Download Pathogenicity

Anti-infectious immunity
Prof. Ilona Hromadníková
3rd year of the curriculum
Most frequent causes of death
Most frequent infectious diseases
causing mortality
Role of normal flora in Host Defense
Against Infectious Disease

Presence of normal flora at a body site has
several benefits:
 Major host immune defense
 Primes immune system

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Antibodies produced and cell mediated immunity
stimulates the immune system
Exclusion of potential pathogens

Competition for space and nutrients
Role of Normal Flora in
Infectious Diseases
– usually normal flora but
can cause disease when host is
compromised or normal environment
disturbed
 Trauma (accident or surgery) – NF
introduced to sterile site
 Immunosuppressive disease or drug –
reduce or alter immune response
 Chronic illness in host (i.e., diabetes)
 Opportunists
Pathogenicity and Virulence
Pathogenicity – ability to produce disease
True pathogens – can cause disease in healthy
host; examples: B. anthracis (anthrax),
N. gonorrhoeae, M. tuberculosis (TBC)
 Opportunists – don’t usually cause disease, but
can when host compromised; examples:
S. aureus, S. pneumoniae (meningitis, sepsis,
pneumonia, etc.)
 Modern medical advances allow these
organisms to cause serious infections
 Virulence – degree of harm produced by the
organism in the host
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Humoral (antibody-dependent)
immune response
 Neutralisation
 Opsonisation
 Opsonisation
followed by C activation
 Antibody-dependent cytotoxicity (ADCC) –
NK cells
Neutralisation
 Antibodies
may neutralize the activity of
bacterial exotoxines (Clostridium tetani tetanus a C. botulinum -botulism,
Corynebacterium diphteriae - diphteria)
viruses
other microorganisms
 Mechanisms: blockage of critical epitopes
– prevention of adherence onto the cell
surface or the entrance into the cell
Neutralisation
Opsonisation
 Microorganisms
are coated with antibodies
IgG, IgA (neutrophiles) or IgE
(eosinophiles), those are recognised by
phagocytes via appropriate FcR
C
system activation on antibody-coated
microorganism, phagocytosis of
complement- opsonized particules (C3b)
via CR on phagocytes
Opsonisation
Opsonisation
C system activation – classical pathway

Antibody-coated microorganism, C1 binds to Fc
fragment of IgM or IgG, creation of C3-convertase 
C3a (chemotaxis) and C3b, further C5-convertase
 C5a (chemotaxis) and C5b (membrane attack
complex, cell lysis)
 Phagocytosis of opsonized microorganisms by
neutophiles and eosinophiles via binding of C3b
onto CR3 and CR4 (degradation can be oxygendependent - production of reactive oxygen species
via NADPH-complex, or oxygen-independent)
Lytic phase
complement activation

C5b678(9)n
membrane attack
complex = MAC
(n = 13-18)
Antibody-dependent cell-mediated
cytotoxicity (ADCC)
 Interaction
of NK cells via CD16 (FCR)
with IgG opsonized cell – lysis (perforines,
granzymes) or production of reactive
oxygen metabolites
 Macrophages,
eosinophiles and platelets
participate in cytotoxic mechanisms, when
target cell is too big for phagocytosis
Immunopatologic reaction type II
dependent on IgG and IgM
Immune response against
extracellular bacteria

Toxigenic bacterial infection
Exotoxines – exclusive virulent factors, immune
response against them eliminate sign of infection
(mainly produced by G+ bacteria, less by Gbacteria)
Endotoxines – components of bacteria cell
surface (LPS with toxic Lipid A) in all G-bacteria
Ab amplify phagocytosis or activate C system
Different antigens (polysaccharides) of various
bacteria
Types of bacteria
Endotoxines
complexes of LPS-protein (toxic
Lipid A), in all G- bacteria
Specific bacterial exotoxines
Specific bacterial enzymes
contributing to microbial invasiveness
Encapsulated bacteria

Streptococcus pneumoniae, Neisseria
meningitides, Klebsiella pneumoniae,
Haemophilus influenzae type B
 An
outer covering, a capsule, made
of polysaccharide - antigens

In pathogens contributes to their virulency and
invasivity
 Resistent to phagocytosis. Capsular
polysaccharide inhibits phagocytosis
(macrophages, neutrophiles)
FcR mediated phagocytosis is inefficient
Effective phagocytosis requires both Fc and CR
(C3b a C3bi) opsonisation
Electric Charge and hydrophilicity of
encapsulated bacteria restrict their
phagocytosis
Identification of bacteria by cells of
innate immunity
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Cells of innate immunity express Pattern
Recognition Receptors (PPR) which recognise Pathogen
Associated Molecular Patterns (PAMPs)  stimulation of
phagocytosis or activation of other inflammatory
mechanisms
G- bacteria – LPS ( contains lipid A)- potent activator of
inflammatory immune response
G+ bacteria – peptidoglycan, lipoteichoic acid,
muramyldipeptid
Mycobacteria – component of Freund´s complete
adjuvans – strong stimulation of non-specific and specific
immunity (peptidoglykan, lipoteichoic acid,
lipoarabinomanan)
Yeasts – glucanes of cell wall (mannoproteins)
Interaction of PPR with PAMPs
PPR– membrane and/or soluble
Eradication of extracellular bacteria
and parasites
Opsonization by antibodies
 streptococcus, staphylococcus, Neisseria,
Hemophilus, enteric bacteria –
Salmonella, Shigella, Helicobacter, etc.)
 Entamoeba histolytica, Giardia lamblia
 Further
stimulation of Th1 (cell-mediated
cytotoxicity) and Th2-B lymphocytes
(production of specific IgM, IgG, IgA and
IgE opsonizing antibodies)
Eradication of intracellular bacteria,
fungi and parasites
 Mycobacteria,
Yersinia, Listeria, Brucella
 Candida albicans, Aspergillus,
Pneumocystis carinnii
 Leishmania, Plasmodium, Toxoplasma
gondii, Trypanosoma
by macrophages (iNOS 
bactericidal NO), stimulation of Th1
lympho, mutual co-operation
 Phagocytosis
Eradication of intracellular bacteria,
fungi and parasites

They elude immune system via growing IC - particularly
in phagocytes. T lymho immune response is
fundamental. A result of incomplete eradication of
pathogen is latent, persistent infection

Inducement of delayed-type hypersensitivity (DTH),
characterised by accumulation of senzibilised T lympho
and activated macrophages (activatory role of IFN-)

When escape of pathogen from phagolysosome to
cytoplasm occurs (Listeria) – eradication of infected cells
by Tc
Mycobacteria Species

Cell wall is rich of lipids
 M. tuberculosis (TBC), M. leprae (leprosy), M. avium
(atypic mycobacteria in AIDS)
 Relevant pathogen in AIDS and immunocompromised
patients
 Czech Republic - vaccination against TBC by Bacillus
Calmette-Guérin (BCG) – atenuated strain of M.bovis,
the effectivity is not 100 %
 PPD (Purified Protein Derivate) used for tuberculin skin
test (induration after 48 h.), identification of infected
individuals and/or the status after vaccination, pozitive
reaction does not protect against M. tuberculosis, it gives
only information about the presence of IV. type of
immune reaction
Bacteria Rezistence Mechanisms
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Bacteria generally escape from the destruction in
phagocytes becouse they enter the other cells (epithelial
cells, fibroblasts)
Escape from killing and degradation in phagolysosome
(opsonization after binding to CR only does not activate
bactericidal mechanisms) – St. Aureus, Str. pyogenes,
mycobacteria
Mycobacteria – expression of C3b-like molecules, enter
to macrophages without their activation
Escape from phagosome to cytoplasm – Listeria,
Shigella, Rikettsia, prevention of phagosome-lysosome
fusion (Salmonella)
Leishmania, Coxiella – able to live in low pH
Legionella – converts phagosome into vacuole
Mechanisms of pathogenic
bacteria to inhibit phagocytosis
Transmission of infection by parasites

Direct invasion – transfusion of parasitic worms through
skin (Schistosoma, Ankylostoma, Nematodes Strongyloides stercoralis)

By food – tapeworms, ascarids, pintleworms, some
protozoa (Toxoplasma, Giardia)

By insect
–malaria- mosquitos
–trypanosomes - tse-tse fly
–Trypanosoma cruzi – reduviid bug (Triatoma, Rhodnius)
- Leishmania – transmission of Phlebotoma
Prevalence and distribution of common parasitosis
Types of
helminths
Numbers infected (million)
Intestinal helminthes
Ascaris
1221
lumbricoides
Hookworm spp.[a] 740
Strongyloides
75
stercoralis
Trichuris
795
trichiura
Schistosomes
Schistosoma
67
mansoni
Schistosoma
1
japonicum
Schistosoma
119
haematobium
Filarial parasites
Onchocerca
37
volvulus
Wuchereria
120
bancrofti
Brugia malayi
10
Loa loa
13
Animal parasites[b]
Distribution
Worldwide
Worldwide
Worldwide
Worldwide
South America, Africa
Eastern Asia
Africa
Africa, Central and South America
Worldwide
Asia
Africa
Basic mechanisms of parasitic
pathogen escape
Eradication of Helminths
 Complex
eucaryotic organisms keeping
long-time infection in human hosts lasting
even decades
 Immune
response is mediated by Th2
lymphocytes, IgE mastocytes, basophiles
and eosinophiles
Anti-viral immune response
Course of viral infection
 Overcoming
of barriers
 Entry to the cells (via appropriate receptor)
and virus replication
 Inducement of non-specific immune
mechanisms
 Inducement of specific immune mechanisms
 Memory T and B cells
 Eventually virus perzistence
Paths of virus entry to the human
body
Specific receptors for viruses
Virus tropism to certain cells or host
 CD4
(T lympho and macrophages), coreceptors = receptors for chemokines
CCR-5, interaction of T lympho and
macrophages with gp120 HIV
 EBV – infects B lymphocytes, its receptor
is CD21
 HBV – entry via CD71 (receptor for
transferrin)
Anti-viral immune response
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First line – non-specific immunity - interferons (INF, inhibition of virus replication) and NK cells
Antibodies Th2 – B lympho co-operation
mucous IgA – blockage of adherence onto epithelium
(Respiratory viruses, enteroviruses)
in circulation – neutralisating Ab – IgG and IgM, C
system activation, virus lysis
Tc – eradication of virus- infected cells
Some aggressive viruses may overcome immune
responses and cause severe morbidity and mortality
Immunocompromised individuals (adaptive and native
immunity) suffer from more severe viral infection
Anti-viral immunity

Lifetime perzistence (especially herpetic viruses in nerve
ganglia) re-activation during weakening of IS
EBV – malignancies of haematopoetic system (Hodgkin
lymphoma)
CMV, VzV, HHV-6, HHV-7 – recurrent aphthae
HSV-1 (herpes labialis) - stomatitis herpetica,
gingivostomatis herpetica
virus varicela-zoster– herpes zoster, gingivitis
papilomaviruses – cervix carcinoma, skin tumors
Priones
Discovery - S.B. Prusiner – Nobel prize
Rare, transmissible, fatal, spongiform
neurodegenerative diseases
 Protein infectious particule able to reproduce,
absence of nucleic acids – PrP
 Organismus codes gene for normal protein PrPc, present in normal brain tissue (CNS), heart
and skeletal muscles and other organs,
unknown function, obviously regulation of
ciarcadian rhythm, neuro-muscular synapsis, ion
transport via membrane
 Abnormal infectious protein - PrPSC found in
brains of animals with scrapie (lamb and goats)
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Priones
 PrPc and PrPSC
differ in primary structure
just by 1 aminoacid, however significant
difference in secondary and tertiary
structures, resistent to proteolytic
degradation, creates insoluble aggregates
similarly like amyloid deposits, damage of
nervous tissue via acumulation of
abnormal PrPSC and/or by lack of normal
PrPc
Priones and human diseases
 Creutzfeldt-Jakob
disease (CJD)
 Variant CJD (vCJD)
 Gerstmann-Sträussler-Scheinker disease
similar to CJD,but amyloid deposits in
cerebelum
 Fatal Familial Insomnia – in families with
CJD, neurone loss
 Kuru – tribesmen New Guinea –
cannibalism– Nobel price Dr. Gajdusek
Creutzfeldt-Jakob disease
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Most frequent between diseases caused by
priones
Sporadic form – 87 % - unknown reason, clinical
symptoms after the age of 60 – dementia,
ataxia, myoclonus
Inborn (familial) form – 8 % - mutation in gene
coding PrPc
Transmission by iatrogennic way – 5 % aplication of GF from hypophysis, Tx of cornea,
brain operation, etc.
Neurone loss, astrocyte and microglia
hyperplasia, amyloid deposits
Variant CJD

Breeding of cattle in UK – BSE – Bovinne Spongiforme
Encephalopathie – mad cow disease – transmission from
cattle to man by food, since 1986 sicken 180 thousands of
animals, the brain looks like spondge, loss of muscle
control, dezorientation, death.
Infection – feeding mixture – meat and bone meal –
transmission of scrapie agens (goats) to cattle, now EC
legislation prohibition of nutrition of livestock and fish,
obligation to test cattle for meat for the presence of BSE
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Human form of this disease, so-called variant CreutzfeldtJakob disease (vCJD), in UK death of 90 people
Slower progression of the disease, deterioration of psyche,
parastesia, ataxia, myoclonus, dementia
CNS (basal ganglia), tonzila, spleen, nodules – plaque and
detection of PrPSC