Term
|
Definition
• Spectrum:
- Streptococci, enterococci, anaerobes (except Bacteroides fragilis), spirochetes (e.g., syphilis)
• β-lactamase-susceptible
- Most Staphylococcus aureus resistant
- B. fragilis resistant
• Niche:
- Streptococci and spirochetes
• Penicillin VK - oral equivalent |
|
|
Term
|
Definition
• β-lactamase-resistant
• Spectrum:
- S. aureus, streptococci
- Loses activity of penicillin against enterococci, anaerobes, and spirochetes
• Niche:
- Susceptible S. aureus infections (not MRSA)
• Dicloxacillin - oral equivalent |
|
|
Term
|
Definition
• Spectrum:
- streptococci, enterococci, β-lactamase negative aerobic gram negative bacteria
• β-lactamase-susceptible
- Most Staphylococcus aureus resistant
- B. fragilis resistant
• Niche:
- like penicillin plus ‘wimpy’ aerobic gram negatives (e.g., sensitive E. coli)
• Amoxycillin = oral equivalent |
|
|
Term
|
Definition
• Spectrum:
- like ampicillin plus Pseudomonas aeruginosa
• β-lactamase-susceptible
- Most Staphylococcus aureus resistant
- B. fragilis resistant
• Niche:
- aerobic gram negative infections, including Pseudomonas aeruginosa |
|
|
Term
|
Definition
• Competitively inhibit β-lactamases
• Prevent hydrolysis of penicillins when used in combination
• Do NOT bind to penicillin binding proteins
Widely used β-lactamase inhibitors include clavulanic acid (oral), sulbactam (intravenous), and tazobactam (intravenous). These compounds aren’t used independently, but are provided in fixed combinations with wide-spectrum β-lactamase susceptible penicillins--specifically as amoxicillin/clavulanate (Augmentin)(oral), ampicillin/sulbactam (Unasyn)(intravenous), and piperacillin/tazobactam (Zosyn)(intravenous). |
|
|
Term
|
Definition
• Available in fixed combinations with various penicillins
• Must match pharmacokinetics of β-lactam antibiotic and β-lactamase inhibitor
• amoxicillin/clavulanate (Augmentin)
○ Spectrum:
- streptococci, enterococci, β-lactamase negative aerobic gram negative bacteria
- plus β-lactamase producing S. aureus, anaerobes including B. fragilis, and some resistant gram negative rods
○ Niche:
- Sinus, middle ear, respiratory tract, and some intra-abdominal infections |
|
|
Term
| First generation cephalosporins - Cefazolin (IV) |
|
Definition
• Spectrum:
- Streptococci, Staphylococcus aureus, some aerobic gram negative bacilli
• Niche:
- Skin and bone infections
- Surgical prophylaxis
• Cephalexin = oral form |
|
|
Term
| Second generation cephalosporins |
|
Definition
• Spectrum:
- Somewhat improved gram negative coverage
• Niche:
- Step towards development of third generation drugs
• Cefuroxime (intravenous) and cefuroxime axetil (oral) are examples of second generation cephalosporins. Drugs in this group have improved gram negative coverage (including H. influenzae and M. catarrhalis) at the cost of slightly reduced activity against gram positives. |
|
|
Term
| Third generation cephalosporins - Ceftriaxone |
|
Definition
• Spectrum:
- Improved aerobic gram negative activity; retain gram positive activity of 1st generation
• Niche:
- community acquired pneumonia
- CNS infections
• Important third generation cephalosporins include ceftriaxone (intravenous), cefotaxime (intravenous), and cefpodoxime (oral). These drugs retain the gram positive activity of the first generation cephalosporins and have excellent activity against most gram negatives including β-lactamase producing strains of H. influenzae, and Neisseria. They do not cover Pseudomonas. As noted above, they have good CNS penetration. |
|
|
Term
| Third and one-half cephalosporin - Ceftazidime |
|
Definition
• Spectrum:
- Resistant aerobic gram negative rods including Pseudomonas aeruginosa
- loses gram positive activity
• Niche:
- Pseudomonas aeruginosa
- Nosocomial infections, febrile neutropenia
• Strictly speaking, ceftazidime (intravenous) is classified as a third generation drug. It’s unique feature is activity against Pseudomonas aeruginosa and many other resistant gram negative rods that cause nosocomial (hospital acquired) infections. This activity comes at the cost of reduced gram positive activity. |
|
|
Term
| Fourth generation cephalosporins - Cefepime |
|
Definition
• Spectrum:
- Excellent gram positive and gram negative activity, including Pseudomonas
• Niche:
- Nosocomial infections
• Cefepime has both the anti-Pseudomonal/gram negative activity of ceftazidime and excellent activity against staphylococci and streptococci. |
|
|
Term
|
Definition
| β-lactam antibiotic. Aztreonam is effective against gram negative rods including Pseudomonas aeruginosa. It has no activity against gram positives and anaerobes. Aztreonam’s unique feature is that it has no cross-allergenicity with the penicillins, and, therefore, can be used safely for treatment of gram negative infections in patients with severe penicillin allergies. |
|
|
Term
|
Definition
• Mostly renal excretion
• Toxicity:
○ Well tolerated
○ ≈ 10% cross allergenicity with penicillins; ≈ 50% if anaphylaxis to penicillin
• Spectrum:
○ Very broad
○ Gram positive cocci, aerobic gram negative rods including resistant gram negative rods (Pseudomonas aeruginosa and Enterobacter spp.), and anaerobes
• Niche:
○ Nosocomial infections, febrile neutropenia, complicated intra-abdominal infections
○ Alternative to 3rd and 4th generation cephalosporins for CNS infections |
|
|
Term
|
Definition
• A glycopeptide
• Inhibits cell wall synthesis
- Binds the D-Ala-D-Ala terminal of the forming peptidoglycan
- Prevents cross-linking
• Bactericidal
• Spectrum:
- gram positives including methicillin-resistant S. aureus
• Niche:
- resistant gram positive infections
- gram positive infections in patients allergic to β-lactams |
|
|
Term
| Vancomycin metabolism and toxicity |
|
Definition
• Not absorbed from the GI tract
• Wide tissue distribution
• Eliminated unchanged in the urine
- Dosage modification is essential in renal impairment
• Toxicity:
- infusion related flushing (“red man syndrome”)
- Dose dependent ototoxicity and nephrotoxicity—especially in the setting of other toxic drugs |
|
|
Term
| Protein synthesis inhibitors |
|
Definition
| These antibiotics achieve selective toxicity by capitalizing on structural differences between bacterial and human ribosomal RNA complexes. Bacteria have 30S and 50S ribosomal RNA subunits, which combine to form a 70S ribosome. In contrast, mammalian cells have an 80S ribosome (except for some 70S rRNA within mitochondria). These protein synthesis inhibitors fall into two broad categories: 1) antibiotics that inhibit the 50S ribosomal subunit, and 2) antibiotics that inhibit the 30S subunit. |
|
|
Term
| What are the classes of antibiotics that inhibit the 50S ribosomal subunit? |
|
Definition
| macrolides (e.g., azithromycin), lincosamides (clindamycin), and oxazolidinones (linezolid) |
|
|
Term
| What are the classes of antibiotics that inhibit the 30S ribosomal subunit? |
|
Definition
| Inhibitors of the 30S ribosomal subunit include the tetracyclines (e.g., doxycycline) and the aminoglycosides (e.g., gentamicin) |
|
|
Term
| Aminoglycosides: Gentamicin |
|
Definition
• Inhibit the 30S ribosomal subunit
• Bactericidal
• Not absorbed orally (IV only)
• Limited tissue penetration
• Toxicity:
- Potentially severe and limits usefulness
- Nephrotoxic
- Toxic to the auditory and vestibular components of the eighth cranial nerve
- Must monitor serum levels and renal function
• Spectrum and therapeutic niche:
- Aerobic gram-negative rods
- Synergistic with cell wall active agents (β-lactams and vancomycin) for gram positive cocci |
|
|
Term
| Aminoglycosides and synergy |
|
Definition
| Aminoglycosides are synergistic in combination with cell wall active agents (β-lactams and vancomycin) against gram positive cocci including S. aureus, streptococci, and, enterococci. This synergy results from increased access of gentamicin to the interior of the bacterium when the cell wall is damaged by β-lactams (see cartoon). |
|
|
Term
| Tetracyclines: Doxycycline |
|
Definition
• Inhibit the 30S ribosomal subunit
• Bacteriostatic
• Comprised of four cyclic rings with four modification sites
• Doxycycline the most widely used
• Toxicity:
- Generally well tolerated
- Diarrhea, vaginal yeast infections, photosensitivity
- Stains the teeth of fetuses and children brown
• Spectrum and therapeutic niche:
- Active against many gram positive and gram negative bacteria, mycoplasmas, chlamydiae, and rickettsiae
- Outpatient treatment of cutaneous MRSA infections
- Oddball infections (e.g., rickettsiae, leptospirosis) |
|
|
Term
|
Definition
• Inhibits the 50S ribosomal subunit
• Bacteriostatic
• Oral or intravenous
• Toxicity:
- Well tolerated—GI upset common
- Drug-drug interactions
• Spectrum and therapeutic niche:
- Active against streptococci, S. aureus, H. influenzae, and atypical bacteria including mycoplasma, chlamydiae, and legionella.
- Used for pneumonia, upper respiratory infections, genital chlamydia infections |
|
|
Term
|
Definition
• Another class of β-lactam antibiotics
• Structure renders the β-lactam ring highly resistant to β-lactamases
• Meropenem:
• Mostly renal excretion
• Toxicity:
- Well tolerated
- ≈ 10% cross allergenicity with penicillins; ≈ 50% if anaphylaxis to penicillin
• Spectrum:
- Very broad
- Gram positive cocci, aerobic gram negative rods including resistant gram negative rods (Pseudomonas aeruginosa and Enterobacter spp.), and anaerobes
• Niche:
- Nosocomial infections, febrile neutropenia, complicated intra-abdominal infections
- Alternative to 3rd and 4th generation cephalosporins for CNS infections |
|
|
Term
|
Definition
• Class: a lincosamide antibiotic (the only one)
• Inhibits the 50S ribosomal subunit
• Bacteriostatic
• Intravenous or oral bioavailability
• Toxicity:
- Associated with Clostridium difficile colitis
• Spectrum and therapeutic niche:
- Narrow spectrum: gram positive cocci, anaerobes excluding the gut anaerobe B. fragilis
- Used for dental infections, mixed infections with anaerobes |
|
|
Term
|
Definition
• Class: an oxazolidinone (a new class)
• Inhibits the 50S ribosomal subunit
• Can be either bacteriostatic or bactericidal
• Intravenous or oral bioavailability
• Toxicity:
- Dose-dependent thrombocytopenia
- serotonin syndrome when used in combination with many anti-depressants
• Spectrum and therapeutic niche:
- Only active against gram positives
- developed for treatment of resistant gram positive cocci (MRSA, VRE) |
|
|
Term
| Folate synthesis inhibitors |
|
Definition
| Trimethoprim and the sulfonamides inhibit folic acid synthesis, an essential precursor for purine synthesis. The sulfonamides were the first clinically useful antimicrobials. They are structural analogues of para-aminobenzoic acid (PABA), which condenses with pteridine in the first step in bacterial synthesis of dihydrofolate. Human cells don’t synthesize dihydrofolate (they rely on dietary folate), and this is the basis for the sulfonamides’ selective toxicity. Trimethoprim structurally resembles folic acid, and inhibits the enzyme dihydrofolate reductase. Its specificity for bacteria is due to its much greater affinity for bacterial dihydrofolate reductase than for the human enzyme. Sulfonamides and trimethoprim inhibit folate synthesis at two different steps. As a result, the two act synergistically when used in combination; furthermore, if a bacterium is resistant to one, it may be sensitive to the other. As a result, the sulfonamides and trimethoprim are almost always used in combination. The most widely used combination is trimethoprim/sulfamethoxazole (Bactrim). |
|
|
Term
| Trimethoprim/Sulfmethoxazole |
|
Definition
• Inhibit bacterial folic acid synthesis:
- Sulfonamides mimic PABA
- Trimethoprim resembles folate—inhibits dihydrofolate reductase
• Synergistic
• Bactericidal in combination
• Metabolism:
- Sulfonamides—some hepatic metabolism and excreted in urine
- Trimethoprim—excreted unchanged in urine
• Oral or intravenous
• Modest tissue levels
• Toxicity:
- Generally well tolerated
- Sulfonamides—rash common; can precipitate in urine
- Trimethoprim—bone marrow suppression and megaloblastic anemia
• Spectrum and therapeutic niche:
• Active against many gram positive and gram negative organisms
- Simple urinary tract infections
- Community-acquired MRSA
• Active against many non-bacterial pathogens
- Pneumocystis jiroveci
- Prophylaxis for immunocompromised patients |
|
|
Term
| Fluoroquinolones: Ciprofloxacin |
|
Definition
• Inhibits topoisomerase II (DNA gyrase)
- Inhibits DNA replication
• Bactericidal
• The first fluoroquinolones to be useful for treatment of serious infections
• Oral bioavailability equivalent to intravenous
• Good tissue levels
• Renal elimination
• Toxicity:
- Mostly well tolerated
- gastrointestinal
- Tendonitis
- Cartilage problems in developing animals
- QT prolongation
• Spectrum:
- Aerobic gram negative bacilli including Pseudomonas aeruginosa
- Staphylococci
- Atypical bacteria—chlamydia, mycoplasma, legionella
- NO activity against streptococci
• Niche:
- Urinary tract infections
- oral treatment of Pseudomonas
- NOT useful for empiric treatment of respiratory infections due to absence of anti-streptococcal activity |
|
|
Term
• Dx: Community Acquired Pneumonia
• S. pneumoniae
• H. influenzae
• Legionella pneumophila |
|
Definition
Rx:
Ceftriaxone plus azithromycin |
|
|
Term
Dx: cystic fibrosis exacerbation
Pseudomonas aeruginosa |
|
Definition
Rx: anti-Pseudomonal regimen
e.g., ceftazidime, meropenem, ciprofloxacin
Must tailor to cultures and look at old cultures |
|
|
Term
Dx:
Likely S. aureus
Methicillin resistant? |
|
Definition
Rx:
Drainage
Methicillin resistant--bactrim or doxycycline (oral treatments) |
|
|
Term
Dx: Diverticulitis with diverticular abscess
Colonic flora
Aerobic gram negatives (e.g., E. coli)
Streptococci and enterococci (gram positive cocci)
Anaerobes including Bacteroides fragilis |
|
Definition
Rx: many possibilities
drainage
Ampicillin/clavulanate (probably beginning with IV equivalent)
meropenem |
|
|
Term
Dx: Acute bacterial meningitis
Streptococcus pneumoniae
Neisseria meningitidis |
|
Definition
Rx:
Must reach CNS
Must include treatment for resistant streptococci
Ceftriaxone plus vancomycin |
|
|
Term
| General virulence factors |
|
Definition
Adhesins
Extracellular enzymes
Anti-phagocytic factors
Toxins |
|
|
Term
|
Definition
○ Staphylococcus spp.
○ Streptococcus spp.
○ Listeria monocytogenes
○ Clostridium spp.
○ Bacillus anthracis
○ Mycobacterium spp. (acid-fast) |
|
|
Term
|
Definition
• Neisseria spp.
• Escherichia coli
• Shigella spp.
• Salmonella spp.
• Pseudomonas aeruginosa
• Bacteroides fragilis
• Helicobacter pylori
• Haemophilus influenzae |
|
|
Term
|
Definition
• Staphylococcal pathogens: Gram-positive cocci
• clusters of cells; catalase-positive
○ S. aureus - most common; skin diseases, food poisoning
○ S. epidermidis - endocarditis, infections of catheters and implants
○ S. saprophyticus - urinary tract infections
• opportunistic normal microbiota: nose (S. aureus); skin (S. epidermidis)
• major source of nosocomial infections; can be resistant to multiple penicillin derivatives, e.g., MRSA - Methicillin-Resistant S. aureus |
|
|
Term
|
Definition
• Streptococcal pathogens: Gram-positive cocci
• aerotolerant anaerobic; chains of cells
• catalase-negative (vs. catalase-positive Staphylococci) |
|
|
Term
|
Definition
(Group A strep)
• pharyngitis; cellulitis; Group A, beta-hemolytic streptococci (GABHS) |
|
|
Term
|
Definition
• (Group B strep)
• neonatal sepsis and meningitis; Group B, beta-hemolytic streptococci |
|
|
Term
|
Definition
• (Group D strep)
• hospital-acquired urinary tract infections; endocarditis; gamma-hemolytic streptococci |
|
|
Term
|
Definition
• - pneumococci
• pneumonia, meningitis, sinusitis, otitis media; alpha-hemolytic pneumococci |
|
|
Term
|
Definition
• (e.g., Streptococcus mutans)
• oral microbiota, dental plaque; endocarditis; alpha-hemolytic viridans streptococci |
|
|
Term
| Antigenic classifications of streptococci |
|
Definition
Lancefield groups - Group A, B, C, D, . . .U
based on antigenic differences in the C carbohydrate |
|
|
Term
| S. pyogenes virulence factors |
|
Definition
• M protein: pili-like structures; superantigen
○ attachment: different M proteins have different tissue specificity
○ anti-phagocytic: interferes with complement component C3b
• Hyaluronic acid capsule: anti-phagocytic
• Streptokinase: dissolves fibrin (blood) clots
• Hyaluronidase: spreading factor
• Hemolysins - Streptolysin S and O; responsible for strep throat
S: oxygen-stable hemolysin; responsible for blood agar reaction
- toxic to tissue, leukocytes, red blood cells
O: oxygen-labile hemolysin
- binds cholesterol, toxic to heart and other tissues
• Erythrogenic toxin - encoded on lysogenic bacteriophage; superantigen
- responsible for Scarlet fever rash
• Exotoxin A - causes streptococcal toxic shock syndrome
- same mechanism as staphylococcal TSST; superantigen
• Exotoxin B - causes necrotizing fasciitis … “flesh-eating” bacteria
- can cause death in ~30% of cases due to rapid effects |
|
|
Term
| Poststreptococcal Sequela Diseases |
|
Definition
• Caused by host immunological reactions to S. pyogenes M protein
• occur after initial infection, usually as a result of untreated infections
• antibodies against different M proteins react with different host cells
• Rheumatic Fever: antibodies against certain M proteins cross-react with myosin protein in heart; damage to heart valves
• Acute Glomerulonephritis: M protein-49 antigen-antibody complexes lodge in glomeruli of kidney |
|
|
Term
|
Definition
• Streptococcus pneumoniae (pneumococci): Gram-positive cocci
- pairs or short chains of cells
- leading cause of meningitis in adults
- originally found by Pasteur in pneumonia patients, hence the name
• Virulence factors:
• capsule: only encapsulated strains are virulent
• secretory IgA protease - destroys IgA antibodies
• pneumolysin:
- suppresses phagocytosis by interfering with lysosomes
- cytolytic toxin: makes pores in cell membrane
- activates complement |
|
|
Term
|
Definition
• Listeria monocytogenes: Gram-positive bacillus; intracellular pathogen
- meningitis in newborns, immunocompromised individuals
- enters body through contaminated food or water
• Virulence factors
- listeriolysin O: breaks down phagosome before lysosome can fuse
- moves from cell to cell using host’s actin network (actin tails)
- evades host immune system |
|
|
Term
|
Definition
• Clostridium spp.: Gram-positive anaerobic bacilli; endospore formers
- C. tetani: tetanus
- C. perfringens: gangrene
- C. botulinum: botulism
- C. difficile: severe diarrhea
--- pseudomembranous colitis can result from long-term antibiotic treatment
• Virulence Factors:
- endospores: resist a variety of environmental stresses; heating
- multiple exotoxins (next slides)
- collagenase
- proteases
- hyaluronidase |
|
|
Term
|
Definition
• Clostridium botulinum
- blocks release of activating neurotransmitter acetylcholine
- inhibits components of exocytosis (VASP, SNAPs)
- muscles can’t contract - flaccid paralysis |
|
|
Term
|
Definition
• Costridium tetani
- inhibits the release of inhibitory neurotransmitters
- inhibits exocytosis like botulinum toxin
- muscles can’t relax - spastic, rigid paralysis; mortality rate is very high |
|
|
Term
|
Definition
• Bacillus anthracis: Gram-positive bacillus; endospore formers
• three portals of entry:
- inhalation (most lethal) - inhale endospores
- gastrointestinal (rare)
- cutaneous (most common) - eschar lesion
• Virulence factors:
- endospores
- glutamic acid capsule
- anthrax toxin: cytotoxic
○ PA: protective antigen
- B subunit of A-B toxin
○ EF: edema factor
- adenylate cyclase
○ LF: lethal factor
- protease |
|
|
Term
|
Definition
• Mycobacterium spp.: acid-fast bacilli; obligate aerobe
- intracellular pathogens
- Mycobacterium tuberculosis: tuberculosis
---- grows within alveolar macrophages in lungs
- Mycobacterium leprae: leprosy
---- grows within neuroglia of peripheral nerve
endings; skin cells of fingers, toes, lips
• Virulence Factors:
- mycolic acid in cell wall; allows cells to remain viable for long periods in aerosol drops
- cord factor: cell wall protein that causes daughter cells to remain attached in parallel alignment
○ toxic to mammalian cells |
|
|
Term
|
Definition
• Neisseria spp.: Gram-negative diplococci
- Neisseria meningitidis – meningococcal meningitis
○ high fever, headache, stiff neck, nausea
- Neisseria gonorrhoeae – gonorrhea; PID
• Virulence factors:
- polysaccharide capsule (N. meningitidis)
- pili (N. gonorrhoeae) are used for attachment to genital and other mucosal epithelial cells
- endotoxin (lipid A)
- protease that cleaves IgA antibodies |
|
|
Term
| bacterial gastroenteritis |
|
Definition
• Inflammation of the stomach or intestines due to the presence of bacteria
• Associated with contaminated foods or water and poor living conditions
• General features:
- symptoms include nausea, vomiting, diarrhea, abdominal pain
- Dysentery, a severe gastroenteritis, produces loose, frequent stool containing mucus and blood
• Examples:
- Cholera - Vibrio cholerae - “rice-water” stools
- Traveler’s diarrhea - E. coli
- E. coli O157:H7 infection; ~10 cells is enough to cause disease
- Shigellosis - Shigella spp.
- Campylobacter diarrhea - Campylobacter jejuni
- Salmonellosis - Salmonella enteritidis and Salmonella typhimurium
- Typhoid fever - Salmonella typhi |
|
|
Term
| Escherichia coli diseases |
|
Definition
• Escherichia coli: Gram-negative bacillus
- facultative anaerobe
- normal fecal flora
- lactose fermentor; distinguishes it from Shigella and Salmonella spp.
• E. coli cell surface antigens:
- O antigen (part of LPS): >150 variants
- H antigen (flagellar): >50 variants
- K antigen (capsule): >90 variants
• Virulence factors:
- adhesins
- fimbriae/pili
- endotoxin (lipid A)
- exotoxins |
|
|
Term
| Enterohemorrhagic E. coli (EHEC): |
|
Definition
• E. coli O157:H7 is example
- produces shiga-like enterotoxin (bacteriophage-encoded) |
|
|
Term
| Enterotoxigenic E. coli (ETEC): |
|
Definition
• “traveler’s diarrhea”
- produces two diarrhea-producing enterotoxins |
|
|
Term
| Enteropathogenic E. coli (EPEC): |
|
Definition
• diarrheal disease in infants, children
- may produce shiga-like enterotoxin |
|
|
Term
| Enteroinvasive E. coli (EIEC): |
|
Definition
• invasive disease in colon
- does not produce toxins!; invasiveness similar to Shigella |
|
|
Term
| Uropathogenic E. coli (UPEC): |
|
Definition
• Urinary Tract Infections (UTIs)
P-pili: major virulence factor |
|
|
Term
|
Definition
• Signs and symptoms: abdominal cramps, bloody stools, nausea, vomiting, diarrhea
- a leading cause of infant mortality world-wide
• Etiological agents: Shigella spp.
- Gram-negative bacillus
- Shiga toxin: A-B toxin; N-glycosidase that modifies 28S rRNA, thereby inhibiting translation |
|
|
Term
|
Definition
• Salmonella enterica serotypes: Gram-negative bacillus
- Enteritidis and Typhimurium - gastroenteritis
Typhi and Paratyphi - typhoid fever
• Virulence Factors:
- endotoxin; exotoxins
- fimbriae: attachment to the mucosal surface
- antigenic variation: change expression of flagellar H antigens
- Pathogenicity Islands: chromosomal DNA
○ Salmonella Pathogenicity Island 1 (SPI-1)
- bacterial-directed endocytosis
○ Salmonella Pathogenicity Island 2 (SPI-2)
- prevents phagosome-lysosome fusion |
|
|
Term
|
Definition
• Pseudomonas aeruginosa: Gram-negative strict aerobic bacillus
- ubiquitous environmental microorganism
- resistant to a wide variety of antibiotics and disinfectants
- major nosocomial opportunistic pathogen, especially burn patients
- very serious threat to cystic fibrosis patients
• Virulence Factors:
- fimbriae and adhesins
- capsule
- pyocyanin: blue-green pigment
○ impairs ciliary function and triggers superoxide formation
- elastase
○ destroys elastin-containing tissues (vessels, lung, skin)
- bacteriocins
○ similar to antibiotics, but directed at microbes that are similar to Pseudomonas |
|
|
Term
|
Definition
• Bacteroides fragilis (“B. frag”): Gram-negative bacillus
- obligate anaerobe
- predominant microbe in the colon
- significant opportunistic pathogen - perforations in colon allow B. frag. to leak out and cause disease
○ septicemia; abscesses in peritoneal cavity
• Virulence Factors:
- endotoxin (lipid A)
- enterotoxin: can cause diarrhea
- capsule: induces abscess formation
- protease: degrades complement components
- most species make b-lactamase: resistant to penicillins |
|
|
Term
|
Definition
- Helicobacter pylori: Gram-negative, curved, motile
• peptic ulcers: recently recognized as infectious disease
• Warren and Marshall: Nobel Prize in 2005
○ to fulfill Koch’s 3rd & 4th postulates,
Marshall infected himself !!
§ Virulence factors:
• urease
○ converts urea to bicarbonate, which neutralizes stomach acid
• flagella
• adhesins
• toxins |
|
|
Term
|
Definition
• Haemophilus influenzae: Gram-negative, pleomorphic coccobacillus
- very small; requires heme and NAD+ for growth
- meningitis; pneumonia (not flu)
○ leading cause of bacterial meningitis
prior to develop of Hib vaccine
• Virulence factors:
- capsule: seven serotypes (a-g)
○ 95% of infections are type b (Hib)
○ H. influenzae type b (Hib) vaccine is very effective
- endotoxin (lipid A)
- fimbriae
- IgA protease |
|
|
Term
|
Definition
| - relative ability to cause disease |
|
|
Term
| Virulence factor categories |
|
Definition
1. colonization
2. invasion
3. spread
4. avoidance of immune mechanisms |
|
|
Term
|
Definition
- lipopolysaccharide - part of Gram negative cell wall
- Lipid A component is the toxic portion |
|
|
Term
|
Definition
- proteins synthesized by microorganism that when released into extracellular space may have local or distant effects
- NOT part of membrane |
|
|
Term
|
Definition
| Dose needed to kill 50% of host |
|
|
Term
| Exotoxin mechanism of action |
|
Definition
- specific unlike endotoxins which elicit overall immune response
1. membrane disruption
2. interruption/alteration of cellular enzymes
3. indiscriminate activation of T-cells |
|
|
Term
| Fever in exo vs endotoxins |
|
Definition
| - in endo usually but not in exo |
|
|
Term
| Endo and exotoxins and heat |
|
Definition
- exo = protein = heat labile
- endo = lipopolysaccharide = heat stable |
|
|
Term
| immunogenic exo vs endotoxins |
|
Definition
- exo sometimes immunogenic
- endo not immunogenic |
|
|
Term
| Vaccines in endo vs exotoxins |
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Definition
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Term
| Membrane disruption by exotoxins |
|
Definition
1. cytolytic
2. disrupt phospholipid layer
3. form protein channel
4. enzymes: phospholipase, amphipathic peptides |
|
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Term
| Membrane disrupting exotoxins |
|
Definition
1. S. aureus
2. S. pyogenes (group A beta hemolytic streptococcus)
3. S. pneumoniae
4. C. perfringens |
|
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Term
|
Definition
- alpha toxin
- forms pores in membrane
- tissue damage, spreading |
|
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Term
|
Definition
- streptolysin O
- forms pores in membrane
- cytotoxin |
|
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Term
|
Definition
- pneumolysin
- forms pores in membrane
- lung damage, inflammation |
|
|
Term
|
Definition
- alpha toxin
- phospholipase
- kills phagocytes; tissue damage |
|
|
Term
| Complications of S. pyogenes exotoxins |
|
Definition
1. erythrodema
2. local necrosis
3. necrotizing fascitis (coagulative necrosis/gangrene)
4. desquamation |
|
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Term
|
Definition
- B is specific for receptor in a host cell (intracellular targets)
- A is toxin that can disrupt anywhere but is guided by B |
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Term
| Intracellular activity of A-B toxins |
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Definition
1. protein synthesis (diphtheria)
2. signal transduction (cholera)
3. intracellular trafficking (botulism)
4. cytoskeleton (clostridium) |
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Term
| Diphtheria and A-B toxins |
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Definition
- interrupt protein synthesis (A subunit of diphtheria toxin ADP-ribosylates elongation factor-2)protein synthesis is terminated
- cause cell death |
|
|
Term
|
Definition
- interfere with signal transduction (cause constitutive activation of G-protein receptor and can't shut off adenyl synthase)
- increase cAMP changing cell function |
|
|
Term
|
Definition
- intracellular trafficking: extrememly potent blocks the Ach from being released and no muscle contractions can occur)
- specific
- flaccid paralysis
- totally afebrile, no cell death or inflammatory response! |
|
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Term
| Clostridium tetani and A-B toxins |
|
Definition
- blocks neurotransmitter release from inhibitory neurons resulting in spastic paralysis
- another toxin interrupts cytoskeleton
- causes disassembly of actin
- not major action*** |
|
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Term
|
Definition
- very rare in US
- associated with pseudomembrane in pharynx that eventually closes off airway
- was major cause of death in early twentieth century in US
- highly effective vaccine against toxin |
|
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Term
| How you contract botulism |
|
Definition
1. ingestion of preformed toxin
2. ingestion of organism and then production of toxin
3. weakness (CNS bulbar signs first like diplopia) |
|
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Term
|
Definition
- puncture wound then you get germination of spores
- causes spasticity |
|
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Term
|
Definition
- BoTox
- whenever want flaccid paralysis:
1. if you have spasticity
2. blepharospasm (vocal cord spasm)
3. wrinkles |
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|
Term
|
Definition
- non-specific binding (side not active site)
- bypass normal binding mechanisma nd activate a whole bunch of cells that shouldn't be (get way too many cytokines
1. antigen-presenting cells present peptide in MHC II
2. only one clone of helper T-cells recognize antigen-MHC complex
3. superantigens bind directly and indiscriminately to MHC and T-cell receptors
4. Therefore activate many clones of T-cells (excessive cytokines produced = shock) |
|
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Term
| Superantigen bacteria names |
|
Definition
1. S. aureus: causes toxic shock and food poisoning
2. S. pyogenes: causes toxic shock |
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|
Term
| Toxic shock syndrome symptoms |
|
Definition
1. fever (not with A-B toxins, but yes here with superantigen that caused excess cytokines)
2. hypotension
3. diffuse erythrodema (sunburn-like rash: flat, blanches, warm and tender)
4. red eyes (due to mucous membrane involvement)
6. sluggish capillary refill (looked at on feet in examples)
5. multi-system organ involvement |
|
|
Term
| S. aureus exotoxin: TSST-1 |
|
Definition
- may be associated with tampon use: but now equally common in boys
- treatment is primarily fluids and pressure support for hypotension
- antibiotics to clear bacteria
- at risk for recurrence (can't really sterilize patient) |
|
|
Term
| Treatment of toxic shock syndrome |
|
Definition
| Nafcillin good for S. aureus because it is a beta-lactamase producer |
|
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Term
|
Definition
| - used to treat pseudomonas and other gram negatives |
|
|
Term
| antibiotic resistance: enzymatic modification or inactivation |
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Definition
- causes loss of function
- either cleave antibiotic to inactivate it (like beta lactamase cleavage of beta lactam ring)
- or modify antibiotic so it can't fit in receptor |
|
|
Term
| Beta- lactamase plasmid vs chromosomal |
|
Definition
- often plasmid mediated:
1. simple structure
2. easy to spread
3. relatively easily overcome
-May be chromosomal: metalloproteases (much chunkier)
1. more complex structure
2. harder to spread
3. harder to overcome |
|
|
Term
| S. aureus beta-lactamase production |
|
Definition
- makes it as needed
- has a sensor (blaR1) that recognizes need |
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Term
| plasmid mediated beta-lactamase producing bacteria |
|
Definition
1. S. aureus
2. B. fragilis
3. E. Coli (50% do)
4. H. influenzae (40%)
5. N. gonorrhoeae (variable) |
|
|
Term
| chromosomally mediated beta-lactamase producing bacteria |
|
Definition
1. enterobacter spp.
2. pseudomonas |
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|
Term
A twenty two year old woman develops painful urination and urgency associated with fever, chills, and vomiting. Which would you treat her with?
1. penicillin
2. piperacillin
3. ampicillin
4. ceftriaxone |
|
Definition
| - ceftriaxone because the rest are natural penicillins that are not able to get past beta lactamase |
|
|
Term
| Treatment strategies for beta-lactamase producing organisms |
|
Definition
1. inactivate beta-lactamase with inhibitors
2. use a penicillin drug that protects the beta-lactam ring like nafcillin
3. use drugs without beta lactam rings:
- cephalosporin (cefazolin)
- macrolide (erythromycin) |
|
|
Term
| Beta-lactamase inhibitors |
|
Definition
1. sulbactam, tazobactum, beta-clavulanate: combine with penicillin (like augmentin with amox and beta-clav)
2. suicide inhibitors: have their own beta lactam ring and when the beta-lactamase cleaves it they both die (work 1:1)
- very weak cephalosporin antibiotics
- organism now susceptible to penicillin products |
|
|
Term
| Penicillinase resistant penicillins |
|
Definition
- block access to beta lactam ring (nafcillin)
- very active against S. aureus |
|
|
Term
| Enzymes that modify antibiotics |
|
Definition
- antibiotic is modified so no longer functions
- three types of aminoglycoside (GENTAMYCIN) modifying enzymes:
1. acetylation of amino group
2. adenylation of hydroxyl group
3. phosphorylation of a hydroxyl group
- confer high level of resistance to aminoglycosides
- plasmid or transposon mediated |
|
|
Term
| Organisms that alter target sites for resistance to antibiotics |
|
Definition
1. S. pneumoniae
2. S. aureus |
|
|
Term
|
Definition
- each type of bacteria has 5 or more
- they are transpeptidases that cross-link peptidoglycan penicillin just happens to bind to and cleave |
|
|
Term
| Penicillin resistant S. pneumoniae |
|
Definition
- developed altered penicillin binding proteins
- several PBPs involved
- chromosomally mediated
- stable |
|
|
Term
| Genetic basis for alteration of PBPs |
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Definition
| - over time slowly let altered DNA into genes that code for PBPs until it reached an amount that the binding proteins were altered |
|
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Term
|
Definition
- mean inhibitory concentration
- amount of drug necessary to inhibit growth of 50% of the organisms |
|
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Term
|
Definition
| - mean amount of drug necessary to inhibit growth of 90% of the organisms |
|
|
Term
| MIC and point changes in PBPs |
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Definition
| - each additional point mutation results in a higher MIC |
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Term
Which of the following is hardest to get antibiotics to?
1. urine
2. pleural fluid
3. cerebrospinal fluid |
|
Definition
3. cerebrospinal fluid
- harder to overcome changes in PBPs when you have a harder site of infection to get to like cerebrospinal fluid |
|
|
Term
| Would amox-clavulanate be more effective at treating penicillin resistant S. pneumoniae than amoxicillin alone? |
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Definition
| - no because S. pneumoniae does not use beta lactamases it alters the PBPs and clavulanate does not overcome PBPs better than amox in high concentrations |
|
|
Term
| Methicillin resistant S. aureus |
|
Definition
-MRSA
- chromosomally mediated: mecA gene/locus
- has a NEW transpeptidase (PBP) that cross-links peptidoglycan in face of Beta-lactam drugs
- confers resistance to ALL beta-lactam drugs
- beta-lactam antibiotics cannot bind to new proteins |
|
|
Term
Which of the following can you treat MRSA with?
1. penicillin in high concentrations
2. cefazolin
3. nafcillin
4. amox-clavulate |
|
Definition
- NONE of these will be useful
- MRSA has diff binding proteins so no beta-lactam drugs can bind! |
|
|
Term
| Nosocomial MRSA vs community acquired: molecular basis |
|
Definition
1. nosocomial: huge cassette with mecA gene
- not very mobile
- resistant to many antibiotics
2. community: small cassette with mecA gene
- very mobile
- resistant to few antibiotics |
|
|
Term
|
Definition
- chromosomally mediated (large cassette)
- restricted to hospitals and health care
- blood stream and catheter infections
- spread by contact
- does not survive well without antibiotic pressure |
|
|
Term
| Community associated MRSA |
|
Definition
- chromosomally mediated (small cassette)
- occurs in healthy individuals
- how it gets in: skina nd skin structure (80%), pneumonia (10-15%), blood stream (5%)
- spread by contact
- survives well in all environments |
|
|
Term
| How do we treat nosocomial MRSA? |
|
Definition
1. vancomycin
2. linezolid
- drugs that do not act on penicillin binding proteins |
|
|
Term
| How do we treat community associated MRSA? |
|
Definition
1. TMP-SMX
2. clindamycin
3. tetracycline
4. vancomycin
5. linezolid
6. ciprofloxacin |
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|
Term
| Innate immune response characteristic |
|
Definition
1. non-specific response
2. fast response (minutes)
3. no memory |
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|
Term
| Adaptive immune response characteristics |
|
Definition
1. very specific
2. slow response (days)
3. memory: adaptability and improvement |
|
|
Term
| Innate immune response components |
|
Definition
1. natural barriers (skin, mucous membranes, acid in stomach)
2. Cells: phagocytes, neutrophils, monocytes, NK cells
3. secreted molecules (soluble factors): complement system, interferons
4. pattern-recognition molecules |
|
|
Term
| Adaptive immune response components |
|
Definition
1. lymphocytes (B and T cells)
2. secreted molecules (soluble proteins): antibodies, cytokines
3. antigen-recognition molecules |
|
|
Term
|
Definition
- chemical messenger of immune system
- low molecular weight
- multiple sources and targets
- usually work through paracrine function (G-CSF is endocrine) and occasionally autocrine too |
|
|
Term
| Communication between innate and adaptive immune systems |
|
Definition
1. cytokines: communication
2. complement: effectors
- also cells:
1. APCs (macrophages nad dendritic cells)
- innate digest foreign material and show it to the cells of the adaptive arm |
|
|
Term
|
Definition
- specificity of the immune response dependent of T and B cells recognizing foreign molecules
2. lymphocytes participating in the immune response have antigen specific receptors:
- immunoglobulin (antibody) for B cells
- T-cell receptor for T cells |
|
|
Term
| Clonal selection theory of immunology |
|
Definition
1. clones of B and T cells that are self-reactive must be deleted
2. each lymphocyte carries on its surface receptor molecules of only a single specificity
3. T and B cells of myriad specificities exist before any contact with foreign material |
|
|
Term
| Divisions of the adaptive response |
|
Definition
1. humoral immunity
2. cellular immunity |
|
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Term
|
Definition
- reacts to NATIVE antigen (not processed)
- mediated by B cells and their antibodies
- work on extracellular pathogens more than intracellular
- only make antibody to what the B-cell is bound to |
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|
Term
|
Definition
- Fab: variable region for antigen binding
- Fc: common binding region |
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|
Term
|
Definition
- T-cells bind antigen PROCESSED by antigen presenting cells at a specific antigen binding site (T-cell receptor)
- mediated by T-cells (cytotoxic and helper T-cells) and cytokines
- work on intracellular pathogens |
|
|
Term
|
Definition
- command and control cells master lymphocyte that tells everyone else what to do
- express CD4+ markers on surface
- inolved in: communication, coordination, inflammation
- can directly kill cells but that is not their main job
- divided into TH-1 and TH-2 with distinct regulatory properties |
|
|
Term
|
Definition
- express CD8+ markers on surface
- kill cells |
|
|
Term
|
Definition
- effector helper T cell
- activate macrophages and cytotoxic T cells |
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|
Term
|
Definition
|
|
Term
|
Definition
- kill one thing specifically:
1. perforin-dependent killing (granzyme B)
2. Fas-dependent killing (caspases) |
|
|
Term
| Humoral and cell-mediated immunity systemic vs local |
|
Definition
- humoral once make antibodies can go anywhere in body so more systemic
- cell-mediated cells stay put so more local |
|
|
Term
|
Definition
Brain: tight cell junctions
Eyes: tears
Mouth: lysozyme
Respiratory: mucous, cilia
GI: gastric acid, bile, mucous, normal flora
Urinary: flushing, acid
Skin |
|
|
Term
| If a person has a defect in the barrier function of his skin, which bacterium could he most likely be infected with? |
|
Definition
| - staph aureus normally part of skin flora |
|
|
Term
|
Definition
1. S. pneumoniae
2. Haemophilus |
|
|
Term
|
Definition
| - pseudomonas (like in cystic fibrosis) |
|
|
Term
| Bacterium most at risk for when have BBB lesion |
|
Definition
|
|
Term
| Chemical barriers and abnormalities |
|
Definition
1. defensins: cationic polypeptides
2. acid in: stomach, sebaceous glands, vagina
Abnormalities:
1. gastic stapling
2. inhibition of gastric acid secretion |
|
|
Term
| As part of the innate immune system how do neutrophils work and what do they work on? |
|
Definition
1. phagocytosis
2. bacteria/fungi |
|
|
Term
| As part of the innate immune system how do eosinophils work and what do they work on? |
|
Definition
|
|
Term
| As part of the innate immune system how do macrophages work and what do they work on? |
|
Definition
1. phagocytosis
2. antigen presentation |
|
|
Term
| As part of the innate immune system how do mast cells work and what do they work on? |
|
Definition
1. histamine release
2. allergy |
|
|
Term
| As part of the innate immune system how do natural killer cells work and what do they work on? |
|
Definition
1. lysis of cells
2. viruses |
|
|
Term
| Differences between neutrophil and macrophages in innate immune response |
|
Definition
1. N: rapid increase in number in infecion. M: little increase
2. N: noramlly in inflamed tissue. M: in healthy tissue
3. N: single mature form. M: many mature forms
4. N: forms pus. M: forms granuloma
5. N: short lifespan. M: long lifespan |
|
|
Term
|
Definition
- phagocyte
- long lived
- in immature state in most tissues
- recognize and phagocytize foreign particles
- MOBILE (take antigens to areas with more defenses like lymph nodes)
- present antigen to T-cells |
|
|
Term
| Mannan-binding lectin receptor |
|
Definition
- pattern recognition receptor
- microbe-expressed polysaccharides with a sugar composition and residue spacing not found on host cells |
|
|
Term
|
Definition
- recognize specific microbial components
- big binding cleft that recognizes polysaccharides in bacteria but not humans |
|
|
Term
| Myeloperoxidase and phagocyte NADPH oxidase |
|
Definition
- key enzymes in making reactive oxygen species
- catalase protect the cytoplasm from the toxic metabolites |
|
|
Term
| Oxygen dependent intracellular destruction mechnisms |
|
Definition
1. NO production
2. iron chelation: transferrin, lactoferrin |
|
|
Term
| Chronic granulomatous disease |
|
Definition
Can digest organism and make phagolysosome but can't generate toxic metabolites
- happens with catalase positive (staph aureus, aspergillus) organisms because the catalase breaks up H2O2 that it makes and the neutrophils are not able to make it themselves
- get chronic inflammation |
|
|
Term
| Laboratory diagnosis of chronic granulomatous disease (CGD) |
|
Definition
1. nitroblue tetrazolium test (put neutrophils in solutioan dns ee if they can reduce it, if can't they are missing myeloperoxidase or the NADPH oxidase)
2. neutrophil oxidative burst assay (same as other) |
|
|
Term
| Downside to inflammation with neutrophils |
|
Definition
- great protective mechanism
- but it causes a lot of local dmage |
|
|
Term
|
Definition
acts on: vascular endothelium
actions: increased permeability, stimulates IL-6 production |
|
|
Term
|
Definition
acts on: liver
actions: production of acute phase proteins (C-reactive protein; fever) |
|
|
Term
|
Definition
acts on: vascular endothelium
actions: activation of endothelium, attraction/activation neutrophils |
|
|
Term
|
Definition
acts on: NK cells
actions: activakes NK cells, inflences lymphocyte differentiation |
|
|
Term
|
Definition
acts on: vascular endothelium
actions: increased permeability, activation of endothelium, increases lymphokine synthesis by Th cells |
|
|
Term
|
Definition
acts on: bone marrow
actions: increased production of myeloid precursors |
|
|
Term
| Macrophages respond to cytokines |
|
Definition
1. chemokines (IL-8) migrate to site of inflammation
2. interferons
- gamma-interferon (IFN-gamma) highly activated and expresses more receptors which increases macrophages |
|
|
Term
| Which proinflammatory cytokines are released by macrophages after exposure to microorganisms in acute phase response |
|
Definition
1. IL-1 (most classic for causing fever)
2. IL-6
3. TNF-alpha |
|
|
Term
| Liver synthesizes which molecules in the acute phase response? |
|
Definition
1. C-reactive protein (measure this because can't measure interleukins or TNF) it is a measure of inflammatory response
- it binds to membrane of certain microorganisms
- activates soluble components (Complement)
2. also releases mannin binding protein |
|
|
Term
|
Definition
-ANC less than 500/mL
- increased risk of local and systemic bacterial and fungal infections |
|
|
Term
|
Definition
- diff from other lymphocytes
- NO ANTIGEN receptor
- REQUIRE NO prior stimulation
- recognize altered feature on membranes of cells: cancer, virus infected
- kills cells that fail to express adequate self-antigen (MHC-I)
- by formation of pores, triggering apoptosis |
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