theme 3

structural components that gram+ bacteria use to induce inflammation

• thick peptidoglycan contains → lipoteichoic acid

• lipoteichoic acid binds to TLR on phagocytes → they start producing cytokines → mediate inflammation

structural components that gram- bacteria use to induce inflammation

• thin peptidoglyan layer + LPS

• LPS binds to TLR on phagocytes → cytokines → mediates inflammation

capsule is a virulence factor to hide → but what do they do

• prevents compelement-mediated phagocytosis

  • normally C3b binds to bac surface

  • factor H degrasdes C3b and binds well to capsule → leads to less opsonization

  • mps are now not activated

which 3 pathogens have a capsule

• streptococcus pneumoniae

• heamophilus influenza

• neisseria meningitidis

streptococcus pyogenes → what kind of patho, diagnos (3), gram

• primary pathogen → transient carrier (throat)

• diagnostics

  • catalase test/beta hemolytic

  • microscopy → gram stain

  • culture → blood agar plates

• gram+

streptococcus pyogenes ENTER

• they enter by adhesion

• through pilus/pili + F protein + lipotehcoic acid

  • on pili → protein M

streptococcus pyogenes KICK → 3

• make streptolysin → class of pore-forming exo-toxins

• kills host cells → erythrocytes, leukocytes, platelets

• helps evade imm sys → induces inflammation with peptidoglycan and lipoteichoic acid

pore forming (membrane active) exotoxins

• causes H2O to get in → swelling → host cell lysis → death (bc osmolarity = high)

• cytoplasmic contents get out → low osmolatiry

enzymes produced by s. pyrogenes = 3

• hyaluronidase → easier for bac to spread infection

• streptokinase → lysis of clot → easier to spread

• C5a peptidase → inact C5 = no effector pw of classical pw

  • so no phagocyte recruitement and peptide mediators of inflamma

M protein

• surface protein on s. pyrogenes

• binds host/H factor → prevents opsonization by C3b

• immune evasion → prolonged infection → inflamma response

toxins and superantigens

• 10% of s. pyogenes has superantigenic toxin

• leads to toxic shock sd

• superantigenic toxin can bind to a lot of TC (master key)

influenza A virus virulence mechanisms = 5

• hemagglutin = HA spike → to enter

• neuroaminidase = NA → to cut

• RNA polymerase

• antigenic drift

• antigenic shift

hemagglutin spike of influ A

• it’s surface glycoprotein on the virus → so for adhesion

• binds sialic acid residues on host cells receptors → mediates viral entry via endocytosis

neuroaminidase of influ A

• is like scissors (enzyme) → this happens at exit

• cleaves sialic acids → allows release of new virions from infected cells

RNA polymerase of influ A

• to replicate its genome → causes cell death

• had no proofreading bc its RNA → mutations are therefore frequent

antigenic drift

• small (evolutional) genetic changes in influenza virus

• caused by errors/mutations during replications

• pre-existing ab’s bind less effectively because spike proteins are now a bit altered

antigenic shift

• major change in influ virus

• happens when 2 diff influ A strains infect same host cell

  • genome segments reassort → new combo of HA and/or NA

• can lead to pandemics

diagnostics of influ A

• DNA/RNA → PCR

• direct immuno-fluorescence → Ag testing

HIV → 4 kenmerken waaronder 3 enzymen

• reverse transcriptase → make DNA of the RNA in virus

• integrase

• HIV protease

• exists by budding

integrase = to evade immune sys

• inserts viral DNA in genome of CD4 cell

• CD4 TC is main target for HIV → progressive destruction of CD4 cells → immunodef = AIDS

HIV protease → 2

• HIV only works/replicates if HIV protease cuts the polyproteins (pp) in pieces

• it cleaved long viral pp into functional proteins → necessary to infect other cells

HIV diagnostics → 2/3

• PCR + combo test

• serology + antigens testing = combo test → ab and ag detection

what are commensals

• non harmful bacteria → normally present in every person, no symptomps

• all the bac that are there to stay

• harmless unless impaired immune sys → opportunists

on your skin you mostly have gram …

positive bac

inside of your body you mostly have gram …

mostly gram neg, but little bit of gram pos too

colonization resistance

• presence of normal microbiota

• protects against adherence of other mo

what causes fever

• when immune cells (like macrophages) release cytokines → act on hypothalamus

• raises body set point → heat production

colonization

• presence of a microbe without disease

• could be commensal or pathogen

• this is called exposure and not infection

source of infection → endogenous

• commensals

• colonization → primary pathogens

commensals on body parts → skin, throat, vag, bowel

• skin → staph epi

• throat → strep pneu, strep pyog, neisseria, candida albicans

  • strep → throat/vag.na

• bowel → e. coli, bac fragi, clos dif

colonization organisms

• kenmerkend → 3

• nog 2

• all have capsule → s. pneu, n. mening, h influ

• s aureus (nose), s pyo (throat)

sourc of infection → exogenous

• other person

• zoonosis

• vector

• environment

staph epidermis → what kind og pathog, def, when inf

• opportunistic + commensal on skin

• granulocytopenia

• foreign body → adhesion to IV catheter/prothesis = biofilm

staph aures → what kind of patho, def host

• primary pathogen + 30% carrier in nose

• no risk factors required, but higher risk if

  • granulocytopenia

  • foreign body

  • IV drug use

what happens if skin is disrupted

• granulocytes will act up → next in line of defense

• but catheter is already in bloodstream → granu cant reach that far → bloodstream infection

• staph epidermis infection

bowel surgery infections

• e coli

• b fragilis

• clostridium species → some can form spores

functionally causes of impaired barrier function → uri cat, gastric acid, tears, airway, other causes

• urinary catheter → e coli

• lack of gastric acid → salmonella, vibrio cholera

• lack of tears → heamophilus influ

• disturbance of normal airway cleanig → strep pneu

• litterally causes → wounds, insect bites, penetration of skin etc.or impaired colonization resistance

where belongs G=, c. albicans, G+ and clostr diff

1. gram +

2. gram -

3. candida

4. clos diff

having candida but havent taken antibiotics

• how do they grow on plate vs in vivo

• candida stomatis/oesophaitis → this infection is associated with TC immune deficiency (HIV)

• on a plate → not much food → grow as yeast

• in vivo → grow as pseudohyphae

no bacteria → which mo can now grow

• c difficile

• the cytotoxin (virulence factor) causes bowel damage

• pseudomembrane consists of → mucus and numerous granulocytes

  • this membrane is caused by c diffi → seen by colitis

eculizumab

anti-C5 antibodies → blocks MAC formation

complement deficiency

• mostly genetic (could be drugs)

• leads to infection with extracell bac and neisseria

• doesnt always give infection

complement def in classic route

• C2, C3, C4

• more sensitive to extracell bac → esp capsulated → pneumococcus, h influ

• C3 def is the worst → no opsonisation

complement def in alt/MBL route

• factor B, D, MBL

• also extracell bac → esp pyo

• often asymp tho

compl def in terminal complement/MAC

• C5-C9

• esp risk on neisseria infection → needs MAC to be killed

• MAC is important for killing gram- bac

neisseria meningitidis → 4

• VF is LOS = same as LPS

• LOS in blood → activates TLR4 → cytokine storm

• endothelial damage + leakage → disseminated intravascular coagulation = DIC

  • could also lead to shock next to DIC

• this leads to necrotic skin lesion = purpura fulminans

causes of hypogammaglobulinemia (+ its what kind of defect)

• defect in antibodies

• congenital

  • X-linked a-gammaglobulinemia

  • part of SCID

• acquired

  • common variable immunodef (CVID)

  • B cell malignancies → CML/myeloma

• iatrogenic → rituximab = anti-CD20

which organisms can make a person sick with hypogammaglobulinemia → 1/3

• all primary pathogens

  • capsulated bac → s pneu, n. menin, h influ

  • campylobacter

  • persistent giardia lamblia or enterovirus infections

• this gives frequent or recurrent infections of these pathogens

spleen disorder

• spleen takes out bac from bloodstream

• causes:

  • asplenia → congenital or surgery

  • functional asplenia → chronic hemolysis syndromes, infarction etc.

what mo can we see in spleen disorder patients → consequences

• all primary pathogens → often asymptomatic

• severe sepsis caused by capsu bac → s pneu, n, men, h influ

• severe plasmodium infections → malaria

causes of phagocyte disorder + leads to no … cells

• = no granulocytes, macrophages and NK

• granulocytopenia is eg → seen in leukemia

• or granulocyte dysfunction → chronic granulomatous disease

what mo seen in phagocyte disorders (primary vs opportu)

• all the mo’s that are associated with defect in barrier function → mostly bac, fungi and yeast

• but in addition:

  • aspergillus pneumonia/fumi

  • a-hemolytic streptococci

which mo’s are associated with defect in barrier function → 6 in total

• primary

  • s. aur → colo nose

  • s pyo → colo throat

• opportu

  • s epi → comm skin

  • e coli → comm bowel

  • clostriduim sp → comm bowel

  • candida albicans → comm throat, vag

impaired cellular immunity → 4 causes

• no T cells CD4/8

• congenital → SCID

• acquired

  • HIV → less CD4

  • chemo → less of all cell counts

  • use of immunosupp drugs

impaired cell immunity leads to infection with

• bac → 3

• virus → 4

• para → 2

• primary pathogens

  • intracell bac → salmonella sp, leg pneum, m TB

  • (herpes)viruses → CMV, EBV, HSV, VZV

  • parasites → toxoplasma gondii, s stercoralis

cholera toxin

• cholera toxin binds to apical membrane of enterocytes → subunit of cholera enters cell

• normally adenylate cyclase (AC) is regulated and produces cAMP only in response to signals

• now with toxin → AC stuck in act state → high intracell cAMP → acti CFTR Cl channels → diarrhea

taenia saginata → how infected/life cycle

• eggs in fec.es → environment → cattle/vee (int host) infected

• in muscle the mo develops → human (def host) ingests them by eating raw/undercooked infected meat

• organism attaches to intestine → becomes adult there

1 → 2 model = 1 mo → 2 outcomes

• VZV

  • primo infection → chickenpox

  • reactivation years later → shingles

• legionella can have 2 diff outcomes

  • legionella pneumonia → severe pneumonia

  • pontiac fever → mild

1 → 3 model: treponema pallidum

• syfilis

  • 1 ulcer

  • 2 fever and rash

  • gumma

• diagnosis

  • early stages → directly detected

  • serology, PCR

1 → 3 model: schistosoma

• worm can penetrate skin in water thanks to snails

  • adult worm in human → eggs secreted through fec.es → eggs hatch into snails

  • entry → swimmers itch

  • migration → katayama sd

  • settles → egg formation

1 mo → many outcomes

• enterovirus

• s. aureus

• s. pyo

• e coli

• m TB

borrelia burgdorferi → 3 stages

• stage 1 → erythema migrans

• lyme

  • stage 2 → meningitis, artritis, carditis

  • stage 3 → neuro(psycho)logical

s pyogenes and s aureus can infect at the same time → how do both present

• s pyo presented as red thick stripe → erysipelas

• s aureus presented as large light pink vesicle and wound → cellulitis

beta lactam and glycopeptides

• doelwit

  • normale proces

• waar werkt het

• werking beta

• werking glycopep

• doelwit = celwand → remmen peptidoglycansynthesis

  • transpeptidase (tpd) katalyseert laatste stap → cross linking van peptidoglycan

• work in periplasmic space

• beta lactams binden aan tpds → inhib → geen crosslink → lyse

• glycopeptides

  • binden aan D-Ala-D-Ala op peptideketens → rem carboxypeptidase → geen celwandopbouw

B lactam antibiotics examples

• 4

• 1

• spectrum

  • small → 1

  • broad → 2

• penicillin

  • penicillin G

  • Flucloxacillin

  • Amoxicillin

  • Amoxicillin + clavulanic acid (β-lactamase inhibitor)

• Cephalosporins

  • Cefuroxim

• spectrum

  • Penicillin → small spectrum (Gram+ cocci, anaeroben)

  • Meropenem, imipenem → very broad, behalve MRSA

glycopeptides example

• vancomycin → vooral tegen gram +

• reserve by MRSA or allergie

gentamicin → doelwit/remming van, binding, wat gebeurd er

• aminoglycoside 30S → doelwit ribosomen → protein syn inhib

• irrev binding

• misreading mRNA

doxycycline

• tetracyclines 30S → doelwit ribosomen → protein syn inhib

• blokkeren tRNA binding

clarithromycine

• macroslides 50S → doelwit ribosomen → protein syn inhib

• blokkeren translocatie

clindamycin

• lincosamides 50S → doelwit ribosomen → protein syn inhib

• remmen peptide bond formation

bactericidal

kills direct

bacteriostatic

inhibits growth and multiplying of bacs but doesnt kill them immediately

ciprofloxacin/quinolones

• DNA syn inhib

• remmen DNA gyrase/topoisomerase II + IV

• geen supercoiling → geen replicatie

metronidazole

• DNA syn inhib

• geact in anaerobes and protozoa

• forms free radicals → DNA strand breaks → cel death

conditions that are bad for bac replication and therefore bad for antibiotics → 4

• lage pH, lage pO2

• necrotisch weefsel

• abcessen

• biofilms

therapy for superantigen of s aureus

• flucloxacilline

• clindamycin

MIC

• lowest conc of an antibiotic that inhibts visible bac growth

• so [AB] >>> MIC is good

• if [AB] < MIC → AB not active

extended spectrum betalactamase = ESBL

• wat doen ze

• in welke soort vooral

• enzymen die uitgebreide beta-lactams afbreken inc veel cephalosporinen

• esp gram - → e coli bv

epstein barr virus infectie → 3

• infectieuze mononucleosis

• dringt binnen via orofaryngeale mucosa

• infecteert met name B cellen → triggeren sterk immuunrespons (vooral door TC)

klinisch beeld EBV = 4

• koorts

• lymfadenopathie vooral in cervicale regio → veroorzaakt door prolig van imm cellen

• atypische lymfocytose → TC hebben afwijkend uiterlijk → wel typerend voor EBV mono

• splenomegalie → door prolif en act van imm cellen

EBV reactivering

• CD8 TC respons → veroorzaakt verschuiving van bloedcellen samenstelling

  • normaal gedomineerd door polymorfonucleaire cellen = granulocyten

  • en nu gedom door mononucleaire cellen = mono en lymfocyten

• onder microscoop zie je blasteren van TC

• FACS → CD8 als marker gebruiken

neisseria gonorrhoeae kenmerken - 5

• gram neg diplokok

• non spore vormend

• oxidase en catalase positief

• heeft antigenische en fasevariatie van pili en opp proteine

• kan overleven in neutrofielen

n. gonorrhoeae manifestatie

• man → typisch met urethritis

  • dysurie - brandend gevoel bij plassen

  • purulente afscheiding → geel/groen

• vrouwn → bac vaginitis en cervicitis

  • ook pijn bij plassen

  • purulente afscheiding

  • intermen bloedverlies

  • kan PID worden → littekenvorming op eileiders

n. gonorrhoeae diagnose

• uitstrijking van cervix of urethra

• gramkleuring daarna doen

• daarna kweek op selectieve media

catalase + of - → hemolyse?

• pos → staph

• neg → strep → hemolysin test doen

  • pos → a of b hemo → pneu of pyo

  • neg → indiff strep

coagulase - or +

• pos → stpah aureus

• neg → andere sp

welke organismen kunnen leiden tot mononucleosis (beeld)

• ebv

• cmv

• hiv

• toxoplasma gondii