Download An immunologist`s perspective on nutrition, immunity, and infectious

©2009 Poultry Science Association, Inc.
An immunologist’s perspective on nutrition,
immunity, and infectious diseases:
Introduction and overview1
M. H. Kogut*2 and K. Klasing†
*Southern Plains Agricultural Research Center, USDA-ARS, College Station, TX 77845;
and †Department of Avian Sciences, University of California, Davis 95616
Primary Audience: Poultry Nutritionists, Immunologists, Veterinarians, Researchers
SUMMARY
The immune system is a multifaceted arrangement of membranes (skin, epithelial, and mucus),
cells, and molecules whose function is to eradicate invading pathogens or cancer cells from a host.
Working together, the various components of the immune system perform a balancing act of being
lethal enough to kill pathogens or cancer cells yet specific so as not to cause extensive damage to
“self” tissues of the host. A functional immune system is a requirement of a healthy life in modern
animal production. yet infectious diseases still represent a serious drain on the economics (reduced
production, cost of therapeutics, and vaccines) and welfare of animal agriculture. The interaction
involving nutrition and immunity and how the host deals with infectious agents is a strategic determinant in animal health. Almost all nutrients in the diet play a fundamental role in sustaining an optimal immune response, such that deficient and excessive intakes can have negative consequences
on immune status and susceptibility to a variety of pathogens. Dietary components can regulate
physiological functions of the body; interacting with the immune response is one of the most important functions of nutrients. The pertinent question to be asked and answered in the current era of
poultry production is whether the level of nutrients that maximizes production in commercial diets
is sufficient to maintain competence of immune status and disease resistance. This question, and
how to answer it, is the basis of this overview. Clearly, a better understanding of the interactions
between the immune signaling pathways and productivity signaling could provide the basis for the
formulation of diets that optimize disease resistance. By understanding the mechanisms of nutritional effects on the immune system, we can study the specific interactions that occur between diet
and infections. This mechanism-based framework allows for experiments to be interpreted based
on immune function during an infection. Thus, these experiments would provide a “real world”
assessment of nutritional modulation of immune protection separating immune changes that have
little impact on resistance from those that are truly important. Therefore, a coordinated account of
the temporal changes in metabolism and associated gene expression and production of downstream
immune molecules during an immune response and how nutrition changes these responses should
be the focus of future studies. These studies could be answered using new “-eomics” technologies
to describe both the local immune environments and the host-pathogen interface.
Key words: nutrition, avian immunity, infectious disease, nutrigenomics
2009 J. Appl. Poult. Res. 18:103–110
doi:10.3382/japr.2008-00080
1
Papers from the Informal Nutrition Symposium, “Modulating Immunity: The Role of Nutrition, Disease, Genetics, and Epigenetics,” were presented at the Poultry Science Association 97th Annual Meeting in Niagara Falls, Ontario, Canada, on July
20, 2008.
2
Corresponding author: [email protected]
JAPR: Symposium
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DESCRIPTION OF PROBLEM
This paper is not a review of nutritional impact on the avian immune system. There are
several recent reviews that do a much more
thorough job than can be approached here [1–5].
However, we will use Klasing’s unique perspective on this topic as presented at the Gordon Memorial Lecture on “Nutrition and the Immune
System” to the World Poultry Science Association (United Kingdom branch) as the basis for
this overview of the topic [3].
The US poultry industry is the most productive in the world, with 15 million metric tons
of broiler meat produced in 2004. The industry
is fully integrated and supports the intensive
production of 8 billion birds annually. The production of a large volume of meat that meets
consumer demands requires birds to be grown
intensively at high population densities. In part,
because of these intensive rearing conditions,
infectious diseases remain a threat to the poultry
industry. Infectious diseases represent a serious
drain on the economics (reduced production,
cost of therapeutics and vaccines) and welfare
of animal agriculture. The outcome of a hostpathogen encounter is determined by virulence
factors of the pathogen and defense factors of
the host.
From an immunologist’s point of view, the
amount of information on poultry nutrition is
vast when compared with the field of avian immunology, which is essentially in its infancy.
For example, many required nutrients have been
identified, the concentrations of these essential
nutrients in feedstuffs and their availability to
the bird are known, and minimal concentrations
of many nutrients required for maximum production have all been defined. However, when
this information is applied to the interactions of
nutrition (diet) and immune status, the outcome
is less definitive. To be sure, it has been shown
that almost all nutrients in the diet play a fundamental role in sustaining an optimal immune response, such that deficient and excessive intakes
can have negative consequences on immune status and susceptibility to a variety of pathogens.
However, based on the current literature, the
pertinent question to be asked and answered in
the current era of poultry production is whether
the concentration of nutrients that maximizes
production in commercial diets is sufficient to
maintain competence of immune status and disease resistance. This question and how to answer
it will be the basis of this overview. We make
no attempt to provide an ultimate answer to the
question, but instead provide an outline for future studies that should provide the foundation
for the answer to the question. Furthermore, we
should all keep in mind that in discussing the
interaction of nutrition (diet) on infection and
immunity, there is a need to consider the agenda
of the bird, determined by its genotype through
metabolic and physiologic mechanisms, in developing and maintaining an optimal immune
system during an infection.
OVERVIEW OF AVIAN
IMMUNE RESPONSE
The immune system is a multifaceted arrangement of membranes (skin, epithelial, mucus), cells, and molecules whose function is to
purge a host of invading pathogens or cancer
cells. Working together, the various components
of the immune system perform a careful balance
of being lethal enough to kill pathogens or cancer cells yet specific so as not cause extensive
damage to healthy “self” tissues of the host. A
functional immune system is a requirement of a
“healthy” life in modern animal production.
The foremost function of an immune response is to identify and eliminate infection. The
immune system of vertebrates is made up of 2
functional elements, the innate and the acquired,
which contrast in their mechanisms of pathogen
recognition [6]. The innate system uses germline encoded receptors, known as pattern recognition receptors (PRR), that recognize the
evolutionarily conserved molecular components
{i.e., pathogen-associated molecular patterns
(PAMP) of infectious microbes [7–10]}. The
acquired response uses highly specific antigen
receptors on T and B lymphocytes that are generated by random processes by gene rearrangement [7, 11]. Therefore, the antigen receptors of
the acquired immune system can be produced
for any given antigen.
Innate Immune Response
The host immune response to pathogens in
the earliest stages of infection is a critical deter-
Kogut and Klasing: informal nutrition symposium
minant of disease resistance and susceptibility.
These early responses are dedicated to the containment of the pathogens, holding infections
to a level that can be resolved by the ensuing
development of acquired immune mechanisms.
The innate immune system is a rapidly induced,
phylogenetically conserved response of all multicellular organisms [6] that depends on PRR
recognition of PAMP on or in major groups of
microbes. The PAMP are critical for pathogen
replication, survival, or both and are unique to
large groups of microorganisms and not host
cells, thus providing the host with an efficient,
nonself means of detecting invading pathogens.
Several well-known examples described are lipopolysaccharides of all gram-negative bacteria, lipoteichoic acids of gram-positive bacteria,
double-stranded RNA of RNA viruses, mannans
of yeast cell walls, unmethylated CpG motifs of
bacterial DNA and not eukaryotic DNA, lipoproteins and peptidoglycans of all bacteria, and
the glycolipids of mycobacteria [6–8].
Recognition of PAMP induces various extracellular activation cascades and intracellular
signaling pathways, leading to the inflammatory
response, recruitment of phagocytic cells for
clearance of the pathogens, and mobilization of
professional antigen-presenting cells. The PRR
are present in 2 separate compartments of the
host: cell membranes and cell cytoplasm. The
PRR on cell membranes have assorted functional
activities, including promotion of phagocytosis,
presentation of PAMP to other PRR, and the initiation of major intracellular signaling pathways.
Cytoplasmic PRR detect intracellular viruses
and bacteria, resulting in the production of type I
interferons and activating inflammasomes. Both
families of PRR are essential to impart global
antimicrobial responses to the host. Each family
of PRR is differentially expressed to optimize
their ability to respond to a variety of pathogens
activating specific intracellular signaling pathways that lead to the release of cytokine profiles
specific for particular PAMP.
Recognition of PAMP by PRR, either alone
or in heterodimerization with other PRR [Tolllike receptors (TLR), nucleotide-binding oligomerization domain proteins, retinoic acidinducible gene-I, and C-type lectins], induces
intracellular signals responsible for the activation of genes that encode for proinflammatory
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cytokines, antiapoptotic factors, and antimicrobial peptides [12–14]. Although a certain degree
of redundancy exists between signals induced
by various PRR, in general, no single PRR is
likely to be the sole mediator of activation of the
innate immune response. Therefore, a variety of
pathogens, each containing different PAMP, can
interact with a certain combination of PRR on
or in a host cell. The variety of PRR complexes
triggers specific intracellular signal transduction
pathways that will induce specific gene expression profiles, particularly cytokine/chemokine
expression, best suited for the invasive pathogen
[15–20]. Furthermore, the induction of cytokine
mRNA transcripts is regulated by molecular
bridges known as transcription factors. The activation of transcription factors, such as NF-κB,
activation protein-1, and interferon regulatory
factors 3, 5, and 7, are required step(s) in intracellular signaling that result in changes in gene
expression.
Over the last few years, it has become readily apparent that an essential function of the innate immune system is to instruct the lymphocytes to develop a particular effector response
to a specific pathogen [6, 11]. Because PAMP
are produced exclusively by microbes and not
by the host, recognition by host PRR signals the
presence of pathogens. The PAMP recognition
activates effector mechanisms of innate host
defenses, including phagocytosis, the synthesis of antimicrobial peptides, and the induction
of respiratory burst and nitric oxide synthase.
Furthermore, PAMP induce the expression and
production of proinflammatory cytokines and
chemokines. These endogenous signals orchestrate the recruitment of leukocytes to the site
of infection and regulate the activation of the
suitable effector mechanisms by controlling differentiation of T lymphocytes into effector cells
of a particular type. Last, and most important,
recognition of PAMP by PRR induces the expression of costimulatory molecules by antigenpresenting cells (i.e., natural adjuvant activity)
and leads to the development of highly antigenspecific memory cells [6, 8, 21]. The ability of
the lymphocytes to differentiate into effector
cells is dependent on, and controlled by, signals produced by the cells of the innate system
[6, 22]. Thus, it can be seen that adjuvants are
primarily PAMP that induce the innate immune
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response to produce the required costimulatory
molecules that result in protection.
In chickens, heterophils, the avian polymorphonuclear leukocyte equivalent to the mammalian neutrophil, and macrophages ingest and
kill a variety of microbial pathogens. Functionally, both cell types exhibit an assortment of cytoskeletal and biochemical activities that include
adhesion, chemotaxis, phagocytosis, and the
microbicidal activities of degranulation, respiratory burst, or both that can be easily assayed
in vitro [23–25]. We have been investigating
whether the avian heterophils and macrophages
have a more direct contribution to host defenses
than their traditional role as professional phagocytes. We have shown that types of phagocytes
can be induced to produce proteins that function
to regulate inflammatory and immune responses
including TLR, nitric oxide, and cationic antimicrobial peptides [26, 27]. Both types of phagocytic cells are also capable of rapid changes in
proinflammatory cytokine and inflammatory
chemokine gene expression following receptormediated phagocytosis [24–26]. Because heterophils and macrophages represent the first
cell types encountering and interacting with an
inflammatory or etiologic agent, the ability to
synthesize and release an array of cytokines provides evidence for their role in both the immunoregulation and pathophysiology of disease.
There are 8 known TLR in chickens (TLR 2,
type 1 and type 2, TLR3, 4, 5, 7, 8, 15, and 16,
formally 1/6/10) [26–33]. We have found that
heterophils constitutively express all 8 known
chicken TLR [26]. However, chicken monocytes constitutively express all but TLR5 and
TLR8 [34], whereas macrophages constitutively
express all but TLR3, 7, and 8 [27–33]. Stimulating heterophils and monocytes with specific
TLR agonists stimulates oxidative burst, nitric
oxide production, and degranulation [35–38]
and induces upregulation of proinflammatory
cytokines and inflammatory chemokines [26,
34].
Acquired Immunity
The acquired immune response is an inducible response found only in vertebrates. The
acquired host defenses, mediated by T (thymusderived) and B (bursa-derived) lymphocytes,
are infinitely adaptable to antigenic response
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because of the somatic rearrangement of immunoglobulin and T-cell receptor genes to create clones of lymphocytes that express distinct
antigen receptors. The receptors on lymphocytes
are generated by somatic mechanisms during the
ontogeny of each individual and thus generate a
diverse repertoire of antigen receptors with random specificities on the lymphocytes. After the
elimination of an infection, the antigen-specific
clones remain expanded as memory lymphocytes that provide a more rapid response to second exposure to the same antigen. Recognition
of an antigen by T or B lymphocytes requires
the antigen to be presented bound to cell surface
proteins called major histocompatibility complex class I or II and costimulatory molecules
[38, 39]. It is important to note that the ability of
the acquired response to differentiate self from
nonself antigens is not absolute.
Acquired immunity differs from the innate
responses by possessing specificity in recognition of foreign invaders (antigens) and the development of memory (i.e., re-exposure to an
antigen results in a more rapid response than was
elicited during the primary exposure). Acquired
immunity is mediated by 2 different types of responses depending on the type of lymphocyte
that primarily responds to the antigen: humoral
(B lymphocyte) or cell-mediated (T lymphocyte) [39]. Humoral immunity is characterized
by the production of antibodies by the B lymphocytes in response to extracellular antigen
recognition, whereas cell-mediated immunity is
characterized by the recognition of infected or
transformed host cells by T lymphocytes. Two
types of phenotypically different T lymphocytes
perform different effector functions to control
the host response: T cytotoxic lymphocytes lyse
viral-infected or neoplastically transformed host
cells, whereas T-helper cells activate B lymphocytes to produce antibodies, inhibit pathogen
proliferation in host cells through the production
of effector cytokines such as interferon-γ, and
direct further cell-mediated immunity through
the production of interleukin-2 [38, 39].
NUTRITION-INFECTIONIMMUNITY INTERACTIONS
Nutrition
The interaction involving nutrition and immunity and how the host deals with infectious
Kogut and Klasing: informal nutrition symposium
agents is a strategic determinant in animal
health. Traditionally, the nutrition-immuneinfection interaction has concentrated on the
role of nutrients in upregulating host defenses,
whereas the effect of infectious agents has been
on host nutritional requirements. Klasing [3]
has suggested that to interpret the available and
future literature as well as to establish whether
changes in diet are beneficial or detrimental, a
first-principles approach to experimental design
should be adopted. These principles can be categorized as mechanisms by which diet can affect
immunity and the response to infections. Simply
put, experiments would be designed by evaluating the effect of a diet on 1 of 5 specific immune
mechanisms. By understanding the mechanisms
of nutritional effects on the immune system, we
can study the specific interactions that occur
between diet and infections. This mechanismbased framework allows for experiments to be
interpreted based on immune function during
an infection. Thus, these experiments would
provide a real-world assessment of nutritional
modulation of immune protection, separating
immune changes that have little impact on resistance from those that are truly important. Thus,
detailing specific mechanisms of how a diet
can affect immunity, one can then evaluate how
these mechanisms relate to various nutrients and
pathogens. For example, knowing how a diet or
nutritional supplements induce temporal changes in host metabolism and the associated function of immune cells and expression of immune
response genes during different stages of an immune response could result in the formulation
of affordable diets that optimize disease resistance to a variety of pathogenic organisms. Each
mechanism provides an applicable hypothesis
that can be tested, answered, and these sciencebased results provided to commercial interests
for the development of least-cost diets:
• Substrates for cells of the immune system
= what is the priority of immune cells for
critical nutrients vs. nonimmune cells?
Examples: amino acids as substrates for
cytokine production by leukocytes, protein production by liver cells.
• Supplying critical nutrients to pathogens =
what nutrients are important for pathogens
as well as immune cell function? Examples: iron, biotin.
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• Modulating signaling in leukocytes =
what nutrients up- or downregulate immune cell function? Examples: vitamin D,
polyunsaturated fatty acids for eicosonoid
production.
• Protecting against immunopathology =
what nutrients can be used to prevent or
manage inflammation, or both? Examples:
antioxidants such as vitamins E and C for
repair of local oxygen radical damage by
phagocytes.
• Influencing intestinal dynamics = what nutrients can stabilize microflora that equals
optimal growth and health? Example: dietary fiber provides growth substrates for
microflora.
Immunity
Until recently, one of the main problems
in avian immunology with application of the
first-principles approach to nutrition-immunity
interactions is the lack of understanding and
characterization of the specific cellular and molecular mechanisms of the immune response,
in particular innate immunity. However, with
the clarification of more cellular and molecular
avian innate immune pathways, from pathogen
recognition by specific cells to the generation
of effector peptides and production of inflammatory and regulatory cytokines, the connection
between nutrition and immunity can be further
delineated. Some recent fundamental discoveries in avian immunology are outlined in Table 1.
Thus, the ability to evaluate the effect of diet on
specific immune mechanisms can now be evaluated at the cellular and molecular level. We can
study the effect of nutritional status on the functioning immune system in practical applications.
These include the use of immune parameters to
assess the nutritional status of flocks, to evaluate the efficacy of nutritional therapy, and to formulate dietary recommendations to achieve the
immune responses needed to prevent specific infectious diseases at the national, regional, or local level. The availability of the chicken genome
sequence provides the opportunity to resolve
questions concerning the molecular components
of the avian immune system. Key developments
in molecular, genetic, and cellular biological
techniques provide us with new approaches to
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108
Table 1. Recent fundamental findings in avian
immunology that will aid in the first-principles approach
to studying the nutrition-immunity-infection interaction
Immune response finding1
Acquired
Th1/Th2 cytokines
cDNA microarray
Innate
TLR expression
Chemokine expression/production
Dendritic cells
Defensins/antimicrobial peptides
References
[40, 41]
[42]
[26, 29]
[43]
[44, 45]
[46–48]
1
Th1/Th2 = T helper cells; TLR = Toll-like receptors.
use the genome to investigate the nutritional effects on functional genomics (the study of how
and why a given gene behaves in a certain way
under specific conditions), pathogenomics (the
study of how genes behave when pathogens
interact with their host) of the avian innate response to pathogens, and also to develop and
apply the specialized field of nutrigenomics (the
study of the influence of nutrition on gene and
protein expression) to poultry production.
CONCLUSIONS AND APPLICATIONS
1. Almost all nutrients in the diet play a
fundamental role in sustaining an optimal immune response, such that deficient
and excessive intakes can have negative
consequences on immune status and susceptibility to a variety of pathogens.
2. Dietary food components can regulate
physiological functions of the body, and
interaction with the immune response
is one such important function of nutrients.
3. Although an optimal immune response
depends on various circumstances in the
host (phenotypic quality, exposure to
multiple stressors, infection status, nutrient intake), the immune system has a
priority in the partitioning of nutrients at
critical times during infections.
4. Simply adding one nutrient to prevent infection by a single organism is obsolete
and expensive, and potentially increases
the susceptibility of the birds to another
pathogen.
5. The immune system is regulated by factors other than simply the degree of antigenic stimulation and immediate nutrient
supply, as evidenced by the fact that if a
strong immune response were resourcecheap, then all hosts would be expected
to respond vigorously to an infection.
6. Clearly, a better understanding of the interactions between the immune signaling
pathways and productivity signaling, for
example, food intake, could provide the
basis for the formulation of diets that optimize disease resistance.
7. Although nutrients can modulate immune
function, nutrient status and intake must
also be considered in immune response
studies during infection. Variations in
nutrient uptake undoubtedly contribute
to variations in immune responsiveness
to pathogens between individual birds
and possibly between groups of birds.
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