IMMUNITY TO INFECTIONIMMUNITY TO INFECTION

INTERACTION BETWEEN PATHOGEN AND HOSTINTERACTION BETWEEN PATHOGEN AND HOST

Parasitic organisms are of about two third of all speciesthey need to find free space (niche) for their life – appropriate host

Infection is the interaction between pathogen and host,the result of this interaction is more or less expressed clinical signs of disease

pathogenity

virulence

Some pathogen destroy his host, some notacute lytic course of infection with cytopathogenic viruses

chronic - persistent course of infection with noncytopathogenic viruses

VARIABILITY OF PATHOGEN AND HOSTVARIABILITY OF PATHOGEN AND HOST

Variability of pathogenic organisms are given byshort generation time

huge number of progeny

pathogenity and virulence

Variability of host (vertebrates) are given by lymphocytes

Primary variability – genes for TCR, BCR, MHC

Secondary variability – genes for other components of immune system (barriers, nonspecific mechanisms of defence ... )

ABILITY OF HOST TO RESIST TO THE INFECTIONABILITY OF HOST TO RESIST TO THE INFECTION

IMMUNITYresistance to some infections

barriers

nonspecific immunity

specific immunity

SUSCEPTIBILITY IS INCREASED broken barriers

insufficient immunocompetence

immunosuppression or immunodeficiency

allergic, autoimmune or lymphoproliferative diseases

IMMUNITY TO VIRUSESIMMUNITY TO VIRUSES

INTERACTION OF VIRUSES WITH THE IMMUNE SYSTEM

INTERACTION OF VIRUSES WITH THE IMMUNE SYSTEM

Viruses are intracellular pathogens which cannot live outside cells

Interaction with the immune systembinding to the surface receptors

replication in the cell of the immune system

disruption of the antigen presentation pathways

inhibition of the regulatory mechanisms

inhibition of the effectors

immunopathology status

BINDING TO THE SURFACE RECEPTORSBINDING TO THE SURFACE RECEPTORS

receptor of T lymphocytes CD4 - virus HIV, FIV

receptor of B lymphocytes CD21 - EB virus

adhesive receptor ICAM-1 - rhinoviruses

REPLICATION OF VIRUSES INSIDE CELLSREPLICATION OF VIRUSES INSIDE CELLS

cell group virus

macrophage paramyxovirus distemper, respiratory syncytial virus, Newcastle

herpesvirus IBR, Aujezsky disease

parvovirus parvovirosis of dogs, feline panleukopenia

pestivirus BVD-MD, hog cholera, virus PRRS

lentivirus FIV, BIV

B lymphocyte herpesvirus virus EB

birnavirus infectious bursitis of birds

retrovirus FIV, bovine leukosis

T lymphocyte paramyxovirus distemper, BRSV, Newcastle

pestivirus BVD-MD, hog cholera,

herpesvirus Marek´s dis.

lentivirus HIV, FIV, BIV

ESCAPING MECHANISMSESCAPING MECHANISMS

antigen variability

antigen drift and shift

antigen mimicryvirokines

viroreceptors

latent or persistent infection

immunotolerance

DIVERSE VIRAL PROTEINSDIVERSE VIRAL PROTEINS

group of inhibitors effect of inhibitors

mimicry of cytokines virokines

mimicry of receptors viroreceptors

inhibitors of cytokine inhibitors of signal pathways and secretion response inhibitors of cytokine synthesis

inhibitors of transcriptive factors

inhibitors of an antigen inhibitors of antigen presentationrecognizing inhibitors of expression of MHC molecules

IMMUNOPATOLOGICAL PROCESSES CAUSED BY VIRUSES

IMMUNOPATOLOGICAL PROCESSES CAUSED BY VIRUSES

secondary immunodeficiency

lymphoproliferative diseases

immune-complex hypersensitivity

other autoimmune diseases

DEFENCE MECHANISMS AGAINST VIRUSESDEFENCE MECHANISMS AGAINST VIRUSES

NONSPECIFIC

interferons (IFNα, IFNβ)

NK cytotoxicity

SPECIFIC IMMUNITY

cell-mediated cytotoxicity (Tc)

regulatory cytokines (IFNγ, TNFα)

ADCC, neutralizing antibodies

antibodies on mucous surfaces

INTERFERON VIRAL ds RNA

inactiveproteinkinasis

activePK P1

inactive

2´5 oligo -

adenylatsyntetasis

active2´5´OAS

activeRNAasis L

inactive

RNAsis L

MECHANISMS OF INTERFERON EFFECTS

elf2

fosforylated

elf2

VIRAL INHIBITION

15

0

0

5 10days after infection

%a

cti

vit

yti

100

75

50

25

clinical signs

DYNAMICS OF ACUTE VIRAL INFECTION

DYNAMICS OF CHRONIC INFECTION (HIV)DYNAMICS OF CHRONIC INFECTION (HIV)

antibodyCD4+

virus

months

ARCVIREMIC AIDS

level of detection

ASYMPTOMATIC

Virus of Porcine reproductive and respiratory syndrome

Virus of Porcine reproductive and respiratory syndrome

Small ssRNA virus, family Arteriviridae

Pathogen of reproductive and respiratory tract

2 types of strains – American and European, only 60% similarity of genome, but similar clinical signs

Problematic vaccination, marked modulation of immune response by virus

Immune responseImmune response

Antibodies can be detected from day 5-7 post infection, seroconversion from day 14

IgG reach maximal levels after 21-49 days PI.

These antibodies are targeted to non-structural protein nsp2 and they are not associated with neutralization.

Neutralizing antibodies against glycoprotein GP5 can be detected from 4th week PI.

Cellular response cannot be detected before 4th week PI and it is associated with IFN-γ production

Modulation of immunity by PRRSVModulation of immunity by PRRSV

It suppresses production of IFN-α

It increases production of IL-10

It down-regulates MHC-I and MHC-II expression on macrophages and dendritic cells

big role in development of secondary bacterial infections mainly respiratory tract

Antibodies as „Trojan horse“Antibodies as „Trojan horse“

Antibodies against nsp2 whose are not associated with neutralisation serve to so called antibody-dependent enhancement and they serve to easier macrophage infection.

ParvovirosisParvovirosis

oral way of infection

replication in tonsils

hematogenic way (viremia) into fast dividing cells – lymph nodes, intestinal crypts, bone marrow

intestinal form – destruction of intestinal crypts, bloody diarrhea, vomiting, dehydratation, translocation of intestinal microflora into blood – sepsis

cardiac form – uteral infection of early postnataly, necrosis of myocard with mononuclear infiltrate

protection by colostral immunity + pup vaccination

CoronavirosisCoronavirosisoral way of infection

virus is acidorezistent – it survives in stomach

infection of upper part of villi in small intestine –matured enterocytes

without viremia

clinical signs: 1-14 day-lasting smelling mild diarrhea, mostly non-bloody

protection by lactogenic or

locally produced IgA

IMMUNITY TO EXTRACELLULAR BACTERIA

IMMUNITY TO EXTRACELLULAR BACTERIA

CHARACTERISTICS OF EXTRACELLULAR BACTERIAL INFECTIONS

CHARACTERISTICS OF EXTRACELLULAR BACTERIAL INFECTIONS

Invasive bacteria

They invade into tissues, develop local inflammatory reaction, often of purulent - pyogenic character

After invasion into blood stream, sepsis can occur.

After massive destruction of bacteria, lipopolyccharide from cell walls releases and gives rise to endotoxin shock

Non-invasive bacteria

They stay on the mucous surfaces, those can colonize.

They usually produce exotoxins.

ESCAPE AND IMMUNOSUPPRESSIVE MECHANISMSESCAPE AND IMMUNOSUPPRESSIVE MECHANISMS

antigenic variability (Naisseria, Enterobacteriaceae…)

antigenic mimicryM protein from Staphylococcus pyogenes is similar to myocardium -developing of autoimmunity

effect of superantigensstaphylococcus produces superantigens leading to polyclonal activation of T lymphocytes, overproduction of IL-2 clinical signs of gut poisoning

inhibition of phagocytosiscapsule and other structures

inhibition of complement cascadeinactivation of selected components

blocking of attachment of MAC on bacterial surface

DEFENCE MECHANISMS AGAINST EXTRACELLULAR BACTERIA

DEFENCE MECHANISMS AGAINST EXTRACELLULAR BACTERIA

NON-SPECIFIC

phagocytosis

activation of complement via alternative or lectine pathway

SPECIFIC

based on antibody (Th2)

opsonisation of bacteria (IgM, IgG)

activation of complement via classical pathway

blocking of adherence to mucosal surfaces (IgA)

Actinobacillus pleuropneumoniaeActinobacillus pleuropneumoniae

G-, family Pasteurelaceae

Obligatory pathogen of pig respiratory tract

16 serotypes

Differences in virulence between serotypes

They differ in Apx-toxins production

Peracute to chronic course

PathogenesisPathogenesis

Crucial importance of mucocilliary removing of bacteria (a role of microclimate)

Phagocytosis by PMN and macrophages

App produces proteins with proteolytic activity (degradation of antibodies ?)

Surviving inside of macrophage – LPS, capsule, dismutase, ammonia (inhibition of phagosome –lysosome fusion, increase of pH)

PathogenesisPathogenesis

Role of Apx-toxins from suppression of chemotaxis and ingestion to toxic impact on alveolar macrophage

Resistance to complement – role of LPS a capsule

Tissue damageTissue damage

Cytotoxic effect of Apx-toxins and role of LPS

Development of inflammatory reaction, production of pro-inflammatory cytokines – IL1, IL8

Influx of neutrophils and production of oxygen intermediates

Activation of complement

Production of Apx toxinsProduction of Apx toxins

activity

toxin hemolytic cytotoxic serotypes

Apx I + + + + + + 1, 5, 9, 10, 11

Apx II + + + all but 10

Apx III 0 + + + 2, 3, 4, 6, 8

Apx IV + ? all

Escherichia coliEscherichia coliG-, family Enterobacterieceae

Obligatory pathogen of intestine

Serogroups differ in expression of adhesive molecules

They differ in production of toxins

Watery diarrhea during first week after weaning

PathogenesisPathogenesis

Colonization of small intestine – factor of virulence, exampl. F4 (K:88) or F18 – crucial role of IgA

Production of toxins – termostabile (ST) and termolabile (LT) toxins, production of hemolysins, presence of flagellas (TLR5).Mainly LT – activation of adenylat-cyclase, followed by activation of chlorine channel and lost of Cl- and water

Staphylococcus aureusStaphylococcus aureus

G+, family Staphylococcaceae

Obligatory pathogen responsible for several toxin-associated or suppurative infections of different tissues – joints, bones, endocard, skin, lung

50 factors of virulence and frequent resistance to ATB

Factors of virulenceFactors of virulence

Polysaccharide capsule and cell wall – biofilms creation, resistance to phagocytosis, adherence to collagen, fibronectin, fibrinogen. Wall consists from lipoteichic acid and peptidoglycan which react with TLR2.protein A – adherence to von Willebrant factor, interference with Ig molecule.Exotoxins able to lyse cells, ex. hemolysins or pore-forming toxins.Exotoxins as superantigens:

• TSST – toxic shock syndrome toxin• staphylococcal enterotoxins• both stimulate T-lymphocytes to production of Th1 and

proinflammatory cytokines.

IMMUNITY TO INTRACELLULAR BACTERIA

IMMUNITY TO INTRACELLULAR BACTERIA

CHARACTERISTICS OF INTRACELLULAR BACTERIAL INFECTIONS

CHARACTERISTICS OF INTRACELLULAR BACTERIAL INFECTIONS

Intracellular bacteria have genes responsible for pathogenicity clustered in so called virulence islands

Based on intensity of dependence on host cell, they can be divided into:

facultative intracellular (Salmonella, Brucella, Yersinia, Mycobacterium, Listeria)

obligatory intracellular (Chlamydia, Ricketsia, Coxiella, Ehrlichia)

Some infections with intracellular bacteria are persistent and chronic with a granulomatous inflammatory reactions

formation of granuloma is example of a tissue damage by immune mechanisms

ESCAPE AND IMMUNOSUPPRESSIVE MECHANISMSESCAPE AND IMMUNOSUPPRESSIVE MECHANISMS

They are associated with different phasis of phagocytosis

interaction in phase of adherencemycobacteria enter into macrophages via CR1, CR3

inhibition of fuses of lysosomes with phagosomestypical for Mycobacterium, Chlamydia

escape from phagolysosome into a free cytoplasmdescribed by Listeria monocytogenes

rezistention to lysosomal enzymessurface leaflets (Mycobacterium, Salmonella) decrease effects of enzymes

DEFENCE MECHANISMS AGAINST INTRACELLULAR BACTERIA

DEFENCE MECHANISMS AGAINST INTRACELLULAR BACTERIA

NON-SPECIFIC

phagocytosis

γδ T lymphocytes

mast cells, TNFα, histamine

SPECIFIC

cellular type (Th1)

interferon activated macrophages

delay type of hypersensitivity

MycobacteriaMycobacteria

family Mycobacteriaceae, G+, aerobic

bacterial wall without cellular membrane

wall is stronger than in other bacteria

wall is hydrofobic, „waxy“, rich in mycolic acid and peptidoglycan, bound together by arabinogalactan

presence of lipoarabinomannan

1-outer lipids, 2-mycolic acid, 3-polysaccharides (arabinogalactan),

4-peptidoglycan, 5-plasma membrane, 6-lipoarabinomannan (LAM),

7-phosphatidylinositol mannoside, 8-cell wall skeleton

MycobacteriaMycobacteria

long cultivation

non-producing toxins, factor of virulence is their ability to survive inside macrophages

infection through mucosal surfaces or skin, creation of granuloma

NK

Th0

Th1

activated macrophage

LYSIS OF BACTERIA

mycobakteria

bacteria surviving in cell

antigen presenting cell

Intravital diagnosisIntravital diagnosis

antibody

cellular immunity:

- detection of interferon-gamma

- hypersensitivity of type IV – tuberculination

intradermal application of 0.1 ml

evaluation after 72 hours

+ when increase of thickness is more than 4 mm

ParatuberculosisParatuberculosis

M.avium subsp. paratuberculosis

infection of calves (by colostrum?)

intermitten shedding without clinical signs

development of Th1 response

suppression of Th1 response -stress?, production?, gravidity?

massive shedding, diarrhoe, emaciation

SalmonellaSalmonella

G-, nonsporulating, facultative anaerobic, Enterobacteriaceae

oral way of infection, infection of enterocytes (during 10 min), after 1-3 h in lamina propria

factors of virulence – SPI (salmonella pathogenicity island), exam. SPI-1 is important for invasion of nonphagocyting cells, SPI-2 for interaction with macrophage

creation of salmonella containing vacuole

IMMUNITY TO INTRACELLULAR PARASITES

IMMUNITY TO INTRACELLULAR PARASITES

INTRACELLULAR PROTOZOA AND IMMUNE SYSTEM

INTRACELLULAR PROTOZOA AND IMMUNE SYSTEM

Characterisation of invasionthey attack cells - macrophages, but also enterocytes, erytrocytes etc.

complicated life cyclus with many hosts

Escape and immunosuppressive mechanismssequestration of antigens

inhibition of phagocytosis (block of phagolysozome formation)

immunosuppression (for example by production of IL-10)

Defence of hostNK cells, γδ T lymphocytes

Th1 type of response - activation of macrophages (IFNγ)

direct cytotoxicity of Tc lymphocytes

ToxoplasmaToxoplasma

unicellular parasite, Apicomplexainfection of all cellsrecognition via TLR (?), TLR-11 (?)active penetration, creation of „parasitoforming vacuole“, which does not fuse with lysosomeproduction so called ROP proteins influencing function of infected cell, exam. ROP16 downregulates production of pro-inflammatory cytokines by macrophagehost produce Th1 cytokines (IFN-g, IL-2, IL-12), stimulating macrophages, Tc and NK

Toxoplasma and gravidityToxoplasma and gravidity

gravidity is associated with increased concentration of hormones – mainly progesterone

it suppresses production of IL-12, NO, increases production of IL-10 and reduces activity of NK-cells

gravidity increases susceptibility to infection

T. gondii can infect trophoblast, eye, brain

possibility of intrauteral infection (?)

reactivation of infection (?)

PARASITIC PROTOZOA

IL-12TNFα

IFNγ

IFNγ

IL-1IL-15

macrophage

NK cell INTRACELLULARKILLING

γδT lymphocyteLYSIS OF INFECTEDCELL

IFNγ

TNFα

IMMUNITY TO EXTRACELLULAR PARASITES

IMMUNITY TO EXTRACELLULAR PARASITES

EXTRACELLULAR PROTOZOA AND IMMUNE SYSTEM

EXTRACELLULAR PROTOZOA AND IMMUNE SYSTEM

Characterisation of invasion

they live extra host cells, often in blood

Escape and immunosuppressive mechanisms

antigenic variability - example of trypanosoma - express only one variety of Variant Surface Glykoprotein (VSG), resistence to complement

non-specific immunosuppression - macrophages, polyclonal activation of B-lymphocytes

Defence of host

based on antibody production TH2

opsonisation for Kupfer´s cells

IMMUNITY TO HELMINTESIMMUNITY TO HELMINTES

HELMINTES AND IMMUNE SYSTEMHELMINTES AND IMMUNE SYSTEM

Characterisationmulticellular organisms

many different species with different level of pathogenesis

Escape and immunosuppressive mechanismsantigenic variability

antigenic mimikry

immunosuppression

Defence of hostinflammatory reaction

hypersenzitivity of 1st type - IgE, mast cells, eosinophils, histamine

cellular cytotoxicity dependent on antibodies (ADCC)

DEVELOPMENT OF IMMUNE REACTION AGAINST HELMINTES

DEVELOPMENT OF IMMUNE REACTION AGAINST HELMINTES

contact of mast cells or eosinophils with parasite

production of IL-4 - differentiation of Th2 lymphocytes

stimulation and proliferation of specific clone B lymphocytes

cytokine switch to IgE is under influence of IL-4

IgE occupate Fc receptors on basophils and started hypersensitive reaction I.typu

activation of eosinophils to phagocytosis and ADCC is under influence of IL5

eosinophils neutrophil

macrophges

trombocytes

SCHISTOSOMULUM

C3b C3b

C3b

IMMUNITY TO FUNGIIMMUNITY TO FUNGI

FUNGI AND IMMUNE SYSTEMFUNGI AND IMMUNE SYSTEM

Bovine trichophytosis is mycotic cutaneous disease caused by dermatophyte Trichophyton verrucosum.

Highly contagious disease with potential transmission to humans.

Conidia can survive in environment – direct contact is not necessary.

FUNGI AND THE IMMUNE SYSTEMFUNGI AND THE IMMUNE SYSTEM FUNGI AND THE IMMUNE SYSTEMFUNGI AND THE IMMUNE SYSTEM

It is supposed that cell-mediated immunity plays key role in a defense against the disease.

For recovery from the disease, inflammatory reaction is crucial.