Strict: regularly cause disease in some proportion of susceptible people with intact defenses

Opportunistic: able to cause disease in people who are immunocompromised

Exo: from external source (another person, animal, vector, fomite etc.)

Endo: colonize one area of the body and cause disease by moving somewhere else, acquiring a virulence gene or a change in host defense

Commensal.

Lots of mutualistic as well, but not the majority.

1. Entry and Attachment

2. Multiplication

3. Local or general spread

4. Evasion of host defenses

5. Shedding from body (exit)

Damage occurs while organism multiples, spreads, and evades host defenses.

-Gp A streptococcus reaches pharynx in respiratory droplets

-Gp A Strep attaches to respiratory epithelium

      Adhesins (M protein,LTA, F protein etc)

      Receptors (fibronectin etc on epithelial cells)

Strep grows and multiplies; avoids phagocytic clearance via presence of M Protein (antiphagocytic protein)

Invades local tissue via production of enzymes and toxins.

Host responds with inflammatory response: neutrophils (PMNs) come; pain, swelling, pus, fever.

Patient resolves infection when antibodies develop, opsonization and phagocytosis.

incubation period = 24-48 hours; replicates fast and inflammatory response is rapid

-present of fimbriae (pili) of bacteria

-prevent removal by normal "washing" mechanisms (saliva, blood, urine)

-Bind to specific host receptors (often Lectins)

-Dictates where bacteria will be located (tissue tropism)

-Loss of adhesins can render organisms avirulent 

-Classic Pili/fimbrial adhesins

-Bacterial afimbrial cell surface proteins acting as adhesins

-Intimin proteins-trigger cytoskeletal rearrangement in host cell; may trigger internalization of organism

-Bacteria secreting its own receptor which is internalized and expressed by host

-most common STD of bacterial cause

-most strains bind only to nonciliated columnar, cuboidal or transitional epithelial cells (infections in limited locations)

-LGV (lymphogranuloma venereum) strains also bind to macrophages--> lead to systemic infections and disease

prevents adhesion of diarrhea causing strains of E.coli

given to pregnant sows and protection passed through colostrum to piglets

Biofilm: bacterial population enclosed in extracellular polysaccharide substance (made by the bacteria)

-often under control of Quorum Sensing

-once in biofilm, more genes may be triggered by quorum sensing

Ex: dental plaque (normal) or on damaged heart valves or foreign bodies

-Provide resistance to antibiotics, phagocytic cells, and immune cells

Pseudomonas aeruginosa is the key colonizing organism in patients with CF and has a family of genes expressing alginate (slime) -- key biofilm polysaccharide

-produces biofilm in the lungs

-resistant to many antibiotics, biofilm makes it worse

-phagocytes are frustrated and destroy tissue

-infections are common COD in CF pts

1. Respiratory Tract: large droplets (resp secretions) or droplet nuclei (<10u in size, can get to alveoli)

2. GI Tract: fecal-oral transmission; presence of diarrhea helps transmission

3. Urogenital tract: sexual contact, perinatal

4. Skin: environmental shedding (skin scales), person-person transmission

5. Blood: needles or vector borne

6. Vertical transmission (mother to fetus): during gestation (thru placenta) or at time of birth

Iron is essential for multiplication but not easily accessible from host tissues (lactoferrin, transferrin, ferritin, hemin).

Virulence Factors:
1. Siderophores: iron chelators

2. Receptors for host iron binding proteins: (e.g. Transferrin) and ability to remove iron at cell surface

3. Enzymes that release iron from cells (hemolysins lyse the RBCs) 

-Byproducts of bacterial growth can damage tissue (acids, gases etc)

-Degradative enzymes

1. used for nutritional needs (hyaluronidase, collagenase, lipase, protease)

2. Production of enzymes to move through tissues (invasive pathogens)

3. Facilitate spread of organism with resulting tissue damage

necrotic lesion in patients with bloodstream infections of Pseudomonas aeruginosa

Elastases produced allow invasion of elastic small vessels. Protease and exotoxin cause local tissue destruction.

virulence factor produced and released into a medium or delivered to a host, that then damages euk cells/tissues

-may be excreted from bacterial cell or injected directly into an effector cell, or may be embedded in the bacterial surface and released upon cell lysis.

Why do bacterium produce toxins?

-destroy neutrophils and macrophages, protecting themselves from phagocytic clearance

-destroy human cells -- release iron and nutrients

Forms of toxins:

-structural components of bacteria

-excreted enzymativ proteins

-receptor bindign proteins

-Response may be tissue-specific or systemic (through cytokines)

-Some toxins are totally responsible for disease presentation (tetanus, botulism, diptheria caused by toxins)

components of cell structure -- PAMP (pathogen associated molecular patterns)

   -endotoxin

   -cell wall/membrane components (lipoteichoic acid)

-signals of infection to host, signal need for response from host to contain the organism

Bacteria breach epithelium, reach tissues, encounter macrophages/dendritic cells (these cells sense the PAMP and secrete mediators) ==> Inflammatory Response

-Pattern Recognition Receptors bind highly conserved bacterial molecules (lipids/sugars):

   Toll-like receptors, CD14, NOD (nucleotide binding oligomerization domain) proteins

-Lots of different molecular patterns recognized on bacteria, fungi, parasites, and viruses. Bacterial examples inclue flaggelin, pilin, and LPS endotoxin (lipopolysaccharide)

part of GN outer membrane.

-Lipid A moiety (endotoxin) is released when GN bacteria die and lyse (this happens all the time)

ex: LPS binding LPS binding protein, LPSBP complexes with CD14 which passes LPS to TLR4. Signal transduction ensues--> inflammatory mediators (upregulation of T cell costimulatory molecules: TNFa, IL-1, IL-6, IL-12, chemokines, PGs and leukotrienes)

-IL-6 causes C-reactive protein release from liver

-clotting times rise, BP drops, HR rises

-acute respiratory failure

==SEPTIC SHOCK due to the presense of GN bacteria in blood donation to a recipient who had antibdies against the GNB

Exo: GP and GN; Endo: GN only

Exo: secreted from viable organisms; Endo: released upon bacterial death

Exo: heat labile; Endo: heat stable (lipids/sugars)

Exo: highly specific action; Endo: low specificity to action, trigger innate immune system

Exo: denaturable to form toxoids; Endo: cannot be converted to toxoid form

Exo: very potent; Endo: potency variable dependent on quantity present

Exo or Endo? 

Heat stable.

Exo or Endo? 

Very potent in activity.

Exo or Endo? 

Produced by GP and GN

Exo or Endo? 

Can be denatured to form toxoids

Exo or Endo? 

GN only

Exo or Endo? 

Secreted from viable organism

Exo or Endo? 

Cannot be converted to toxoid and had variable potency depending on quantity present.

-proteins secreted by microbes and which harm tissue or trigger destructive biologic activities

-Majority are enzymes (may be carried on chromosome but many are plasmid; many carried on lysogenic phages)

-quorum sensing

-secreted via the 4 main secretion systems (1-4)

-damage cell membranes

-inhibit protein synthesis

-activate secondary messenger pathway

-inhibit NT release

-activate host immune response

I: bind but do not translocate (trigger signal; superantigens)

II: destroy host membrane via depolarization

III: bind and translocate into host cell (AB toxins: active binding)

IV: use type III and IV secretion systems to gain access to host cell (bring own insertion device with them)

-Powerful T-cell mitogens

-GP bacteria are the most significant superantigen producers

-Bind to cell surface, but not internalized

-Bring MHC II antigens of APC into contact with TCR on CD4 T cell. No processed antigen needed.

-stimulate up to 20% of T cell population

-Trigger T cell (Vbeta) massive cytokine release: IL-2 which triggers TNFa, IL-1, chemokines, platelet activating factor.

-Shock and Multi-system organ failure

-activation of self-reactive T-cells can also lead to autoimmune attack

-toxic shock caused by staphlococcus aureus

-toxin-mediated (ingested) diarrhea caused by staphlococcus aureus

-scarlet fever, necrotizing fasciitis, or toxic shock caused by streptococcus pyogenes

-Type II Toxins

-insert into host cell membrane via cholesterol receptor

-cell leakage thru pores

-can also release phagocytosed bacterium inside phagosome into the cytoplasm

-Type II Toxins

-remove charged head from phospholipids of cell membrane

-destabilizes the membrane

-Ex: Lecithinase of Clostridium perfringens (gangreene)

-toxin is a phospholipase (lecithinase)

-results in lysis of RBCs, platelets, leukocytes, and endothelial cells

-increases vascular permeability, massive hemolysis, bleeding, tissue destruction, hepatic toxicity, and myocardial dysfunction

-amount and location of toxin matter

-most serious: myonecrosis (gas gangene)

-Intracellular A-B Toxins

-binding region (B) that recognizes a specific receptor bound to a translocation region that introduces the A portion into the cell cytoplasm

-A (active) portion (often enzyme) acts on some intracelular protein

-these are usually lethal toxins

Diptheria Toxin

-toxin spread systemically

-toxin binds susceptible cells through B portion 

-Translocation region inserts into endosomal membrane

-Insertion catalyzes movement of A (active) into cytosol

-A=ADP-ribosylates EF-2 (involved in bringing in the AAs)

*interaction of mRNA and tRNA blocked

**protein synthesis stopped

-death to cells in pharynx, cardiac and nerve tissues (lots of receptors)

-formalin-inactivated toxin (aka "toxoid")

-stimulate antibody formation against (B) binding portion of toxin

-no longer contains active enzymatic function

-inflammatory cells triggered by infection cause damage at site of rxn ("bystander damage")

-enzymatic damage

-replacement of normal tissue with inflammatory response tissue (granulomas)

-damage due to cross-reactive antibodies

Ex: rheumatic fever, mycoplasma pneumoniae, and Guillaine-Barre syndrome ((Type II Sensitivity))

Two general categories of bacterial pathogens

1. Extracellular pathogens

2. Intracellular pathogens

-destroyed once they are phagocytized

-they try to avoid phagocytosis

-TH2 (antibody) host responses are often effective against these organisms

-infections are acute (develop and progress rapidly)

Mechanism of avoid Host defenses:

Evade recognition and killing by phagocytic cells and Avoid activation of complement system

Facultative or Obligate

-can survive phagocytosis inside phagocytes (macrophages)

-protected from antibody and humoral response

-active cell mediated (TH1) response required for clearance

-Infections are chronic and/or persistent

-Develop mechanisms to survive inside professional phagocytic cells or to initiate uptake by normally nonphagocytic cells!

Extracellular Pathogen Defense Mechanism

Capsules

Slippery polysaccharides cause the phagocytes to slip off. 

-Complement not activated through Alternate Pathway due to presence of Sialic Acid on capsule; shedding of capsular polysaccharide (complement decoy); masking of C3b

-Phagocytosis prevented until anticapsular antibody develops--allows for opsonization

Extracellular Pathogen Defense Mechanism

Antigen Mimicry/Masking

-organisms have antigens very similar to host (seen as self)

-organisms coat themselves in host antigens

-organisms have surface molecules that interfere with immunoglobulin binding preventing opsonization

Extracellular Pathogen Defense Mechanism

Antigenic shift or variation

-organism has multiple genes for antigenic surface molecules

-antigens are replaced as gene expression cycles and new antigens are not recognized by antibody

Extracellular Pathogen Defense Mechanism

Production of IgA protease

Enzyme which cleaves and degrades secretory IgA

-useful protective mechanisms for organisms colonizing or infecting mucosal surfaces

Extracellular Pathogen Defense Mechanism

Serum Resistance

-resistance to lytic effects of complement: bacteria are not killed by the MAC of complement

-especially important for extracellular GN bacilli that reach blood stream (bc LPS is a strong activator of complement)

Extracellular Pathogen Defense Mechanisms

Destruction of Phagocytes

Extracellular Pathogen Defense Mechanisms

-organism produces enzyme which inactivates chemotactic complement components

-organism produces enzymes which reduce effect of neutrophil oxidative burst (catalase)

-organism stimulates host to wall-off infection site (limits effectiveness of phagocytic cells; ex: abscess formation--impedes PMN function)

Extracellular Pathogen Defense Mechanisms

-stimulates epithelium or endothelial cells to uptake bacterium

-provides protection from antibody

Intracellular Pathogen Defense Mechanism

Survival inside phagocytes

-dependent upon successful TH1 immune response for resolution of infection

-inhibition of phagosome/lysosome fusion

-resistance to lysosomal enzymes

-escape from lysosome with replication free inside cytoplasm

-delay the TH1 response