Institute for Microbiology, Medical Faculty of Masaryk University Institute for Microbiology, Medical Faculty of Masaryk University and St. Anna Faculty Hospital in Brno and St. Anna Faculty Hospital in Brno

Miroslav Votava, Vladana WoznicováMiroslav Votava, Vladana Woznicová

FACTORS OF PATHOGENICITYFACTORS OF PATHOGENICITYAND VIRULENCE – II AND VIRULENCE – II

Lecture for 2nd-year studentsLecture for 2nd-year studentsApril April 2020thth, 200, 20099

Ability to overcome the defence – AAbility to overcome the defence – A

A) Ability to overcome the A) Ability to overcome the innateinnate immunity immunity: :

To To resistresist complement complement to to inhibitinhibit complement activation complement activation to to protectprotect one‘s own surface one‘s own surface

To To resistresist phagocytosis phagocytosis not not to allowto allow being engulfed being engulfed to to survivesurvive inside the phagocyte inside the phagocyte

To To interfere withinterfere with the the cytokine cytokine functionfunction

Ability to resist complementAbility to resist complement

Inhibition of complement activation Inhibition of complement activation capsule – shielding surface molecules capsule – shielding surface molecules (meningococci, pneumococci) (meningococci, pneumococci) activation inhibitors (gonococci – addition of sialic activation inhibitors (gonococci – addition of sialic

acid to terminal acid to terminal saccharidessaccharides, , many many viruses, viruses, E. coli E. coli and and S. pyogenes – S. pyogenes –

production of regulation factor H, production of regulation factor H, S. pyogenes S. pyogenes and and P. aeruginosa P. aeruginosa – – enzymes enzymes splitting C3b a C5a)splitting C3b a C5a)

Protection of the surfaceProtection of the surface (salmonellae and (salmonellae and E. coliE. coli in in S phase, flagella of motile bacteria)S phase, flagella of motile bacteria)

Ability to resist complement Ability to resist complement →→ sseroresistance eroresistance

http://inst.bact.wisc.edu

Ability to resist phagocytosis – IAbility to resist phagocytosis – I

1. 1. NNot to allow being engulfedot to allow being engulfed

inhibitors ofinhibitors of chemotaxischemotaxis (bordetellae, (bordetellae, vaginal anaerobes, pseudomonads)vaginal anaerobes, pseudomonads)

leucocidinsleucocidins and lecithinase (staphylococci, and lecithinase (staphylococci, streptococci, pseudomonads, clostridia)streptococci, pseudomonads, clostridia)

injecting injecting YopYop (yersiniae) (yersiniae)

formation of formation of capsulecapsule ( (mostmost importan important!t!))

agents of meningitis and pneumonia agents of meningitis and pneumonia ((N. meningitidis, H.N. meningitidis, H. influenzae, E. coli, influenzae, E. coli, S.S. pneumoniae,pneumoniae, K. pneumoniaeK. pneumoniae))

http://www.coll-outao.qc.ca

Ability to resist phagocytosis – II Ability to resist phagocytosis – II

2. 2. To survive inside the phagocyteTo survive inside the phagocyte

blockade of phagolysosome formation blockade of phagolysosome formation ((CChlamydia, hlamydia, MMycobacteriycobacteriumum, , LLegionella, egionella, TToxoplasmaoxoplasma) )

escape from phagosome escape from phagosome ((RRickettsia, ickettsia, SShigella, higella, LListeria, isteria, LLeishmania, eishmania, TTrypanosomrypanosomaa))

production of antioxidants production of antioxidants (staphylococci, gonococci, meningococci)(staphylococci, gonococci, meningococci)

markedmarked tenacity tenacity ((CCoxielloxiellaa, , EEhrlichiahrlichia))

Ability to overcome the defence Ability to overcome the defence – B– B

B) B) Ability to overcome the Ability to overcome the acquiredacquired immunity: immunity:

Always an attempt to Always an attempt to avoid antibodiesavoid antibodies or immuneor immune lymphocyteslymphocytes::

to reproduce quickly to reproduce quickly (respiratory viruses, diarrhoeal (respiratory viruses, diarrhoeal agents, agents, malarialmalarial plasmodia) plasmodia)

attempt toattempt to deceive deceive immune systemimmune system

to hide itselfto hide itself

to change one‘s to change one‘s own own antigensantigens

to induce toleranceto induce tolerance

attempt to attempt to suppress immune reactionsuppress immune reaction

Ability to deceive the immune Ability to deceive the immune system – Isystem – I

• To hide itself To hide itself in ganglions in ganglions (HSV, VZV) (HSV, VZV) on intracellular membraneson intracellular membranes (HIV, adenov.) (HIV, adenov.) in infectious focuses in infectious focuses ((M. M. tbctbc, echinococci) , echinococci) in privileged in privileged sites sites (agents of mucosal (agents of mucosal infections, infections, T. T. gondii gondii inin eye, retroviruses eye, retroviruses in cellular in cellular genome)genome)

2. To induce the immune tolerance2. To induce the immune tolerance(CMV, rubella v., leishmaniae, cryptococci, (CMV, rubella v., leishmaniae, cryptococci, maybe even HIV)maybe even HIV)

Ability to deceive the immune Ability to deceive the immune systemsystem – II – II

3. 3. To change antigens of one‘s ownTo change antigens of one‘s own

antigenic mimicry antigenic mimicry ((S. pyogenes, T. pallidum,S. pyogenes, T. pallidum,M. pneumoniaeM. pneumoniae))

antigenic camouflage antigenic camouflage (schistosomes – (schistosomes – blood proteins, staphylococci – protein blood proteins, staphylococci – protein A, A, streptococci – protein G, CMV – streptococci – protein G, CMV – βmG)βmG)

antigenic variability antigenic variability (trypanosomes, (trypanosomes, borreliae, gonococci, influenza virus)borreliae, gonococci, influenza virus)

Ability to deceive the immune Ability to deceive the immune systemsystem – III – III

4. 4. To suppress immune reactionTo suppress immune reactioninvasion into the immune system invasion into the immune system (HIV, m(HIV, measleseasles

virus) virus) interference in cytokine formation interference in cytokine formation ((M. lepraeM. leprae, , protozoa) protozoa) production of production of superantigenssuperantigens (staphylococci, (staphylococci, streptococci) streptococci) production of proteases production of proteases (meningococci, (meningococci, gonococci, haemophili, gonococci, haemophili, pneumococci) pneumococci) binding Fcbinding Fc fragment fragment of IgG of IgG (staphylococci, (staphylococci, streptococci, HSV)streptococci, HSV)? ? (influenza virus, HBV, EBV)(influenza virus, HBV, EBV)

Toxicity – I Toxicity – I

DamageDamage by by direct effect of infectious agent direct effect of infectious agent

Cellular death Cellular death lysis by toxins, viruses, immune lymphocytes lysis by toxins, viruses, immune lymphocytes apoptosis (HSV, shigellae) apoptosis (HSV, shigellae)

Metabolic injury Metabolic injury – influence of exotoxins– influence of exotoxins

Mechanical causes Mechanical causes (schistosomal eggs, (schistosomal eggs, P. jiroveciiP. jirovecii, , pseudomembranes in diphtheria) pseudomembranes in diphtheria)

The most frequent cause of death The most frequent cause of death → → septic shock septic shock triggered by triggered by endotoxinsendotoxins

G G –– : lipopolysaccharide : lipopolysaccharide G + : teichoic acid + peptidoglycan G + : teichoic acid + peptidoglycan

Bacterial exotoxinsBacterial exotoxins

Spreading factors Spreading factors (hyase, DNase, elastase, (hyase, DNase, elastase, collagenase)collagenase)

Cytolysins Cytolysins (lecithinase, sfingomyelinase, (lecithinase, sfingomyelinase, hemolysins)hemolysins)

Inhibitors of proteosynthesis Inhibitors of proteosynthesis (diphtheria toxin)(diphtheria toxin)

Pharmacologically effective toxins Pharmacologically effective toxins (choleragen, (choleragen, E. coli E. coli thermolabile enterotoxin, pertussis toxin)thermolabile enterotoxin, pertussis toxin)

Neurotoxins Neurotoxins (tetanotoxin, botulotoxin)(tetanotoxin, botulotoxin)

Superantigens Superantigens (staphylococcal enterotoxin and (staphylococcal enterotoxin and exfoliatin, streptococcal pyrogenic toxin)exfoliatin, streptococcal pyrogenic toxin)

Toxicity – II Toxicity – II

DamageDamage as a as a result of result of defencedefence reactions reactions

a) a) Injuries caused Injuries caused byby inflammatory reaction: inflammatory reaction: calor, rubor, tumor, dolor, functio laesacalor, rubor, tumor, dolor, functio laesa = typical markers of inflammation = typical markers of inflammation = symptoms of disease = symptoms of disease

edemaedema: : encephalitis, epiglottitisencephalitis, epiglottitis inflammatory infiltrate: inflammatory infiltrate: pneumoniapneumonia suppuration: suppuration: blennorrhoeablennorrhoea neonatorumneonatorum formation of connective tissue: formation of connective tissue: scarringscarring

Toxicity – III Toxicity – III

Injury as a Injury as a result of defence reactionsresult of defence reactions

b) b) Injuries caused Injuries caused by specific immune reaction by specific immune reaction (immunopathological consequences of (immunopathological consequences of hypersensitivityhypersensitivity))

1st type: 1st type: (IgE, anaphylaxis)(IgE, anaphylaxis) helminthoseshelminthoses

2nd type: 2nd type: (cytotoxicity) hepatitis B, febris rheumat.(cytotoxicity) hepatitis B, febris rheumat.

3rd type: 3rd type: (immunocomplexes) poststreptococcal (immunocomplexes) poststreptococcal nephritis, systemic reactions during sepsisnephritis, systemic reactions during sepsis

4th type: 4th type: (late, cellular) tbc, lepra, syphilis, (late, cellular) tbc, lepra, syphilis, actinomycosis, rash in measlesactinomycosis, rash in measles

Recommended reading materialRecommended reading material

Paul de Kruif: Microbe HuntersPaul de Kruif: Microbe Hunters

Paul de Kruif: Men against DeathPaul de Kruif: Men against Death

Axel Munthe: The Story of San MicheleAxel Munthe: The Story of San Michele

Sinclair Lewis: ArrowsmithSinclair Lewis: Arrowsmith

André Maurois: La vie de Sir Alexander FlemingAndré Maurois: La vie de Sir Alexander Fleming

Hans Zinsser: Rats, Lice, and HistoryHans Zinsser: Rats, Lice, and History

Michael Crichton: Andromeda StrainMichael Crichton: Andromeda Strain

Albert Camus: PesteAlbert Camus: Peste

Victor Heisser: Victor Heisser: An American Doctor OdysseyAn American Doctor Odyssey