport, their surplus can overwhelm cellular detoxification mechanisms, resulting in oxidative stress [45]. Excessive ROS inflicts damage upon various cellular components, including proteins, lipids, and DNA, resulting in reversible alterations or, under severe oxidative stress, apoptosis and cell demise [46].

3.2.3 Acid-base disbalance

The absence of sebaceous glands and feather covering in birds compromises their thermoregulation, necessitating active heat dissipation methods such as panting [47]. Panting involves increased respiratory frequency and evaporative cooling through open-beak breathing. This rapid exhalation of carbon dioxide (CO₂) during panting alters the standard bicarbonate buffering system in the blood. Hypocapnia results in reduced concentrations of carbonic acid (H₂CO₃) and hydrogen ions (H⁺) in the bloodstream, while bicarbonate ion (HCO₃−) concentrations increase, causing blood alkalinity [48]. To counteract this, birds eliminate excess bicarbonate ions and retain hydrogen ions through renal mechanisms to maintain normal blood pH. Elevated H⁺ ion levels disrupt the acid-base balance, resulting in respiratory alkalosis and metabolic acidosis, ultimately contributing to decreased production performance due to resultant immunosuppression [47].

3.2.4 Coccidia-induced immunosuppression

Avian coccidiosis, caused by Eimeria spp., poses a significant threat to the poultry industry due to its adverse economic impact. These intracellular protozoan parasites target intestinal epithelial tissues, resulting in a range of clinical manifestations, including bloody diarrhea and reduced body weight, resulting in substantial economic losses [49]. The complex life cycle of coccidia involves both intracellular and extracellular stages, with rapid reproduction resulting in the production of infective oocysts that enhance parasite spread [50]. Poultry develop immunity against coccidiosis through both innate and adaptive responses, with innate immunity triggered by pattern recognition receptors like toll-like receptors, resulting in immune cell activation and cytokine production [51]. Adaptive immunity, involving B and T lymphocytes, plays a crucial role in antigen-specific responses to prevent pathogen colonization [51]. While B cell depletion studies suggest antibodies may not be essential for anticoccidial immunity, passively transferred humoral immunity remains significant [52]. Cell-mediated immunity, mediated by T cells, particularly CD4⁺ T helper cells and CD⁸⁺ cytotoxic T lymphocytes, is vital for protection against Eimeria spp. infections [53]. Further research is needed to elucidate the role of various T cell subpopulations in avian coccidiosis for the development of effective control strategies.

Treg cells, a subset of T lymphocytes, play a crucial role in immunosuppression. In mammals, Treg cells exhibit a CD⁴⁺CD²⁵⁺FoxP³⁺ phenotype [54]. Although the avian FoxP3 ortholog has not been identified, CD⁴⁺CD²⁵⁺ T lymphocytes in chickens act as Treg cells, suppressing activated immune cells and producing IL-10, TGF-β, CTLA-4, and LAG-3. IL-10, significantly upregulated in CD⁴⁺CD²⁵⁺ cells, plays a pivotal role in evading the host’s immune response during coccidiosis pathogenesis, aiding parasite invasion and survival by inhibiting the IFN-γ-associated Th1 response. Differential expression of IL-10 in chicken genetic lines suggests its crucial role in modulating immune responses to Eimeria spp. infection [55]. Neutralization of IL-10 in Eimeria-infected poultry improves growth rates, highlighting its involvement in coccidiosis pathogenesis. Treg cells also mitigate pathological intestinal changes induced by Eimeria spp. by suppressing Th17 cells, reducing parasite pathogenicity [56]. The interplay between Treg and Th17 cells during immunoinflammatory events is critical in determining the outcome of Eimeria parasite infestation [57].

Two groups of coccidial species have been associated with immunosuppression, namely Cryptosporidium baileyi and several species of the genus Eimeria, although the evidence for the immunosuppressive effect of these parasites is rather limited. Cryptosporidium baileyi replicates in the epithelial cells of the bursa of Fabricius and the respiratory tract of chickens, and the prevalence of this disease is probably significantly higher than the number of diagnosed cases indicates [57]. Oral inoculation of high infectious doses of C. baileyi to young commercially bred poultry caused histopathological changes in the epithelium and interfollicular tissue of the bursa of Fabricius and reduced the production of specific antibodies, but also the production of antigen-dependent and independent T lymphocytes. Antibody titers in the serum of chickens after vaccination against infectious bronchitis virus (IBV), Newcastle disease virus (NDV), and avian influenza virus (AIV) were reduced after the experimental inoculation of C. baileyi chickens [58]. However, infection with C. baileyi did not increase the incidence of Marek’s disease or affect the efficacy of the Marek’s disease virus (MDV) vaccine strain CVI988. Also, these authors found that Marek’s disease, which appeared before or after infection/infestation with C. baileyi, leads to its worsening. In addition, MDV vaccination administered 4 days post-infection with C. baileyi caused respiratory lesions at 6 days post-vaccination.

3.2.5 Virus-induced immunosuppression

Infectious bursal disease virus (IBDV), a member of the Birnaviridae family, comprises two serotypes, with only serotype 1 inducing immunosuppression and disease in chickens. Various pathotypes within serotype 1 exhibit differing virulence levels. Genetic grouping of serotype 1 strains reveals distinct variations based on sequencing techniques. The IBDV genome consists of double-stranded (ds)RNA segments A and B, encoding viral proteins crucial for pathogenicity [59]. Serotype 1 strains predominantly replicate in B cells expressing chB6 and surface immunoglobulin, resulting in bursal atrophy and apoptosis [60]. Early infection reduces B cell populations, affecting primary antibody responses, while recovery may take up to seven weeks post-infection [61]. IBDV-induced immunosuppression compromises vaccine efficacy against avian influenza A virus and Campylobacter jejuni bacterial colonization. Furthermore, highly virulent IBDV strains (serotype 1) alter cecal microbiota, although the significance of this alternation remains unclear [62]. The VP5 protein of IBDV plays a role in pathogenesis, modulating apoptosis and survival in infected cells [31, 62]. IBDV infection induces complex interactions between viral proteins and B cells, resulting in apoptosis and subsequent recovery [63]. Post-recovery, two types of follicles emerge, indicating diverse immune responses [64]. Besides B cells, IBDV targets macrophages and T cells, contributing to immunopathogenesis [65]. Vaccination with live attenuated strains controls IBDV, but residual pathogenicity and vaccine-induced immunosuppression pose challenges [66]. Overall, IBDV infection triggers intricate immune responses involving B cells, macrophages, and T cells, resulting in bursal destruction and long-term immune suppression.

Chicken infectious anemia virus (CIAV), a small DNA virus approximately 25 nm in size, belongs to the genus Gyrovirus, family Anelloviridae, boasting a single-stranded covalently closed DNA genome encoding three proteins [67]. It has remarkable resistance to disinfectants and heat treatment, making it a common contaminant in chicken flocks, complicating studies on the immunosuppressive properties of other pathogens, especially in vaccine production [68]. Vertical transmission during egg production or horizontal transmission within the first few weeks of age can result in clinical disease, although most chicks are protected by maternal antibodies. Infections occurring in animals older than three weeks are often subclinical but can induce significant immunosuppression [69]. CIAV primarily targets rapidly dividing cells, utilizing them for viral DNA replication. Infected cells include hemocytoblasts in the bone marrow, T cell precursors in the thymus, or antigen-stimulated T cells. Hemocytoblast infection results in decreased erythrocyte, platelet, and granulocyte numbers, increasing susceptibility to secondary bacterial infections [67]. CIAV-induced immunosuppression is associated with reduced cytotoxic T lymphocyte (CTL) responses, facilitating prolonged viral replication [70]. The virus also affects CD⁴⁺ and CD⁸⁺ cell populations, particularly during co-infections with other pathogens [71, 72]. Furthermore, CIAV has been linked to reduced local antibody responses to other viral infections, such as infectious bronchitis virus (IBV) and avian influenza viruses [73, 74]. Studies on cytokine modulation during CIAV infection remain limited but suggest alterations in Th1, Th2, and Treg-associated cytokines [75]. Early changes in cytokine expression are crucial for understanding subsequent immunosuppression and require further investigation [69].

Marek’s disease virus (MDV), scientifically known as Gallid herpesvirus 2 and classified under the genus Mardivirusin the subfamily Alphaherpesvirinae, induces T lymphocyte tumors in chickens. The advent of highly effective vaccines against MDV in the early 1970s marked a significant milestone in veterinary virology, but subsequent evolution of the virus into highly virulent strains has posed new challenges [76]. These highly virulent (vv) pathotypes not only increase tumor incidence but also induce severe damage to lymphoid organs, potentially exacerbating immunosuppression [77]. The immunosuppression associated with MDV manifests in two phases: an early phase characterized by lymphocyte destruction within lymphoid organs and a late phase marked by virus reactivation with or without tumor development [78]. During the early phase, severe atrophy of the thymus and bursa of Fabricius occurs within the first 2 weeks of infection, with implications for long-term immunity [78]. The pathogenesis model of Marek’s disease elucidates how the virus targets B and T cells, causing depletion in lymphoid populations [79, 80]. The cytokine IFN-γ is upregulated as early as 3 days post-infection, possibly enhancing IL-8 receptor expression and facilitating viral transfer from B to T cells [72, 81]. Enhanced vIL-8 production by vv+ strains promotes cytolytic infection, exacerbating lymphoid damage [82]. Notably, vv+ MDV induces a significant upregulation of proinflammatory cytokines, potentially exacerbating immunosuppression [83]. Apoptosis plays a pivotal role in lymphocyte depletion during MDV infection, affecting both thymocytes and peripheral T cells [84, 85]. While MDV primarily infects B cells during early cytolytic infection, subsequent effects on thymocytes remain incompletely understood [86]. Several MDV gene products, including LORF4, VP23, and Meq, contribute to lymphoid atrophy, underscoring the multifaceted nature of MDV-induced immunosuppression [87]. MDV-induced immunosuppression extends beyond lymphoid tissue, affecting macrophage activation and cytokine regulation [88]. The inhibition of CTL migration and reduction of CD8 glycoprotein levels in feather follicle epithelium highlight the complex interplay between the virus and host immunity [89]. Moreover, MDV vaccine strains, while crucial for disease prevention, can paradoxically induce immunosuppression, impacting host responses to secondary infections [89]. Understanding these dynamics is essential for optimizing vaccine strategies and mitigating the impact of MDV-induced immunosuppression in commercial poultry production [88].

3.2.6 Mycotoxin-induced immunosuppression

Derived from ‘mykes’ (fungi) and ‘toxicon’ (poison), mycotoxins are toxic byproducts of mold metabolism with a low molecular weight [90]. Produced by a limited number of molds, some molds can synthesize multiple mycotoxin types, while others produce a single type [91]. Commonly found in mold-contaminated animal feed, mycotoxins pose a significant risk to animal health due to their widespread presence in feed, including poultry feed [92]. Approximately 25% of cereal, rice, and nut crops worldwide are contaminated by molds and fungi, raising concerns for human and animal health [93]. Therefore, mycotoxins such as aflatoxins, ochratoxins, and deoxynivalenol (DON) have detrimental effects on the immune system of farm animals.

Mycotoxins, derived from mold metabolism, exhibit a peculiar dual effect on immunity. At low concentrations (<5 mg/kg of food), they stimulate immune responses, while higher concentrations suppress immunity [92]. Chronic exposure to elevated levels of mycotoxins like DON damages immune organs and gastrointestinal mucosa [94]. This dual immune modulation, termed hormesis, involves mechanisms such as oxidative stress, apoptosis, and autophagy of immune cells, alongside regulation of immune signaling pathways including ERK 1/2, P38, mitogen-activated protein kinases (MAPK), JNK-STAT1, and MyD88-dependent toll-like receptor (TLR) pathways [91]. In addition, mycotoxins impact dendritic cells, T- and B-lymphocytes, and monocytes, influencing the secretion of pro- and anti-inflammatory cytokines and the differentiation of macrophages. Additionally, they directly activate JNK-STAT1 and MyD88-dependent TLR signaling pathways, inducing immunosuppressive and inflammatory responses [91].

Aflatoxin, primarily produced by Aspergillus molds like A. flavus and A. parasiticus, encompasses various types, with AFB1 being the most toxic and carcinogenic. Widely found in moldy agricultural products, especially animal feed ingredients, AFB1 poses significant health risks to livestock and poultry [95]. Its mechanism of action involves DNA damage, oxidative stress, apoptosis, hepatotoxicity, and nephrotoxicity [95, 96]. Bioactivation by cytochrome P450 in the liver transforms AFB1 into its highly toxic component, aflatoxin-8,9-epoxide, which binds to mitochondrial or nucleic DNA, resulting in cytotoxicity upon hydrolysis [96]. In poultry, AFB1 induces cell death in primary lymphoid organs, compromises intestinal integrity, and reduces production performance, with effects on both humoral and cell-mediated immunity [31, 97]. While AFB1 may initially elevate antibody levels, chronic exposure results in reduced immune function in hatchlings [98]. AFB1 can bypass primary immune responses, penetrating poultry organisms and compromising intestinal innate immunity [97]. The discovery of aflatoxin and ochratoxin elevated awareness among both the scientific community and the public about the potential dangers posed by mycotoxins [91]. Ochratoxins, produced by Penicillium and Aspergillus fungi, particularly ochratoxin A (OTA), emerged as significant contributors to diseases in human and veterinary medicine [99]. OTA exhibits nephrotoxic, hepatotoxic, teratogenic, and immunotoxic effects in poultry [99, 100]. Absorption of OTA primarily occurs in the glandular stomach and proximal jejunum of poultry, with unabsorbed OTA interacting with intestinal microbiota in the large intestine [101]. OTA, even present in chicken eggs from OTA-fed hens, reduces both innate and acquired immune responses, increasing susceptibility to diseases. Notably, OTA supplementation in feed significantly increases chicken mortality caused by Salmonella enterica subsp. enterica serovar Gallinarum [91].

DON, a significant trichothecene mycotoxin produced by Fusarium molds, is prevalent in various grains like wheat, rye, barley, and oats. Experimental studies in pigs, poultry, and cell culture models have documented DON’s adverse effects on immune function [101]. DON’s impact on the immune system varies from immunosuppression to immunostimulation, influenced by concentration, duration, and timing of exposure [94]. Like other trichothecenes, DON inhibits host protein biosynthesis by binding to the 60S ribosomal subunit, inducing metabolic stress and activating mitogen-activated protein kinases (MAPK) in poultry. Elevated prostaglandin levels following cyclooxygenase 2 (COX2) induction further exacerbate immune responses via increased expression of nuclear factor κB (NF-κB) and proinflammatory cytokines [94].

Experimental evidence suggests DON’s role in dysregulating cell signaling pathways and immune reaction genes, potentially predisposing poultry (and wild birds) to infectious diseases [102]. DON suppresses antibody responses to infectious bronchitis vaccine (IBV) and Newcastle disease virus in broilers and layers, while also reducing tumor necrosis factor-alpha (TNF-α) concentration in broiler plasma, indicative of weakened immune function and increased susceptibility to infectious diseases [103]. Additionally, DON adversely affects intestinal morphology, electrophysiology, absorption, and barrier function in chickens [104].

Beyond DON, the Fusarium genus produces several mycotoxins, including fumonisin B1, T-2 toxin, and zearalenone (ZEA), each with immunotoxic implications for chickens, turkeys, and ducks [105]. Fumonisin B1, even at low concentrations, reduces macrophage activity, antibody responses to vaccines, and gene expression of interleukins in broilers without affecting growth performance [106]. T-2 toxin administration reduces vaccine-induced protection against Marek’s disease virus in chickens. DON inhibits DNA, RNA, and protein synthesis, affecting tissues with rapid turnover, like intestinal epithelial cells and immune organs [104]. While low doses of T-2 and DON enhance antibody titers against Newcastle disease virus (NDV), high doses induce immunosuppression [107]. Zearalenone, a nonsteroidal estrogenic mycotoxin, binds to estrogen receptors, potentially interacting with chicken infectious anemia virus due to shared receptor affinity [104]. Interactions between trichothecenes and poultry immune responses are intricate, with low doses often stimulating cytokine production while high doses induce apoptosis in immune cells. Combined mycotoxin exposure exacerbates immunosuppressive effects, complicating the interpretation of immune dysfunctions in commercial flocks [108].

4. Impacts of intensive farming on poultry welfare and immunosuppression

Intensive farming methods wield a significant influence on poultry welfare, exacerbating immunosuppression and compromising the health and well-being of birds [109]. Central to this issue are the stressors and constraints inherent in high-density production systems. Overcrowding, a hallmark of intensive farming, imposes profound social stress on poultry populations. Densely packed housing conditions foster heightened competition for resources, escalating aggression among birds and inducing physiological responses that undermine immune function, thereby heightening susceptibility to infectious diseases [110]. Inadequate ventilation compounds these challenges, compromising air quality within intensive production facilities. The accumulation of airborne pollutants, including dust, ammonia, and microbial contaminants, irritates the respiratory tract and compromises lung function. Respiratory distress, a consequence of poor ventilation, predisposes birds to respiratory infections, exacerbating the burden of immunosuppression within poultry populations [111]. Moreover, the high stocking densities characteristic of intensive farming environments foster rapid pathogen transmission. Close confinement facilitates the spread of infectious agents through various modes, including direct contact, airborne transmission, and contaminated surfaces. Consequently, disease outbreaks are not only frequent but also severe, imposing significant immunosuppressive burdens on poultry populations [112]. The stressful environment further compounds these challenges, as chronic stressors associated with confinement, artificial lighting, and limited behavioral opportunities disrupt physiological homeostasis and compromise immune function. Stress-induced immunosuppression renders birds more susceptible to infections, exacerbating welfare concerns in intensive production systems. Additionally, intensive farming practices may prioritize production efficiency over optimal nutrition, potentially compromising immune function due to inadequate nutrient provision. Diets formulated to meet basic nutritional requirements may lack essential immune-supporting nutrients, further exacerbating immunosuppression in intensive rearing of poultry.

5. Evaluation techniques for assessing and monitoring immunosuppression in poultry

Assessing and monitoring immunosuppression in poultry is paramount for ensuring the health and welfare of flocks. A diverse array of scientific methodologies is employed to comprehensively evaluate the immune status of poultry populations, encompassing diagnostic tests, clinical observation, and welfare assessment. Laboratory assays are pivotal in assessing immune function in poultry. Parameters such as leukocyte counts and serum protein levels provide valuable insights into immune status. Additionally, specific assays like ELISA and PCR enable the detection of antibodies or pathogens associated with immunosuppressive diseases [4]. Observation of clinical signs serves as a primary method for gauging immunosuppression in poultry. Indicators such as increased morbidity and mortality rates, reduced growth rates, and poor feed conversion efficiency signify compromised immune function. Monitoring temporal changes in these parameters offers valuable insights into flock immune status [113]. Evaluating welfare indicators yields crucial information about the overall health and well-being of poultry. Behavioral alterations, including heightened lethargy and altered feeding behaviors, may indicate immunosuppression. Furthermore, monitoring environmental parameters such as air quality, temperature, and humidity aids in identifying stressors that compromise immune function [114]. Post-mortem examination and histopathological analysis of tissues provide valuable insights into the immunological status of poultry. Histopathological lesions such as lymphoid depletion and inflammation serve as indicators of underlying immune dysfunction [115]. Specialized immunological assays, including lymphocyte proliferation assays and cytokine profiling, offer quantitative assessments of cellular and humoral immune responses in poultry. These assays elucidate the functional capacity of immune cells and the production of immune mediators, providing comprehensive insights into immune function [116].

6. Strategies for preventing and mitigating immunosuppression in poultry

Mitigating immunosuppression in poultry is paramount for safeguarding flock health and welfare. Employing effective strategies grounded in scientific principles can substantially reduce the prevalence and severity of immunosuppressive conditions. Improving housing environments is crucial for minimizing stressors that contribute to immunosuppression. This involves optimizing ventilation systems to ensure optimal air quality and reducing stocking densities to alleviate social stress. Providing adequate space allocation, comfortable bedding materials, and environmental enrichment are also vital for promoting physiological and behavioral well-being [117]. Proper nutrition is fundamental for supporting immune function in poultry. Formulating diets tailored to meet the specific nutritional requirements of birds at various life stages and production phases is essential. Supplementation with micronutrients, antioxidants, and immunomodulatory additives can enhance immune responses and mitigate immunosuppressive effects. Quality assurance in feed formulation and ensuring access to clean water sources are also critical components of nutritional optimization strategies [118]. Robust biosecurity measures are indispensable for preventing the introduction and spread of pathogens associated with immunosuppression. This includes stringent control of personnel, equipment, and vehicle movements, as well as the implementation of disinfection and pest control protocols. Comprehensive biosecurity programs encompassing flock isolation, quarantine procedures, and regular health monitoring are essential for safeguarding flock health and mitigating disease risks [119]. Vaccination plays a pivotal role in disease prevention in poultry production. Tailoring vaccination programs to the specific disease challenges faced by the flock is crucial. Regular evaluation of vaccine efficacy, adjustment of vaccination protocols based on epidemiological data, and adherence to strict vaccination schedules are critical for ensuring robust immune protection and reducing immunosuppressive risks [120]. Regular monitoring and surveillance of flock health are essential for early detection of immunosuppressive conditions. This encompasses routine health assessments, diagnostic testing, and surveillance for emerging diseases. Timely identification of immunosuppressive factors facilitates prompt intervention and mitigation strategies, minimizing disease outbreaks and welfare impacts [121].

7. Conclusion

This chapter provides a comprehensive exploration of the intricate relationship between poultry welfare, immunosuppression, and alternative production systems. Key points discussed underscored the profound impact of housing conditions, nutrition, stressors, and disease exposure on immune function and overall welfare in poultry farming. Additionally, the potential benefits of alternative production systems, such as free-range and organic farming, in promoting poultry welfare and reducing immunosuppression are elucidated, highlighting their alignment with principles of animal welfare and sustainable production practices. Throughout the discourse, emphasis was placed on scientific evidence and best practices, emphasizing the necessity of evidence-based approaches in addressing poultry welfare and immunosuppression challenges. By integrating scientific knowledge with practical management strategies, producers can optimize flock health, welfare, and productivity while minimizing adverse environmental impacts. Moreover, the discussion touched upon the growing consumer demand for ethically produced poultry products and its influence on market trends. Consumer preferences for products from alternative production systems underscore the economic viability of sustainable poultry production practices and the importance of aligning with consumer values to ensure market competitiveness. The insights gleaned extend beyond poultry production to encompass the broader spectrum of animal agriculture and welfare across diverse settings, including zoos and captive animal facilities. Prioritizing animal welfare, implementing evidence-based practices, and fostering consumer awareness are paramount in promoting a more sustainable and ethical approach to animal husbandry, from farm to zoo. This holistic perspective emphasizes the interconnectedness of animal welfare considerations and underscores the importance of collaborative efforts to enhance the well-being of animals across various contexts.

Acknowledgments

We would like to acknowledge that this book chapter is based on the graduation thesis of the first author (Amra Alispahic, DVM). In addition, we acknowledge the use of ChatGPT, an AI language model developed by OpenAI, which capabilities were useful in enhancing the clarity of the manuscript.

Conflict of interest

The authors declare no conflict of interest.