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Immunology in the Animal: Microbial Interaction, Stress and
Nutrition
Chris ChaseDept. Vet. & Biomed Sci
South Dakota State UniversityBrookings, SD
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Credits� Kuby Immunology
� Immunobiology, 9th edition
� Bruns et al, 2010 PLoS Pathog
� David Topham, University of Rochester
� Mike Kogut, ARS
� Lance Baumgard, Iowa State
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Topics� Three Levels of Immune Protection
� Mucosa-Barrier- New Frontier, Good
� Innate Immunity-Good, Bad, Ugly
� Acquired Immunity-Good, Bad
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“I Know It When I See It”
Supreme Court Justice Stewart Potterto describe his threshold test for
Obscenity in Jacobellis v. Ohio (1964)
Gut Health Symposium Dec. 3-5 , 2012
What is gut health ?
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The ”Gut”� the largest interface between the external environment & the internal
host milieu
� constitutes the major barrier through which molecules can either be absorbed or secreted
� largest residence of immune cells in body; acts as a physical & immune barrier to pathogens
� natural habitat for a large & dynamic community of microbes that participate & regulate gut & systemic functions
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1. Effective digestion/food absorption
2. Stable microbial population
3. Effective immune status
4. Effective gut barrier
5. Effective neuroendocrine system
Components of a Healthy GI System
Kogut Gut Health Symposium Dec. 3-5 , 2012
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Neuro-Immune Interaction
Margolis KG, Gershon MD, Bogunovic M. Cellular Organization of Neuroimmune Interactions in the Gastrointestinal Tract. Trends Immunol 2016;37:487–501.
MAMPs microbial-associated molecule patterns
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Think of the body as a hollow plastic tube…
The food is digested within the hole in the tube, but it never actually enters into the solid plastic material.
Tube inner surface ~Digestive System~
Plastic interior ~Body~
Tube outer surface ~Skin~
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Immune responses
Invasion& infection
Barriers
Innate immunity
Adaptive immunity
+
+
Inflammation
From David J. Topham, Introduction to Viral Immunology:Part I
1st Line of DefenseBarriers
mucous, tears, gastric pH,saliva, skin
Cellular and humoral defensesinterferon, cytokines (pro-inflammatory and
T stimulatory), complement proteins, phagocytosis, NK cells
2nd Line of Defense
Cellular and humoral defensesAntibodies, cytokines, T helper cells,
cytotoxic T cells
3rd Line of Defense
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Stressors at the Farm
� Co-mingling
� Injury
� Water - palability and supply
� Feed - time to first
� Pen density
� Pen total number
� Heat Stress
� Handling and movements
� Fear and Flight
� New �add-ons�
� Weather extremes
� Dust
� COMPETITION
� Vaccination
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Adapted from Reiche et al. 2004. The Lancet Oncology 5:617-625.
Stress
Hypothalamus
CNS
Pituitary
Inflammation/Innate Immunity
AdaptiveImmunity
Hormones and cytokinesNeuropeptides and neurotransmitters
AutonomicNerves
EndocrineSystem
Immune System
InfectionsTrauma Fear & Flight
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Mucosal Immune Responses
2nd Line of DefenseHumoral and Cellular Defenses
Cellular, cytokine and protein defensesInterferons, defensins, chemokines, cytokines
(pro-inflammatory and T stimulatory), complement proteins, TLRs, phagocytosis, NK
cells
Invasion& infection
Barriers
Innate immunity
Adaptive immunity
+
+
Inflammation3rd Line of Defense
Humoral and Cellular Defenses Cellular and humoral defenses
Antibodies, cytokines, chemokines,T helper cells, cytotoxic T cells
•1st Line of Defense•Barriers
Skin & Mucous membranes and secretions
Barrier, rapidly regenerating surfaces, peristaltic movement, lysozyme, sebaceous/mucous
secretions, stomach acid, commensal organisms
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Epithelial Cells and First Line of Defense
Decrease water intake- dehydration barrierê
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Epithelium and Kill Zone
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Epithelial Cells� Location
� GI tract� Respiratory tract� Reproductive tract� Skin
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Epithelium and Immune Function
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Microbiota (Microflora)� The collection of organisms found in and on our body- very location
specific and individual specific (genetic component)
� Gastrointestinal microbiota is the most diverse and has the largest interaction both with mucosa and ingesta- “superorganism”
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Commensal Organisms� 1014 organisms-eukarya, archae and bacteria
� 1012 commensal bacteria/ml- 10X higher than the combined somatic and stem cells in man
� Commensals are essential for immune development
� Composition of commensal bacteria influenced by the host immune status
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Microbiota and Immune Development
Global Effect of Microbiota
Reynolds, L. A., & Finlay, B. B. (2013).. Expert Review of Clinical Immunology, 9(11), 1019–1030.
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Commensal Bacteria
Front. Vet. Sci., 23 September 2015 | https://doi.org/10.3389/fvets.2015.00036The gut microbiome and its potential role in the development and function of newborn calf gastrointestinal tract
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Commensals Mucosal Barrier and Immunity
Obata, Y., Furusawa, Y., & Hase, K. (2015). Epigenetic modifications of the immune system in health and disease. Immunology and Cell Biology, 93(3), 226–232. http://doi.org/10.1038/icb.2014.114
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Adapted from Cell 156, Issues 1–2, 2014, Pages 7
YY
YYYY
YYU
YYU
YYU
YYUY Y
U
Y Y
U
Microbes and Regulating Innate Immunity
Anti-inflammatory response is keyfor healthy mucosa
Commensals Mucosal Barrier and Immunity
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Timsit E, Holman DB, Hallewell J, et al. The nasopharyngeal microbiota in feedlot cattle and its role in respiratory health. Animal Frontiers 2016;6:44–50.
Stress and Dysbiosis
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Commensals and their Induced Immune Changes
Khosravi and Mazmanian, Current Opinion in Microbiology 2013, 16:221–227
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Microflora, Diet and Stress� Nutrition isn’t just feeding the “animal” it is also feeding the
“microbes”
� Production of vitamins
� More efficient bacteria- increase opportunity for obesity
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• Innate Immunity - 2nd Line of Defense
• the troops are called to battle…– injury & infection– macrophages are on patrol– cytokine chemicals attract other �troops�– Absolutely essential for vaccine responses
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Inflammatory Response
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Neuro-Immune Interaction
Obata Y, Pachnis V. The Effect of Microbiota and the Immune System on the Development and Organization of the Enteric Nervous System. Gastroenterology 2016;151:836–844.
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Epithelial Cells- Immunomodulation� Pro-inflammatory cytokines-
� Epithelial Cell Enemy# 1� Tumor necrosis factor-alpha
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Leaky Gut� Leaky gut explains the negative consequences of heat stress and off-
feed events (all farm animals)
Baumgard L, International Symposium on Dairy Cattle Nutrition, Wageningen NL October 26, 2017
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Leaky Gut Mucosa
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Inflammatory Response
Systemic response
First Immune Organ
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Neutrophils-Blowing Up-Collateral Damage
Bruns S, Kniemeyer O, Hasenberg M, et al. . PLoS Pathog 2010;6:e1000873.
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Tissue Damage- Overactive Immune System
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Overactive Inflammatory Response
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Heat Stress and Gut Health� Diversion of blood flow to skin and extremities
� Coordinated vasoconstriction in intestinal tissues� Reduced nutrient and oxygen delivery to enterocytes� Hypoxia increases reactive oxygen species (ROS)
� Reduced nutrient uptake increases intestinal osmolarity
Baumgard L, International Symposium on Dairy Cattle Nutrition, Wageningen NL October 26, 2017
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Cytokine Storm
Tisoncik J R et al. Microbiol. Mol. Biol. Rev. 2012;76:16-32
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Cytokine Storm� High Temps- 104˚-106˚F
� Respiratory Disease-� Acute Lung Injury� Acute Respiratory Disease Syndrome
� Is BRSV???
� Is Vaccination or Aspirin the Answer?
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Acute Respiratory Disease Syndrome
Tisoncik J R et al. Microbiol. Mol. Biol. Rev. 2012;76:16-32
Acute
Chronic
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Brain-Gut-Microbiota axisInflammation and Obesity- Overconditioned Weaned
Calves, Fat Cattle, Transition Cow
Cluny, N.L., et al. Cannabinoid signaling regulates inflammation and energy balance: The importance of the brain–gut axis. Brain Behav. Immun. (2012), doi:10.1016/j.bbi.2012.01.004
DietChange Microbiome
CB-cannabinoid receptor
Endocannabinoid system
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Documented Causes of Increased Intestinal Permeability (“leaky gut”)Large Intestine
Acidosis
Distant Inflammation
Weaning
Small Intestine Bacteria OvergrowthLarge Intestine PTN Fermentation
Feed Restriction
Transition Period Heat Stress
Leaky Gut
Psychological Stress
Baumgard L, International Symposium on Dairy Cattle Nutrition, Wageningen NL October 26, 2017
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Inflammation and Production� Proinflammatory Cytokines
� Tumor Necrosis Factor-! (TNF-!)� Interleukin 1-" (IL-")� Interleukin 6 (IL-6)
� Proinflammatory Cytokines- Turn on Acute Phase Proteins
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Inflammation and Effect on Production Parameters
� Increase Sickness Behavior-listlessness
� Decrease feed intake- Inappetence-
� Increase body temperature sweats
� Decreased feed conversion
� Decrease gain
� Decrease milk production
� Increased Mastitis
� Increased Metritis
� Increased BRD
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Consequences of Leaky Gut and LPS
Johnson JS, Abuajamieh M, Fernandez MVS, et al. Thermal stress alters postabsorptive metabolism during pre-and postnatal development. In: Sejian V, ed. Climate Change Impact on Livestock: Adaptation and Mitigation. New Delhi: Springer India; 2015:61–79.
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Overactive Inflammatory Response
Tissue Damage
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Proinflammatory Summary
� Innate Pro-inflammatory response� Cell Recruitment� Neutrophil Migration� Acute Inflammation� Humoral Immunity IgG� Cell mediate immunity-Memory
Pro-Inflammatory
Disease Immunity
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Anti-inflammatory Summary
� Innate Anti-inflammatory response� Maintains gut homeostasis� Humoral immunity-IgA� Cell Mediated Regulatory T cells- Helps to Control
Acute Inflammation-
Anti-Inflammatory
Disease Function-IgA
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Innate Immunity Interventions
� NSAIDS� Aspirin-� Meloxicam
� Cytokine� Imrestor (pegbovigrastim injection)- Granulocyte Colony Stimulating Factor
(PEG bG-CSF)- Elanco- Off the Market
� Immunomodulators� Immunoboost- MCWF Amplimune Bioniche- Nova Vive� Zelnate- Liposome-DNA- CpG-Bayer-
� Gut Health- Nutriceuticals� Prebiotics� Probiotics
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Mucosal Vaccine Responses
2nd Line of DefenseHumoral and Cellular Defenses
Cellular, cytokine and protein defensesInterferons, defensins, chemokines, cytokines
(pro-inflammatory and T stimulatory), complement proteins, TLRs, phagocytosis, NK
cells
Invasion& infection
Barriers
Innate immunity
Adaptive immunity
+
+
Inflammation3rd Line of Defense
Humoral and Cellular Defenses Cellular and humoral defenses
Antibodies, cytokines, chemokines,T helper cells, cytotoxic T cells
•1st Line of Defense•Barriers
Skin & Mucous membranes and secretions
Barrier, rapidly regenerating surfaces, peristaltic movement, lysozyme, sebaceous/mucous
secretions, stomach acid, commensal organisms
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Where Does The Intranasal Vaccine Response Occur?
Brandtzaeg P. Potential of nasopharynx-associated lymphoid tissue for vaccine responses in the airways. Am J Respir Crit Care Med 2011;183:1595–1604.
T cells B cells
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From: Kuby Immunology 4/E by Goldsby, Kindt & Osborne, 1992, 1994, 1997, 2000 by W. H. Freeman and Company. Used with permission
2
1
Danger and Activation of the Acquired Immune System
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3rd Line of Defense “mucosal immune system�
Nasal Cavity
Lymph Node
BloodVessel
Lymphatic Duct
Spleen
LactatingMammary Glands
Reproductive Tract
Middle Ear
RespiratoryTract
Gastrointestinal Tract
TonsilsSalivaryGlands
LacrimalGlands
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Take Home: A Healthy Gut is a Necessity- What About
Nutriceuticals?
� Essential Oils, Organic Acids, Bioactives (Plasma Proteins, colostrum), Bacterial cultures, yeast, cell wall products, metabolites
� Problem: how do we measure it
� Do we need them all the time? Depends- times of stress
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Summary
� Immune System is the Body’s Defense System- 3 lines of defense
� Mucosa-Barrier- New Frontier, � Good- Antimicrobial proteins, IgA, cytokines� Bad-inflammatory cells- leaky gut
� Innate Immunity-� Good-Primary “reactive” defense, necessary for acquired� Bad-leaky gut� Ugly-collateral damage
� Acquired Immunity-� Good- specific immunity, duration� Bad-allergy, chronic inflammation
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Harvey Dunn (1884-1952) Prairie is My Garden, South Dakota Art Museum
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Cattle First, Then PARTY