Genetic factors Natural resistance associated macrophage

protein (Nramp) Hormones Stress Nutritional factors Specific chemical factors Free fatty acids Antibacterial peptides & proteins

Natural resistance associated macrophage protein

Nramp gene – Nramp 1 protein Human, mice, sheep, bison , red deer &

cattle Protein expressed only in macrophages Macrophage activation – early step More NO sythase, more phagosome-

lysosome fusion

Stimulation of immunitythyroxinesteroids (low doses)estrogen

Immunosuppressionsteroids (high doses)testosteroneprogesterone

Immunosuppressive Steroids production increase Shipping fever in cattle Horse – Salmonella enteritis

Malnutrition Negative protein balance Vaccination – after decreasing parasite

burden

Antibacterial molecules Lysosyme

◦ In tissues & all body fluids◦ Except in CSF and urine◦ Absent in bovine neutrophil & tears◦ High concentration in egg white◦ Cleaves the bond between NAM and NAG of

peptidoglycans of Gram +ve bacteria◦ In conjunction with C’ can act on Gram –ve

bacteria

Sites of bacterial invasion & acute Inflammation SitesNeutrophils – lysozyme present in some neutrophil granules – accumulation of lysozyme in acute inflammatory areas

Neutrophil lysosomes – high conc. of lysozyme

pH optimum – 3 to 6 Inflammatory Site and phagosomes – pH

easily achieved Potent innate opsonin

Can inhibit bacterial growth Unsaturatted F.As – Bactericidal for

Gram+ve Saturated F.As – fungicidal

Mammalian cells & tissues, > 800 identified so far

Short, cationic peptides (most 29-35 A.As) – rich in lysine & arginine

Interact with microbial PLs, LPS or teichoic acids (host cell protected)

Has the ability to form amphipathic structures◦ Hydrophobic region- insert into lipid rich bacterial

memb.◦ Hydrophillic region – form channel-like pores or cover

the memb. ◦ Membrane disrupting and bacterial death

Cathelicidins (12-80 A.As)– neutrophil granules – antibact. Activity – Eg. Protegrins, novispirin, ovispirin

Serprocidins – antimicobial serine protease – neutrophil primary granules

Granulysins – peptides from NK cells ◦ Antibacterial, also chemo-attractants and activate

macrophages BPI (bactericidal permeability increasing protein)

– primary granules of human & rabbit neutrophils – bind LPS & damage their inner memb.

Calprotectin – in neutrophils, monocytes & macropages and epidermal cells – forms about 60% of neutrophil cytoplasmic protein – released in inflammation

Platelets & Immune complexes interaction – release β lysin – Bacillus anthracis & Clostridia

Equine leukocytes – several cysteine rich peptides – act against bact. Pathogens.

Typical antimicrobial peptides (28 to 42 A.A), produced constitutively or in response to infection, > 50 in mammals

Vertebrate defensins – α, β or θ α defensins: 15% of the total proteins in neutrophil

granules (cattle neutrophils – 13 diff. α defensins produced)

β defensins – expressed in epithelial cells lining the airways, skin, salivary gland and urinary system

θ defensins – circular peptide found only in primate neutrophil

Can kill or inactivate some bact., fungi or enveloped viruses

Some defensins neutralize microbial toxins – toxins from B. anthracis, Corynebacterium diphtheriae, Staph . aureus

Lectins – CH2O binding proteins CH2O-major components of bacterial cell wall Lectins - opsonin or activators of other innate

defenses P-type, S-type and C-type lectins P-type - Pentraxins – 5 protein subunits

arranged in a ring, bind LPS in a Ca2+ dependent manner ◦ include C-reactive protein (CRP), serum amyloid P

(SAP)◦ These are called acute-phase proteins (their blood

levels climb greatly during infections or following trauma)

◦ Activate C’, stimulation of leukocytes, augment the activities of neutrophils, monocytes/macrophages

S-type – Galectins ◦ Mediate binding of leukocytes to extracellular matrix –

have role in inflammation C-type – require calcium to bind to CH2O

◦ Selectins and Collectins◦ Selectins – involved in leukocytes adherence to blood

vessels◦ Collectins – involved in innate immune system

C-terminal domain bind to bacterial CH2O & N terminal domain interact with cells and C’ components

Mammals - Six different collectins – conglutinin, MBL, pulmonary surfactant proteins (SP-A, SP-D), collectin-46, collectin-43

conglutinin, collectin-46, collectin-43 – only in bovidae

A collectin found in serum Has multiple CH2O binding sites Bind to N-acetylglucosamine, mannose, glucose,

galactose and N-acetylgalactosamine Plays important role in activating the C’ system Bind to leukocytes, platelets, endothelial cells and

fibroblasts MBL coated bacteria – readily phagocytosed

through interaction with surface receptors (opsonization)

Collectins are especially important in young animals Congenital deficiency of MBL – in children – highly

susceptible to infections

One of the most imp. Innate factor that determine bacterial invasion - availability of iron

Many pathogenic bacteria require large amounnts of iron for growth - S. aureus, E. coli, B. anthracis, Pasteurella multocida, M. tuberculosis

Host also require iron to survive - Microbe & host compete for iron

Body – iron – found in association with iron binding proteins ◦ Transferrin, Lactoferrin, Haptoglobin, Ferritin & Siderocalin

Bact. Invasion - Iron absorption ceases MΦ – IL-1 –hepatocytes – secrete transferrin

& haptoglobin - ↑incorporation of iron (Liver)

Mammary Gland – bact. Invasion – milk neutrophils – release of stores of lactoferrin

Sequestration of iron Hemolytic anemia – serum iron level ↑ -

more susceptible to bact. Infection

Potent Iron binding proteins (M. tuberculosis, E.coli and B. anthracis) – Siderophores - withdraw iron from serum proteins

Mycobacteria – caroboxymycobactin (siderophore)- remove iron from ferritin

E. coli – enterochelin (siderophore) Mammals – liver, spleen, macrophage –

synthesis Lipocalin 2 (siderocalin) – binds enterochelin with very high affinity