Staphylococcus aureus
HPR: Normal flora, opportunistic
MOT: Auto-inoculation, direct contact (person-to-person)
POE: Skin
INC: 2-4 days (depends on host)
VFs: see below
STRUCTURAL FEATURES
Capsule: Karakawa type 5 or 8
Peptidoglycan TLR-2, TLR-4 cytokines, IL1β, IL2 = pyrogenic
Protein A: molecular mimic for FCγ receptor
Lipoteichoic Acid, Lipo-phosphate ribitol (an LPS-like material):
mimics endotoxic shock.
Plasminogen
↓ Bradykinin
Plasmin Kininogen ------ Kinin
↓ ↑ ↓clot dissolution
Fibrinogen ------ Fibrin multimerizes clot
X
VII Citrate inhibits these factors to keep blood from clotting
COAGULASE PROMOTES THE BOTTOM HALF OF THIS PATHWAY.
Coagulase does not need factors X and VII to clot, so S. aureus is not inhibited by citrate.
EXOENZYMES
1) Coagulase, which is a clumping factor (fibrinogen is the substrate)
A) Keeps out PMNs by coagulating blood
B) Fibrin also coats bacteria to hide it from PMNs, and forms an
obstruction to keep PMNs from being able to get through to them.
2) Catalase: Deactivates the toxicity of H2O2 H2O + O2
3) Lipase/ Phospholipase (degrades fatty acids and sebum)
Promotes sebaceous gland colonization causes abscess in sebaceous
gland, which hardens because of coagulase carbuncle
4) β Lactamase: degrades β lactams
5) Hyaluronidase: degrades hyaluronic acid/ neuraminic acid
-Causes Necrotizing Fascitis: necrosing tissue and moving through fascia layers.
6) Staphylokinase: mimics bradykinin (dissolves clots)
NOTE: Coagulase and Staphylokinase cannot function at the same time.
EXOTOXINS
1) Hemolysins
α hemolytic: 34 KDa transposition-mediated (“Jumping Genes”).
Lyses RBC’s, Platelets, WBC’s
β hemolytic: Degrades RBC’s, Platelets, Fibroblasts.
γ hemolytic: “Detergent”-like lysis of RBC’s, Platelets, Endothelial cells.
Leukocidin: WBC lysis. “S” subunits bind GM ganglioside,
“F” subunits bind sphingomyelin to cause WBC lysis.
Pantone Valentine Leukocidin (PVL): Creates mini-cytokine
storm to contribute to shock.
2) Exfoliative Toxin (ET)
ETA (30KDa) and ETB (25 KDa) has a trophism for squamous epithelium
and their capillaries; they injure and lyse them. “Scalded Skin Syndrome”.
3) Toxic Shock Syndrome Toxin (TSST- 1,2): A Super Antigen
TSST + Mg MHC II / Macrophage T cell = hypersecretes cytokinins.
4) Enterotoxins: A, B, C1, C2, D,E
NAD+ Dependent G-Protein ribosylase (like cholerae)
5) Quorum Sensing Regulon and VF gene regulation
This regulon is found on the chromosome of S. aureus. It contains the genes shown below as block arrows.
(requires RNA II) P1 P3 (requires RNA III)
Agra C D B SK Hα Hβ PVL ETA Cat
Transcript Sensor Encodes 8-AA peptide
Activator for Octap. = Octapeptide
STIMULATES GENES FOR EXOTOXINS AND EXOENZYMES
AGR = Accessory Gene Regulator
P1 = Promoter P1 (Controls AGR genes, requires RNA II)
RNA II = Regulator for AGR genes
RNA III = Regulator for exotoxins and exoenzymes
Inoculation Coagulase to coat itself, hide, and allow it to replicate
High cell density ↑waste, ↓nutrients, immune challenge
triggers P1 activation expresses RNA II Expression of AGR genes.
Octapeptide can activate itself = AUTOCRINE = Self-Stimulating
S. aureus uses to ESTABLISH (SAR)METASTASIZE (AGR)
CoagulaseStaphylokinase
Capsule ONCapsule OFF
Protein A Toxins ON
Adhesins ONAdhesins OFF
Enzymes OFFEnzymes ON
Establish new colony
Non-Infectious Food Poisoning
Shigella / Vibrio / ETEC / S. aur. / Bacillus / ClostridiumToxins / Shigatoxin / Choleragen / Entero-
toxin / Ent B / Ent Tox / Botulinum
INC / 12-72 h / 12-24 h / 24-72h / 1-6 h / 3-18 h / 6-12 h
Mech. / Protein synthesis / NAD G-rib / G-ribo / G-ribo / G-ribo / Ntrans inhibt
Duration / 2-4 d / 2-5 d / 2-4 d / 1-2 d / 1-2 d / 2-5 d
Diarrhea / ++++ / ++++ / ++++ / - / - / +/-
Vomiting / - / - / - / ++++ / ++++ / +/-
Pathogenesis:
Furuncle (sebaceous glands) or Carbuncles (hair follicles) abscess /boils
Cellulitis/ soft tissue infections.
Scalded Skin Syndrome ETA/ETB dermatitis (similar to scarlet fever by Strep)
Necrotizing Faciitis
Toxic Shock
Enterointoxication (enterotoxin-mediated diarrhea). This is Dz, not infection.
Pneumonia (even though there’s no IgA protease) = 50% mortality rate =
MORE LETHAL than URI pathogens.
Pyemea (see below)
Osteomyelitis (diaphyseal = middle part of long bones). Requires 6-8 weeks of iv antibiotics
Renal Abscess infarcts (seeds from renal artery, forms abscess, clots blood beyond that site)
Endocarditis (heart valve vegetation) destruction of valve valvular regurgitation septic embolism
Staphylococcus epidermidis
Has fewer virulence factors, needs immunocompromised conditions
It has Protein A, but no coagulase
Pathogenesis:
Surgical wounds
Artificial Heart Valves
Prosthetic devices (hips, etc)
Catheters
NOTE: S. epidermidis is similar to Strep’s viridans group
S. aureus is similar to Strep A
ENDOTOXIC SHOCK
GRAM NEGGRAM POS
GI InfectionIngestion of organismIngestion of toxin
LPS/LOSPeptidoglycanEnterotoxin ABDC12E
CD14 and LPS-BP TLR 2,4Needs NAD+
Macrophages IL 1β, IL 2G-protein ribosylate
Cytokine Storm Fever↑ CAMP
TNFαLipoteichoic Acid Na+ and H2O leave
TSST 1, 2 Diarrheas
Hypovolemia
Streptococcus: Mostly opportunistic pathogens with various virulence factors
GROUPSPECIESPOE
Apyogenesnasopharyngeal
Bagalactiaeoral mucosa
C-G (viridans)mutans/salivariusoral mucosa
mitisoral mucosa
Enterococcus faecalisGI
Enterococcus faeciumGI
Nonpneumoniaeairway
Virulence Factors
St. pyogenes(frequent co-infection with St. pneumoniae)
1) Capsule
2) Protein M (mimics Fcγ R)
3) hemolysins
4) Streptolysin S (SLS) = O2 labile can function with or without oxygen
5) Streptolysin O (SLO) = O2 stable
6) Pyrogenic exotoxin: Chromosome-encoded by viral lysogeny (some strains)
7) Neuraminidase (like Hyaluronidase in Staph aureus)
8 DNAse
9) +/- IgG protease
10) Streptokinase (fibrinolysis): used for therapeutic medicine post heart-attack
St. pneumonia (frequent co-infection with St. pyogenes)
1) Special Capsule to deal with alveolar macrophages: Quelling Reaction (swells).
2) IgA, IgG, IgM protease
3) pneumolysin (like SLO, O2 stable)
4) Peurpera Producing Principle(PPP): targets subdermal capillary endothelial cells, causes
embolism infarcts (like N. meningitis)
St. mutans
1) Capsule
2) Dextram Sucrase: cleaves sucrose into (glucosedextrams) and (fructoselevans)
Enterococci: Capsule +/-
Pathogenesis:
ACCESS-TISSUE INTERACTION-IA-VFs-CLINICAL MANIFESTATIONS
St. pyogenes
1) Impetigo/erysipelas: Skin infections, especially around face
2) Acute purulent pharyngitis (Strep Throat)
3) Acute Necrotizing Fasciitis (using enzymes)
4) Scarlet Fever
5) Endocarditis
Non-infectious, post-infectious sequelae: From our Ab response to the Ags; confusion between MHC I and II, causes autoimmunity from pyogenes challenge.
1) Rheumatic Fever
2) Rhematoid Arthritis
3) Rheumatoid Glomerulonephritis
St. pneumoniae
1) Meningitis (#1 cause of adult meningitis)
2) Lobar pneumonia (with rusty seropurulent exudates, high fever): #1 cause of death in US due to infection
St. mutans
1) Dental caries
2) Endocarditis
Enterococcus: normal GI flora
MDR, especially VRE (Vancomycin resistant enterococcus)
SPORE FORMERS: Bacillus (aerobic) and Clostridium (anaerobic)
Bacillus cereus: Produces enterotoxins in food, which is then ingested. No sepsis.
Causes rapid onset of vomiting, but not as fast as S. aureus.
B. anthracis:
Strict aerobes
Found in soil
Long bacilli with ROUNDED ends.
Infections are from spore exposure (from soil), esp around livestock.
SPO regulon activates MEDIAL spores. Occurs when there is lack of nutrients, uv light, noxious agents (like Antobiotics), or dessication (↓water).
Growth Cycle:
SPO H2O
------------
Poor growth conditions Medial endospore Germination
HPR: Obligate pathogen, “zoonotic agent” (transmitted around other animals, esp. livestock)
MOT: Livestock/ soil aerosol or direct contact
POE: Inhalation or skin contact
INC: 4-10 days (virulent = ↓↓MOI)
VFs:
1) Polyglutamyl capsule (glutamic acid): prevents opsonization, C’, phagocytosis
2) Anthratoxin: Three component exotoxin
a) Protective Ag (PA)
b) Edema Factor (EF) Joined by a protein
c) Lethal Factor (LF)
3) FIP
4) Superoxide Dismutase (SOD) Can tolerate macrophages
5) Catalase
Px of Anthratoxin: Endospores bind to the host cell membrane (alveolar or dermal epithelial cell, or macrophage). then it germinates from body moisture, temp, and host stress. It produces anthratoxin, which causes ↑Furin response in the host. Furinis an enzyme which cleaves the linking protein of anthratoxin, releasing the toxin componants). This is exploitation of the host cell protease.
PA binds to the host’s VWF I receptor, and serves as a docking site for the toxin.
EF is a bacterial Adenyl Cyclase
LF is a metaloprotease.
Px of Bacillus anthracis
1) Edema and local lymphadenopathy (esp inhalation mediastinal lymph nodes)
2) Papule (vesicular) goes from blue purple black (necrosis of cell). These
papules form in both the skin and lung forms of anthrax.
3) Eschar (temporary cap on vesicle, but organisms are not being killed).
Leads back to #1 above, and cycle repeats.
Inhalation Anthrax = “Wool-handler’s Disease”
Kindlization: 1) kill vegetative cells and germinate spores 2) kill new veg. cells.
NOTE: Anthrax is a category “A” bioterrorism agent
Clostridium
Gram + bacilli
Strict anaerobes or microaerophilic
Soil bug
SPO
“Boxcar” (square ends) =(vegetative) --- “Drumstick” (terminal endospore)
Three main groups (Except C. difficile is normal flora)
A) Histolytic
1) C. perfringes
2) C. sporogenes
3) C. histolyticum
4) C. septicum
B) C. botulinum
C) C. tetani
Histolytic
HPR: Obligate pathogen
MOT: contact with soil
POE: crushingtrauma or compound Fx (dirty injuries with devascularization)
INC: 2-4 days
VFs: 1) Lipase
2) Protease
3) DNAse
4) SOD
5) Catalase
6) AA Decarboxylases (to use our AA to make their own AA’s)
gas production(CO2, CH4, H2S, H2)
AAdeCO2ase removes the carboxyl groups from amino acids 1° amines
1° amines: Putresceine and cadaverine
Liquifaction occurs from phospholipases, proteases, and DNAses.
All of the above in red leads to GAS GANGRENE. Frequently seen in diabetic and decubitus ulcers. Soil grown garlic used on arrowheads = Bioterrorism.
TREATMENT: Amputation
C. botulinum“sausage”
HPR: Obligate pathogen, or just intoxification (need not to be present)
MOT: Contact with soil or food thereof
POE: 1° = Ingestion
a) Infection: usually neonate (honey, etc, can contain spores)
b) Intoxication: adults
2° = Intravenous Drug Abuse (Dirty drugs and paraphenelia)
INC: 6-8 hours (intox)
4-20 days (infect)
VFs: Botulinum toxin
Px: Descending Symetric Paralysis
1) Ptosis in eyes
2) Gag/swallow reflex
3) Diaphragm paralysis (CAUSE OF DEATH) and weak limbs
TREATMENT: No organisms present, so no antibiotics
C. tetani
HPR: Obligate pathogen
MOT: Contact with soil
POE: wound, deep puncture
INC: 2-10 days
VFs: Tetani toxin
Px: Non-descending. Starts with major muscles (esp masseters = “Lock-Jaw”) and spinous muscles arched back, breaks spinal cord.
Cause of death is from suffocation (paralysis of diaphragm)
“Rhizous Sardonis” = Sardonic smile, eyebrows up, can’t blink.
TREATMENT
Tetanus Toxoid (Ag, but not toxogenic). Not anamnestic (need vaccine every five years). No actual damage to cleft; so one can recover. Supportive treatment with intubation, wound care, antibiotics).
Phage-Mediated Transduced Toxins: A, B, E. Pt serum is injected into several mice
Anti-A anti-toxinAnti BAnti ENone
The mouse that lives is the one that has the same anti-toxin as the toxin type that isaffecting the human.
BOTLINUM TOXINTETANUM TOXIN
Targets pre-synaptic cleft Targets post-synaptic cleft
Prevents release of acetylcholine Inhibits acetylcholinesterase
no neurotransmission Inhibits acetylcholine re-uptake
FLACCID Paralysis neurotransmitters hang out in cleft,
constantly triggering nerve stimulation
CHRONIC CHOLINERGIC ACTIVATION
= TRISMIC PARALYSIS
Corynebacterium
Lipid in cell envelope (like mycobacterium)
Unusual cell wall and membrane
Unusual gram +, pleomorphic
Acid fast (like M. turberculosis)
Divide by snapping fission = Chinese letter bacteria
C. diphtheriae
HPR: Obligate pathogens, humans are reservoir
MOT: droplet nuclei
POE: Inhalation nasopharyngeal colonization
INC: 2-6 days
VFs: 1) Heat labile K Ag
2) Capsule with proteins, not just carbohydrate
3) Heat stable O Ag (like Gram neg’s): Lipo-arabinogalactan (lipid-sugars)
serves as an LPS orthologue
4) Diphtheria toxin: Two subunits with disulfide bond. ADP dependent
EF-2 ribosolase (like Shigatoxin, but trophism for nasal epithelium
instead of GI)
DIPHTHERIA TOXIN
A –-S—S-—B
Nasal Epithelial Cell
EF-2 (Elongating Factor-2; for protein syn)
(A)a
ADPTransaminase
EF-2 ribosolase
Px: Nasopharyngeal colonization
Mucoid pseudomembrane and Necrotic NPG Epi cells death by suffocation
possible systemic intoxification. The organisms don’t metastasize, just the toxin.
altered CNS status, cardiomyopathy, nephropathy
The pseudomembrane is grey material (from nectrotic tissue) behind the uvula,
not made of pus. The cell dies from not being able to make protein.
This happens to unvaccinated adults and children < 1yr in other countries.
Tx:
1) Tracheostomy and intubaation
2) surgical debridement of membrane
3) Anti-diphtheria antitoxin
4) Antibiotics
Vaccine: Diphtheria toxoid: this is inactive because it’s oxidized by treatment with aldehyde. Our body responds to the protein in the inactive toxin.
Mycobacterium
Unusual G+ pleomorphic bacillus (gram variable)
“Beaded” bacillus from fission scar which doesn’t always break off
Acid-Fast
Slow growth (germination time = days instead of minutes)
M. tuberculosis TB
M. Leprae Hansen’s Diseas
M. avium intracellulare (MAI) common cause of death in HIV
M. tuberculosis
HPR: Obligate pathogen
MOT: Droplet nuclei
POE: inhalation lung alveolar macrophages survives there
INC: days-months
VFs: NO EXOTOXINS OR ENDOTOXINS
VFs:
1) Mycolate: Trehalose -6, 6’-deiycolate (polysaccharide + 60% lipid)
2) Sulfolipids (makes up 60% of the organism)
3) Intracellular Parasite
Px: Intracellular Parasite prevents phagolysosomal fusion by coating the interior of phagosome to prevent fusion of lysosomes eventual macrophage lysis re-phagositized by other macrophages cycle repeats granulomatous lesion = accumulation of macrophages and monocytes (unlike pus, which is PMNs)
Host tries to isolate the lesion by forming calcified nodule = Ghon complex around macrophages with living organisms inside them, causing caseative (cheese-like) necrosis
REACTIVATION
GRANULOMATOUS
Aveolar MФ survival in MФ eventual MФ lysis Calcification
1° INFECTION (ACUTE) CHRONIC INFECTION
TB TEST
Mycolate and Sulfolipids can be extracted from culture to make a
Purified Protein Derivitive (PPT) injected into arm for TB test.
Positive reaction shows evidence of previous exposure (if test was recently negative, person gets one pill a day x9 months).
Then, do chest x-ray to see if there are Ghon complexes (tubercles). If so, person gets three pills a day for 12 months.
1.8 billion people have TB, out of a possible 6 billion (more common than malaria).
M. avium intracellulare (MAI)
Can be killed by type I immunity, but if the person has no CD 4+ cells, can be fatal.
M. leprae
HPR: Obligate pathogen
MOT: droplet nuclei
POE: inhalation alveolar MФ IP trophism for cool parts of the body
(toes, fingers, nose, eyebrows, earlobes)
INC: days - months
VFs: see M. tuberculosis
TWO FORMS OF LEPROSY
1) tuberculoid: trophism for distal Schwann cells (which make the myelin that coats nerves). Infects the cell, but doesn’t kill it demyelenates anesthesia in those tissues. It’s disfiguring (face skin thickens = stone face; body hair falls out)
trauma occurs without pain death from 2° bacterial infections.
2) Lepromatous: (seen in those with lower immunity)
metastasis (brain, lung, spleen, liver, bone)
OTHER GENUS/SPECIES TO KNOW: Nocardia asteroides, Actinomyces israelii, Listeria monocytogenes, Erysipelothrix
ANSWERS TO SOME QUESTIONS
What does Karakawa type 5 or 8 capsule MEAN?
Karakawa was an expert on S. aureus capsules; types 5 and 8 are the most common serotypes associated with human disease; 5 vs. 8 differ in carbohydrate composition.
Can you explain the terms "Jumping genes" and "transposition-mediated"?
That would take a while – would suggest you read the following essay:
Essentially, transposons, or jumping genes, are genes that can move within a genome, and thereby become more or less active.
Regarding leukocidin: what is a "GM ganglioside" and "sphingomyelin"?
Two constituents of mammalian cell membranes not found in prokaryotic membranes; not lipids, but not sterols – sort of in the middle / hybrids.
If leukocidins mainly lyse WBC's, how does PVL cause a mini-cytokine storm?
Leukocidins can delay / deflect PMN attack, but can’t prevent it; PVL evokes hypercytokine response from PMNs and macrophages that do show up.
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