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

PATHOGENESISPATHOGENESISOF INFECTION – IOF INFECTION – I

Lecture for 2nd-year studentsLecture for 2nd-year studentsMay 4May 4tthh, 200, 20099

What is the pathogenesis?What is the pathogenesis?

Pathogenesis: Pathogenesis: explains explains the origin and the origin and development of pathological symptomsdevelopment of pathological symptoms

What does the What does the pathogenesis ofpathogenesis of infection infection include?include?

• Way of Way of spreading the agent spreading the agent through through macroorganismmacroorganism

• Mechanisms of Mechanisms of defence defence against it;against it;• Actual Actual causes of symptoms:causes of symptoms:

a) either directly thea) either directly the infectious agent, infectious agent,

b)b) or the reaction or the reaction ofof macroorganismmacroorganism to itto it

Spreading of agent through the Spreading of agent through the macroorganismmacroorganism

Portal of entry Portal of entry (skin, mucosae, placenta)(skin, mucosae, placenta) →→→ → sites of primary multiplicationsites of primary multiplication::

portal of entry vicinity portal of entry vicinity regional lymphatic nodes regional lymphatic nodes

→ → actual spreadactual spread (dissemination of agent): (dissemination of agent): by means of lymph, blood, per by means of lymph, blood, per continuitatem, along nervescontinuitatem, along nerves

→ → target organtarget organ: : typically in viral diseasestypically in viral diseases→ → sites of elimination from sites of elimination from macroorganismmacroorganism: :

may not be the same as portal of entrymay not be the same as portal of entry

PPORTAL OF ENTRYORTAL OF ENTRY

Respiratory tract mucosaRespiratory tract mucosa

LungsLungs

GastrointestinalGastrointestinal tract mucosa tract mucosa

SkinSkin andand hypodermis hypodermis

UrogenitalUrogenital tract mucosa tract mucosa

ConjunctivaConjunctiva and cornea and cornea

PlacentaPlacenta

Respiratory tract mucosa – IRespiratory tract mucosa – I

Nose and nasopharynx: Nose and nasopharynx: respiratory viruses respiratory viruses ((rhinoviruses,rhinoviruses, coronavirusescoronaviruses, adenov, adenov..), ), HSV, viruses of exanthematic infections HSV, viruses of exanthematic infections (measles, rubella, chickenpox), amoebae (measles, rubella, chickenpox), amoebae ((Naegleria , Acantamoeba, BalamuthiaNaegleria , Acantamoeba, Balamuthia))

Secondary bacterial agents:Secondary bacterial agents: Haemophilus Haemophilus influenzae, Strept. pneumoniae, Staph. influenzae, Strept. pneumoniae, Staph. aureus, Moraxella catarrhalisaureus, Moraxella catarrhalis

ChronicChronic infections: ditto + infections: ditto + Klebsiella Klebsiella pneumoniae, K. rhinoscleromatispneumoniae, K. rhinoscleromatis

Respiratory tract mucosaRespiratory tract mucosa – II – II TonsilTonsilss and pharynx: and pharynx: respiratory viruses, respiratory viruses,

EBV, coxsackieviruses A; EBV, coxsackieviruses A; Str. pyogenesStr. pyogenes, other , other β-hemolytic β-hemolytic streptoc., streptoc., S. pneumoniae, S. aureus, H. S. pneumoniae, S. aureus, H. influenzae, Neisseria meningitidis, N. influenzae, Neisseria meningitidis, N. gonorrhoeae, Arcanobacterium gonorrhoeae, Arcanobacterium haemolyticum, Corynebacterium haemolyticum, Corynebacterium diphtheriae; diphtheriae; Candida albicans; Candida albicans; Toxoplasma gondiiToxoplasma gondii

Epiglottis: Epiglottis: Haemophilus influenzae Haemophilus influenzae type btype b

Respiratory tract mucosaRespiratory tract mucosa – III – III Larynx and trachea: parainfluenza viruses, Larynx and trachea: parainfluenza viruses,

influenza viruses,influenza viruses, RSV, adenoviruses; RSV, adenoviruses; ChlamydChlamydophilaophila pneumoniaepneumoniae, Mycoplasma pneumoniae, , Mycoplasma pneumoniae, Corynebacterium diphtheriaeCorynebacterium diphtheriae

Secondarily: Secondarily: S. aureus, H. influenzaeS. aureus, H. influenzaeBronchi: Bronchi: influenza v., adenoviruses, RSV, influenza v., adenoviruses, RSV,

parainfluenza v., RSV; parainfluenza v., RSV; M. pneumoniae, M. pneumoniae, Ch. pneumoniae, Ch. pneumoniae, BordetellaBordetella pertussispertussis

Sec.: Sec.: S. pneumoniae, H. influenzae, S. pneumoniae, H. influenzae, S. aureus, Moraxella catarrhalisS. aureus, Moraxella catarrhalis

Bronchioles: RSVBronchioles: RSV

nasopharyngeal, laryngeal swab

Lungs Lungs Bronchopneumonia: Bronchopneumonia: S. pneumoniae, S. aureus, S. pneumoniae, S. aureus,

H. influenzae; Legionella pneumophila, K. H. influenzae; Legionella pneumophila, K. pneumoniaepneumoniae, E. coli, Pseudomonas aeruginosa; , E. coli, Pseudomonas aeruginosa; Francisella tularensis, Yersinia pestis Francisella tularensis, Yersinia pestis

Atypical pneumonia: Atypical pneumonia: M. pneumoniae, M. pneumoniae, influenza influenza virus A, virus A, Ch. pneumoniaeCh. pneumoniae; ; Chlamydia psittaci Chlamydia psittaci (ornithosis)(ornithosis), Coxiella burnetii , Coxiella burnetii (Q fever);(Q fever); Pneumocystis jirovecii, Pneumocystis jirovecii, CMV, atypical CMV, atypical mycobacteria, mycobacteria, Nocardia asteroidesNocardia asteroides

Subacute and chronic pneumonia: anaerobesSubacute and chronic pneumonia: anaerobes ((Bacteroides fragilis, Peptostreptococcus, Bacteroides fragilis, Peptostreptococcus, PrevotellaPrevotella), ), Mycobacterium tuberculosisMycobacterium tuberculosis

Gastrointestinal tract mucosaGastrointestinal tract mucosaOral cavity: HSVOral cavity: HSV, , Candida albicansCandida albicans

Oesophagus: Oesophagus: CMV, CMV, C. albicansC. albicans

Stomach: Stomach: Helicobacter pyloriHelicobacter pylori

Small intestine: Small intestine: Campylobacter jejuni, Campylobacter jejuni, salmonellaesalmonellae (incl. (incl. Salmonella Salmonella Typhi),Typhi), ETEC, EPEC etc., ETEC, EPEC etc., Yersinia Yersinia enterocolitica, Vibrio choleraeenterocolitica, Vibrio cholerae; ; enterovirusesenteroviruses (polio!), (polio!), rotaviruses,rotaviruses, noroviruses; noroviruses; Giardia lamblia, Giardia lamblia, Cryptosporidium parvum; Cryptosporidium parvum; tapeworms, pinworms, tapeworms, pinworms, roundworms, flukes etc.roundworms, flukes etc.

Large intestine and rectum:Large intestine and rectum: ShigellaShigella sonneisonnei (bacterial dysentery),(bacterial dysentery), Entamoeba histolytica Entamoeba histolytica (amoebic dysentery)(amoebic dysentery)

Urogenital tract mucosaUrogenital tract mucosa

Classic venereal infections: Classic venereal infections: NeisseriaNeisseria gonorrhoeaegonorrhoeae ((gonorrhoea),gonorrhoea), Treponema Treponema pallidumpallidum (syphilis),(syphilis), Haemophilus ducreyiHaemophilus ducreyi (chancroid), (chancroid), Klebsiella Klebsiella granulomatisgranulomatis (granuloma inguinale),(granuloma inguinale), Chlamydia Chlamydia trachomatis trachomatis L1-L3L1-L3 (lymphogranuloma venereum) (lymphogranuloma venereum)

Other sexually transmitted diseases (STD): Other sexually transmitted diseases (STD): Ch. Ch. trachomatis trachomatis D-K,D-K, Mycoplasma hominis, Mycoplasma hominis, Ureaplasma urealyticum; Ureaplasma urealyticum; papillomaviruses,papillomaviruses, HBV, HBV, HCV, HSV-2, HIV-1; HCV, HSV-2, HIV-1; CandCandidaida albicans; albicans; TrichomonasTrichomonas vaginalisvaginalis

Conjunctiva and corneaConjunctiva and cornea

Conjunctiva: Conjunctiva: Strept. pneumoniaeStrept. pneumoniae, S. aureus, , S. aureus, H. influenzae, Moraxella lacunata; Chlam. H. influenzae, Moraxella lacunata; Chlam. trachomatis trachomatis D-K, D-K, N. gonorrhoeae;N. gonorrhoeae; adenovirusesadenoviruses (types (types 3, 3, 88, 19), , 19), enenteroviruses (typeteroviruses (type 70), HSV70), HSV

Cornea: Cornea: S. aureus, Strept. pneumoniae, S. aureus, Strept. pneumoniae, P. aeruginosa; Acanthamoeba castellanii;P. aeruginosa; Acanthamoeba castellanii; Bacillus cereus;Bacillus cereus; oportunistically oportunistically pathogenic moulds; pathogenic moulds; HSVHSV, VZV, , VZV, adenoviruses (adenoviruses (type type 8)8)

Skin and hypodermis – I Skin and hypodermis – I Intact skin: Intact skin: leptospirae, larvae of hookworms leptospirae, larvae of hookworms

((Ancylostoma duodenale, Necator americanusAncylostoma duodenale, Necator americanus) ) and and Strongyloides stercoralisStrongyloides stercoralis, , cercariae cercariae of of schistosomes, bilharziellae and trichobilharziae schistosomes, bilharziellae and trichobilharziae (swimmers itch)(swimmers itch)

Small cracks in skin:Small cracks in skin: S. aureus, S. pyogenes,S. aureus, S. pyogenes, Bacillus anthracis, F. tularensis, Rickettsia Bacillus anthracis, F. tularensis, Rickettsia prowazekii; prowazekii; wartwart viruses, milker´s nodes v., viruses, milker´s nodes v., cowpox virus; cowpox virus; dermatophytesdermatophytes

Bite of arthropods:Bite of arthropods: arboviruses;arboviruses; borreliae, borreliae, ehrlichiae, rickettsiae, coxiellae, bartonellae, ehrlichiae, rickettsiae, coxiellae, bartonellae, Yersinia pestisYersinia pestis; plasmodia, trypanosomes, ; plasmodia, trypanosomes, leishmaniae and others)leishmaniae and others)

Skin and hypodermisSkin and hypodermis – II – II

Wounds: Wounds: S. aureus, S. pyogenes, Clostridium S. aureus, S. pyogenes, Clostridium tetani,tetani, gas gangrene clostridia, coagulase gas gangrene clostridia, coagulase negative staphylococci etc.negative staphylococci etc.

Wounds and bites by animals:Wounds and bites by animals: rabiesrabies v.,v., Spirillum minus,Spirillum minus, Pasteurella multocidaPasteurella multocida, , Capnocytophaga canimorsus, S. aureus, Capnocytophaga canimorsus, S. aureus, Streptobacillus moniliformis; Streptobacillus moniliformis; Erysipelothrix Erysipelothrix rhusiopathiaerhusiopathiae, Burkholderia pseudomallei, Burkholderia pseudomallei

Burns: Burns: Pseudomonas aeruginosa,Pseudomonas aeruginosa, pyogenic pyogenic coccicocci

http://www.textbookofbacteriology.net

Skin and hypodermisSkin and hypodermis – III – III

Wounds in water: Wounds in water: Pseudomonas aeruginosa, Pseudomonas aeruginosa, AeromonasAeromonas hydrophilahydrophila; ; Vibrio vulnificus, Vibrio vulnificus, V. parahaemolyticus, V. parahaemolyticus, MycobacteriumMycobacterium marinummarinum

Wounds in the tropics: Wounds in the tropics: Dermatophilus Dermatophilus congolensis, Rhodococcus equi, congolensis, Rhodococcus equi, Mycobacterium ulcerans, Mycob. marinum; Mycobacterium ulcerans, Mycob. marinum; Sporothrix schenckii Sporothrix schenckii and many other and many other micromycetesmicromycetes

PlacentaPlacenta

Congenital infectionsCongenital infections

Viral: rubella v.Viral: rubella v. (Rubivirus(Rubivirus), parvovirus B19 ), parvovirus B19 ((ErythrovirusErythrovirus), ), cytomegaloviruscytomegalovirus (CMV), (CMV), varicella-zoster v. (VZV), herpes simplex v. varicella-zoster v. (VZV), herpes simplex v. (HSV)(HSV)

Bacterial: Bacterial: TreponemaTreponema pallidum, Listeria pallidum, Listeria monocytogenesmonocytogenes

Parasitic: Parasitic: ToxoplasmaToxoplasma gondiigondii

SSPREADINGPREADING

http://www.wyrebc.gov.uk

Spreading by means of lymphSpreading by means of lymphsskinkin →→ regional regional lymphatic nodes: lymphatic nodes: pyogenic cocci, pyogenic cocci,

F. tularensis, Y. pestisF. tularensis, Y. pestis; arboviruses; arbovirusesoropharynx, tonsilsoropharynx, tonsils →→ cervical nodes: cervical nodes: S. S.

pyogenes, C. diphtheriae, M. tuberculosis, pyogenes, C. diphtheriae, M. tuberculosis, anaerobes (anaerobes (Actinomyces israeliActinomyces israeli, , PrevotellaPrevotella), ), T. gondiiT. gondii

llungsungs →→ hilar nodes: hilar nodes: M. tbc, B. anthracis, M. tbc, B. anthracis, other respiratory pathogensother respiratory pathogens

genital mucosagenital mucosa →→ inguinal nodes: inguinal nodes: Treponema Treponema pallidum, Ch. trachomatis pallidum, Ch. trachomatis L1-L3L1-L3, H. ducreyi, H. ducreyi

Peyer plaquesPeyer plaques →→ mesenteric nodes: mesenteric nodes: Yersinia Yersinia enterocoliticaenterocolitica, enteric adenoviruses, , enteric adenoviruses, enterovirusesenteroviruses

Spreading by means of bloodSpreading by means of bloodAgents of all generalized infections: Agents of all generalized infections:

exanthematic viruses, enteroviruses, exanthematic viruses, enteroviruses, arboviruses, arboviruses, Treponema pallidum, Treponema pallidum, Salmonella Salmonella Typhi and many othersTyphi and many others

Agents of pneumonia commonly appear in Agents of pneumonia commonly appear in blood: blood: especially especially Strept. pneumoniaeStrept. pneumoniae

More rarely agents of other systemic and local More rarely agents of other systemic and local infections: infections: during meningitis, pyelonephritis during meningitis, pyelonephritis (urosepsis), suppurating wounds and (urosepsis), suppurating wounds and suchlikesuchlike

http://www.msevans.com

Spreading Spreading per continuitatemper continuitatemFrom cell to cell: From cell to cell: HSV, RSV, listeriae, yersiniaeHSV, RSV, listeriae, yersiniae

By means of secretion down the mucosa: By means of secretion down the mucosa: agents of agents of respiratory, enteric and urogenital infectionsrespiratory, enteric and urogenital infections

From the site of arthropod biting to its vicinity: From the site of arthropod biting to its vicinity: arboviruses, arboviruses, Borrelia burgdorferiBorrelia burgdorferi

From the wound to adjacent tissue: From the wound to adjacent tissue: Streptococcus Streptococcus pyogenes, Clostridiumpyogenes, Clostridium perfringensperfringens

From the middle ear to meninges: From the middle ear to meninges: S. pneumoniae, S. pneumoniae, Haemophilus influenzae Haemophilus influenzae type btype b

From lungs to pleura:From lungs to pleura: agents of pneumonia agents of pneumonia

Spreading along nervesSpreading along nerves

Either Either axonallyaxonally (within nerve fibres), or by (within nerve fibres), or by

progressive progressive infection of Schwann sheathinfection of Schwann sheath

HSV, VZV, B-virus, rabies virusHSV, VZV, B-virus, rabies virus

Mycobacterium lepraeMycobacterium leprae

Naegleria fowleriNaegleria fowleri

tetanic toxintetanic toxin

EELIMINATIONLIMINATION

Elimination of agent from the bodyElimination of agent from the body

From the mucosa of From the mucosa of respiratory tract respiratory tract and oral cavity, and oral cavity, intestine, intestine, urogenital tract, urogenital tract,

eye eye

From skin lesionsFrom skin lesions

By means of urineBy means of urine

From bloodFrom blood

Elimination from respiratory tractElimination from respiratory tract

Sneezing: Sneezing: in particular agents of common cold in particular agents of common cold (rhinoviruses, coronaviruses), (rhinoviruses, coronaviruses), fromfrom bacteria bacteria e.g.e.g. Neisseria meningitidis Neisseria meningitidisCoughing: Coughing: other respiratory viruses (primarily influenza other respiratory viruses (primarily influenza virus), virus), exanthematic viruses (VZV, morbilli virus, exanthematic viruses (VZV, morbilli virus, rubella virus), rubella virus), N. meningitidisN. meningitidis, , B. pertussis, M. tuberculosis, B. pertussis, M. tuberculosis, Y. pestisY. pestis

Elimination from alimentary tractElimination from alimentary tract

Saliva:Saliva:

HSV, EBV, mumps virus, HSV, EBV, mumps virus, Str. pyogenesStr. pyogenes

Stool:Stool:

enteroviruses (incl. poliovirus), HAV, HEVenteroviruses (incl. poliovirus), HAV, HEV

salmonellae incl. salmonellae incl. S. S. Typhi, shigellae, EPEC, Typhi, shigellae, EPEC, ETEC etc., ETEC etc., V. cholerae, C. difficileV. cholerae, C. difficile

Entamoeba histolytica, Giardia lambliaEntamoeba histolytica, Giardia lamblia

Ascaris lumbricoides, Taenia saginataAscaris lumbricoides, Taenia saginata

Elimination from urogenital tractElimination from urogenital tract

From diseased mucosae:From diseased mucosae:

Agents of classic venereal infections: in Europe Agents of classic venereal infections: in Europe N. gonorrhoeae, T. pallidumN. gonorrhoeae, T. pallidum

Agents of other sexually transmitted diseases Agents of other sexually transmitted diseases (STD): (STD): C. trachomatis C. trachomatis D-K,D-K, papillomaviruses, papillomaviruses, HSV-2HSV-2

By means of urine:By means of urine:

Salmonella Salmonella TyphiTyphi

Congenital infections (rubella virus, CMV) Congenital infections (rubella virus, CMV)

Exotic viruses of hemorrhagic fevers (Ebola)Exotic viruses of hemorrhagic fevers (Ebola)

Elimination from skin lesionsElimination from skin lesions

Staphylococcus aureus Staphylococcus aureus

Streptococcus pyogenesStreptococcus pyogenes

Varicella-zoster virus (agent of chickenpox Varicella-zoster virus (agent of chickenpox and shingles)and shingles)

Papillomaviruses (agents of warts)Papillomaviruses (agents of warts)

Dermatophytes (e.g. Dermatophytes (e.g. Trichophyton Trichophyton rubrumrubrum))

Sarcoptes scabiei Sarcoptes scabiei (itch-mite)(itch-mite)

Elimination from bloodElimination from bloodBy means of vectors: By means of vectors:

tick-borne encephalitis virus, yellow tick-borne encephalitis virus, yellow fever virus fever virus Rickettsia prowazekii, Yersinia pestis Rickettsia prowazekii, Yersinia pestis Borrelia recurrentis Borrelia recurrentis Plasmodium malariaePlasmodium malariae

By means of small cracks in mucosa: By means of small cracks in mucosa: HBV, HBV, HIVHIV

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

Richard Preston: The Hot ZoneRichard Preston: The Hot Zone

David Tyrrell David Tyrrell && Michael Fielder: Cold Wars Michael Fielder: Cold Wars

Please mail me other suggestions at:Please mail me other suggestions at:

mvotava@med.muni.cz

Thank you for your attentionThank you for your attention