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107 Cards in this Set

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Listeria monocytogenes
Associated with:
Bacterial meningitis in neonates

ID:
Gm+ rods (bacilli)
Catalase positive
High or low WBCs

Found in:
Contaminated food (manure)
Soft cheeses (Mexican?)
Poultry products
Organic products

Special features: tumbling motility
E. coli K1
Associated with:
Bacterial meningitis in infants

ID:
Bacterial meningitis in neonates

Special features: Not very antigenic, so most adults don't have specific IgG for K1 capsular antigen
Coagulase negative Staph
Assoc. with:
- Bacterial meningitis in premature infants
- Commensal flora of the skin

ID:
Gm+
Coag negative
Streptococcus pneumoniae
Assoc. with:
- Bacterial meningitis in infants and children

Usually sporadic. Nasopharyngeal colonization can leading to bacteremia, seeding, and meningitis.

ID:
Encapsulated (requires specific IgG for good phagocytosis)

Treatment: Penicillin works, but need 20x the minimum inhibitory concentration for it to work in the CSF (10x the blood level).

So, the pneumococcal vaccines are used preventatively.
Neisseria meningitidis
Assoc. with:
- Bacterial meningitis in infants and children

ID:
Gram negative (LPS!)

Rapid uptake by epithelial cells via receptor-mediated endocytosis.

Encapsulated (requires specific IgG plus complement for good phagocytosis).

Some people are carriers, and are asymptomatic.

Because N. meningitidis is Gram-negative, LPS causes a fulminant meningitis with a rapid progression (violent host response to LPS).

"Meningitis belt" in Africa where N. meningitidis is endemic.

Vaccine exists for Types A, C, Y, and W135. Type B is associated with sporadic cases, and has sialic acid epitopes that look like self.

Prophylaxis includes Rifampin, Ciprofloxacin, Ceftriaxone (these all reach high enough levels in nasal secretions to work).
Haemophilus influenzae
Assoc. with:
- Bacterial meningitis in infants and children.

Also causes otitis.

ID:
Encapsulated with polyribose phosphate capsule (requires specific IgG for good phagocytosis). Acquires a Type B capsule.

Conjugate vaccine (diphtheria toxin, meningococcal OMP) has virtually eliminated this disease in children.
What are some factors that predispose to meningitis?
1) Infants 6 months to 2 years of age (after maternal IgG has run out, before they make their own efficiently)

2) Adults who lack specific IgG

3) Adults who lack splenic function

4) Anatomical defects (e.g., fracture) that allow bacterial entry to CNS

5) Complement deficiency
What is the pathogenesis of meningitis?
Hematogenous route (most common)

Extension from infection adjacent to the nervous system
How do meningitis-causing organisms enter the body?
- Attach to specific surface structures of nasopharyngeal/epithelial cells.

- Transported into blood stream via vacuole
How does IgA protect against meningitis? What defenses do bacteria have?
IgA in mucosal secretions inhibits adhesion of bacteria that cause meningitis.

This IgA is cross-reactive, having encountered similar organisms before.

Some bacteria (including S. pneumoniae) produce IgA proteases that cleave IgA at the hinge region, inactivating it.

Pathogenic bacteria also have capsules that evade complement-mediated phagocytosis.
What are some virulence factors of bacteria that cause meningitis?
- IgA proteases

- Anti-complement, anti-phagocytic polysaccharide capsules.
How do bacteria invade the subarachnoid space?
Cells in choroid plexus and cerebral capillaries have receptors that bacteria can bind to, allowing transport into CSF.

Outer membrane proteins, lipopolysaccharide (Gm -) and techoic acid (Gm +) evoke inflammatory response.

Example: Group B strep recognize specific receptors in meninges and are internalized by glial cells, which protect them from the immune response and antibiotics.
Why do bacteria proliferate so rapidly in CSF?
- No complement

- Ig levels very low

- No resident macrophages
What is the host response to meningitis-causing bacteria?
Cell wall fragments, peptidoglycan, and teichoic acid --> inflammatory cascade.

Endothelial expression of selections (ELAM-1), then integrins (ICAM-1, CD14) is upregulated to draw in neutrophils.

Gram-negative bacteria (LPS) also stimulated TNF-alpha and IL-1 expression, which further increases neutrophil diapedesis and binding via LAM-1.
What actually causes the pathology of meningitis?
The host response:

Activated leukocytes secrete ROS and enzymes (elastase) that directly damage tissue.

Pathological changes in the CSF occur (leukotrienes, vasoactive lipid autocoids) cause interstitial edema, impaired CSF resorption, and impairment of autoregulation of CNS blood flow.

Amount of inflammation is directly related to severity of presentation.
What are the sequelae of meningitis?
Increased intracranial pressure.

Increased CNS metabolism of glucose --> lactate production.

Vascular: vasculitis, vessel narrowing, thrombosis, ischemia or infarction of the brain
How has H. influenzae-type bacterial meningitis been virtually eliminated?
Development of an anti-capsular antibody for Type B capsular antigen (H. influenzae) in 1992. Prevents high-grade bacteremia needed to infect meninges.
Tell me a lot of stuff about Neisseria meningitidis.
Epi:
Sporadic disease: Type B
Epidemics: Types A and C
Other: D, X, Y, W135, 129E

Populations:
- infants under 1 year
- elderly
- military/crowded conditions
- people with earlier viral infections
- those who lack complement C5-9


Pathogenesis: Attachment to nasopharyngeal epithelium, receptor-mediated endocytosis, entry to bloodstream

Asymptomatic carriers: Those with antibodies to N. lactamica have cross-reactive immunity to N. meningitidis, but can carry it and infect others. Occurs in families and the military.

Virulence factors:
- IgA protease
- Sialylated glyco-conjugates that mimic neuronal adhesion molecules
- Type B capsule especially non-antigenic

Vaccine: Types A, C, Y, W135. Recommended if asplenic, terminal-complement deficient, in military, traveling to endemic areas, college freshmen.
What infection usually leads to pneumonia? What are some rarer causes?
Usually pneumococcal bacteremia.

Rarely: pneumonia, otitis, sinusitis.
What vaccines are available for pneumococcal meningitis?
Pneumococcus vaccine is 23-valent, based on capsular carbohydrate antigens. Used for adults and older children.

New "conjugate vaccine" for infants and young children has 7 common pneumococcal antigens linked to protein carriers to cause a T-cell response.
What is the clinical presentation of meningitis in neonates? Why are they so susceptible?
Clinical presentation is nonspecific: fever or no fever, lethargy, irritability, vomiting, seizures.

Susceptible due to:
- Lack of Ab response (after maternal Ab wears off)
- Defects in PMN chemotaxis
- Possible defects in bacterial killing
- Less highly developed BBB
What is the clinical presentation of meningitis in children and adults?
Children: Fever, headache, lethargy, vomiting, seizures. Stiff neck, back pain (but not always). May be flushed. May have altered consciousness.

Brudzinski sign: hip/knee flexion upon neck flexion.

Kernig sign: Pain upon knee extension when hips/knees are in flexed position.
What is the Brudzinski sign?
When patient's neck is flexed (forward), knees and hips reflexively flex.
What is the Kernig sign?
Meningitis.

When hip and knee are fully flexed, then knee is extended, pain is elicited.
What gives a lab diagnosis of bacterial meningitis?
- Elevated WBCs
- Cloudy CSF with elevated PMNs, elevated protein ( > 50 mg/dL), low glucose (less than half of serum glucose)

CSF may look yellowish due to RBC breakdown and protein. Will look grossly turbid if WBCs over 200 per cubic mm (normal is less than 5; lecturer says "one angry poly" is diagnostic).
What are latex agglutination tests, and do they work?
Used to detect capsular antigen in the CSF. Don't really work well.
What are the long-term sequelae of meningitis?
Correlated with degree of inflammation, vascular insults, and parenchymal damage, but include:

- developmental problems
- hearing problems (or deafness)
- blindness
- learning disorders
- hemiplegia
What is pneumolysin?
A virulence factor released by lysing S. pneumoniae cells. Pneumolysin binds to cholesterol in host cells and creates a pore that lyses the host cell. In meningitis, pneumolysin causes neuronal apoptosis.
How can you improve the clinical outcome during treatment of meningitis with antibiotics?
Give corticosteroids first.

Steroids prevent the secondary increase in TNF due to the release of bacterial cell wall fragments when they're being killed by antibiotics.

Thus, there is less inflammation and a better outcome.
How do pili affect what parts of the body are affected by bacterial infections?
Pili mediate attachment to cell surfaces.

Pili can be very specific, so they only bind to certain types of tissue. This is why infections can be limited (e.g., only upper urinary tract infections).
What is the glycocalyx, and what does it do for bacteria?
Glycocalyx is a polysaccharide layer on the surface of the cell capsule.

The glycocalyx helps the bug attach to certain surfaces, especially slippery surfaces like plastic or prosthetics.
What makes up bacteria peptidoglycan?
Alternating units of NAM (N-acetylmuramic acid) and NAG (N-acetylglucosamine) linked by peptide bonds.

These chains are cross-linked by an enzyme called transpeptidase, in the periplasm.

The D-ala-D-ala sequence is required for cross-linking.

Penicillins interrupt transpeptidase cross-linking.
What is transpeptidase, and how is it important?
Transpeptidase links peptidoglycan chains of the bacterial cell wall using D-ala-D-ala sequence.

Cross-linking is essential for cell wall synthesis.

PENICILLINS interfere with transpeptidase action.
What the heck is periplasm?
Periplasm is the space between the inner cytoplasmic membrane and outer external membrane of a GRAM-NEGATIVE bacterium.

The periplasm contains peptidoglycan subunits and enzymes, including transpeptidase (the penicillin target).
What are the special features of the gram-negative cytoplasmic membrane?
It separates the cytoplasm from the periplasm.

It fulfills many functions equivalent to eukaryotic organelles, including:
- ATP production
- Energy for flagellation
- Transport proteins
- Numerous biosynthetic processes
What are the three types of exotoxins?
1) A-B toxins (cholera, tetanus)

2) Membrane-disrupting toxins (hemolysins, alpha toxins)

3) Superantigens
Tell me how A-B toxin works.
A-B toxin is an exotoxin with broad specificity.

A-B toxins create pores on cell membranes of host cells; the A subunit is active, while the B subunit is for binding.

For example, cholera toxin is an A-B toxin. It creates pores in GI cells, stimulating adenylyl cyclase. Na+ is released from cells, and fluid follows. This explains "rice-water stools."
What do membrane-disrupting toxins do? Give two examples of membrane-disrupting toxins, please.
Membrane-disrupting toxins are exotoxins.

They work by poking holes in cell membranes.

Some examples are hemolysins and alpha toxins.
What do superantigens do?
Superantigens are a type of exotoxin.

They cause massive cytokine release, which causes huge amounts of host self-inflicted damage.
What kinds of super-nasty enzymes do bacteria have, and what do they do?
Hyaluronidases, proteases.

These degrade the ECM and provide nutrients for the bacteria.
Give me some features of Gram-positive bacteria.
Gram positive bacteria:

- Have a thicker cell wall

- Can cause a cytokine response with teichoic acids from their cell walls

- Have cell walls that trap Gram stain (turn purple)

- Some can FORM SPORES (but Gram-negative bacteria can never do this).
Give me some features of Gram-negative bugs.
Gram-negative bugs:

- Have an OUTER MEMBRANE with associated proteins

- Have lipoproteins linking the outer membrane to the peptidoglycans in the periplasmic space

- Have porins on the outer membrane that allow certain substances into the cell (including antibiotics--yay!)

- Have endotoxins in the outer membrane.
Describe the structure of endotoxin.
Endotoxin has three parts:
- Lipid A
- Core
- O antigen

Lipid A is embedded in the outer membrane of Gram-negative bacteria. The endotoxin's tail contains the core and the O antigen, and the tail sticks into the environment.

O antigens allow typing of bacteria.
What does endotoxin do?
Endotoxin is part of the Gram-negative bacterial cell wall.

It is a permeability barrier for bacteria.

It is released from bacteria during replication or death.

When released, endotoxin binds to LPS or Toll-like receptors, triggering cytokines. (Ex: binds to CD14 on macrophages, or TLR-4.)
What are the Henle-Koch postulates?
An organism is responsible for the disease if:

1) It is regularly found in the lesions of the disease

2) It can be isolated in pure culture on artificial media

3) Inoculation of pure culture into a susceptible animal produces the disease

4) The organism can be recovered from the lesions of the newly diseased animal
What is the difference between a common-source outbreak and a propagated epidemic?
Common-source outbreak: Can be traced to one source. Epidemic disappears when source is removed. Ex: John Snow's cholera epidemic.

Propagated epidemic: Spread from individual to individual. Ex: SARS.
Contrast primary and opportunistic pathogens.
Primary pathogens infect anyone.

Opportunistic pathogens cause infections only under unique circumstances (e.g., immunosuppression).
What does colonization involve?
Ecological niche for bacteria; survival and replication without tissue invasion.
How does colonization progress to infection?
Infection involves tissue invasion, replication, and stimulation of an immune response.
What is virulence? What about virulence factors?
Virulence is the severity of disease casued by an agent.

Virulence factors are bacterial components or products that contribute to its ability to cause disease. Examples include adhesive pili, LPS.
What percentage of infections are asymptomatic?
More than 90% of infections are asymptomatic.
What are some reservoirs of infection?
- Humans (HIV, hepatitis B)

- Animals (rabies, leptospira, brucella)

- Soil (clostridium tetani, botulinum)

- Water (legionella, shigella, pseudomonas)
Steps needed for bacterial infection:
- Adherence/colonization

- Evasion of host defense mechanisms (phagocytosis, intracellular killing)

- Adaptation to host environment

- Invasion of local or systemic tissues

- Host response to infection (causes most of tissue damage)
What organism evades phagocytosis?
- Pneumococcus
What organisms block phagosome-lysosome fusion?
- Legionella
- Tuberculosis
What organisms escape the phagosome?
- Listeria
- Shigella
What organism resist intracellular defense mechanisms?
- S. typhi
What organisms can alter their antigens to avoid lymphocytes?
- Neisseria
- Borrelia
- Relapsing fever
How do Listeria and Shigella spread after escaping the lysosome?
They recruit actin and propel themselves from cell to cell.
How does TB prevent us from getting rid of it? (Name 3 ways.)
- TB inhibits ciliary activity in the lungs, preventing us from getting it out.

- TB also blocks phagosome-lysosome fusion, preventing its degradation.

- It also evades destruction by alveolar macrophages.
How does rhinovirus get into cells?
By attaching to ICAM-1.
What factors increase susceptibility to disease?
- Extremes of age
- Malnutrition
- Genetic immune defects
- Acquired immune defects (e.g., AIDS)
- Chemotherapy
- Immune suppressants
- Prosthetic implants
- Organ transplantation
Describe the chromosomal structure of bacteria.
Usually a single chromosome and several plasmids.

Some bacteria have 2-3 replicons (minichromosomes or megaplasmids, depending on your perspective).

Bacterial chromosomes have a high gene density.

High amount of flux; allows rapid evolution.
Describe plasmids.
Plasmids:
- are usually circular
- vary in size
- are NON-essential (carry supplemental genetic material)
- can contain genes for replication, maintenance, transfer, virulence, drug resistance, rRNA operons, and exotoxins.
Name 2 general types of mutation.
- point mutations
- rearrangements
Describe bacterial chromosome structure.
Most bacteria have one circular chromosome.

Bacterial chromosomes have a high gene density.

Most bacteria have at least several plasmids.

Some bacteria have 2-3 replicons, which are "megaplasmids" or "minichromosomes."

Bacterial chromosomes are constantly changing.
Describe plasmids.
Plasmid contain non-essential genetic information.

Plasmids are usually circular (but are sometimes linear).

Plasmids include genes for antibiotic resistance, replication, maintenance, virulence, transfer, rRNA operons, and exotoxins.
What are 2 sources of genetic variation?
- point mutations
- DNA rearrangements
Describe 3 types of point mutations.
1. missense (single nucleotide change causes a different AA to be inserted)

2. nonsense (single nucleotide change causes a stop codon to be inserted)

3. frameshift (nucleotide change causes following codons to be read in a different frame, resulting in a different or truncated protein)
What is a transition vs. a transversion?
Transition: purine to purine substitution, or pyrimidine to pyrimidine

Transversion: purine to pyrimidine, or vice versa
How do DNA rearrangements occur?
Insertion sequences, which encode genes for mobilization and insertion, have inverted terminal repeats at their ends that allow the transposon to enter the bacterial chromosome.

Transposons usually enter at a 5bp sequence they recognize. They cut the target and insert themselves into the DNA; gaps are filled in by DNA polymerase and ligase.

The insertion sequence affects the sequence into which it is incorporated; for instance, it may lead to overpromotion of a sequence, or disinhibit a toxin by inserting itself into the repressor sequence.
What are the types of mutation, from most frequent to least frequent?
Most frequent: Homologous recombination

Plasmid transfer
Transposition

Least frequent: Point mutations?
Differentiate between horizontal and vertical transmission in bacteria.
Horizontal: between bacteria (transformation, transduction, conjugation).

Vertical: from a bacterium to its daughter cells.
What are the 3 mechanisms of horizontal transformation?
1. Transformation (uptake by competent bacteria)

2. Transduction (phage transfer)

3. Conjugation (sex pili)
Describe bacterial transformation.
A cell lyses, and its DNA is released.

Naked donor DNA is floating around, and is taken up by a "competent" cell.

This must be done quickly, because naked DNA breaks down very fast.

One strand of donor DNA enters the cell while the other is degraded.

Recombination occurs via a double crossover; the new chromosome is heteroduplex, with one donor strand and one host strand.

When the cell divides, one will have an "old" chromosome, while one will have a "new" one.
What makes a bacterium competent for transformation?
It produces competent factor (CF).
What is the basic mechanism of transduction?
A bacteriophage infects a donor cell.

The cell lyses, and some donor DNA is packaged into a released bacteriophage.

Donor DNA is transferred to a recipient cell when the phage particle infects it.
How are generalized and specialized transduction different?
Generalized transduction: DNA fragment is transferred by a lytic bacteriophage that is carrying donor bacterial DNA due to an error in lytic maturation. LYSIS OCCURS.

Specialized transduction: DNA fragment is transferred by a temperate bacteriophage that undergoes an error in lysogenic maturation. DOESN'T LYSE BACTERIA.
Describe generalized transduction in detail.
Phage adsorbs to bacterium and inserts its genome. Tells the cell to make more bacteriophage.

Occasionally, a bacteriophage head encapsulates donor DNA.

The cell lyses and bacteriophages are released to infect other cells.
Describe specialized transduction in detail.
Temperate bacteriophage (not lytic) infects a susceptible bacterium.

The phage genome is incorporated into the host genome.

Occasionally during induction, a small piece of donor DNA is picked up as part of the phage's genome instead of a part of the phage's DNA, which remains in the nucleoid.

The phage replicates, and the segment of DNA replicates as part of it. Every phage carries that segment of host DNA.

The phage leaves the cell and adsorbs to a new bacterium.
What is the basic model for conjugation?
1. Contact via sex pilus (requires special plasmid in donor).
2. Retraction of sex pilus, bringing cells close together.
3. Donor DNA is transferred directly to recipient.
What "genotype" is necessary for a bacterium to donate DNA via conjugation?
F+ (the cell must have an F plasmid).
Describe F+ conjugation.
Transfer of F plasmid (but NOT chromosomal DNA) via a sex pilus.

First, the "male" connects via a sex pilus. The sex pilus retracts, pulling the cells together.

One strand of an F+ plasmid enters the second cell.

Both cells make the complementary strand for the F+ plasmid.

Other plasmids may be transferred.
To what other organisms can E. coli transfer DNA via conjugation?
E. coli can conjugate with Salmonella, Shigella, and Proteus.
Describe Hfr conjugation.
"Homologous F Recombination."

F+ plasmid DNA is integrated INTO the host chromosome via homologous recombination (frequency of 10^-5 per generation).

This Hfr "male" adheres to an F- "female" via a sex pilus. One donor strand breaks in the middle of the inserted F+ plasmid.

The sex pilus retracts, making a bridge between the cells. One strand begins transfer, but is broken off before finishing, USUALLY NOT TRANSFERRING THE ENTIRE F PLASMID.

Each cell makes a complementary copy of the single-stranded DNA.

The donor DNA fragment undergoes exchange with the female's chromosome.

The female usually remains F- (because the entire F plasmid wasn't transferred).
What are R factors?
R factors are plasmids encoding antibacterial resistance.
Describe R conjugation.
R plasmid encodes drug resistance and allows the cell to donate DNA via conjugation (it's a "male").

Sex pilus --> retraction --> adherence

One strand of the R plasmid enters the new cell.

Both cells make a complementary strand.
What sucks about R conjugation?
Treatment with antibiotics selects for cells with R plasmids, increasing the frequency of drug resistance.

Also, R plasmids often encode multi-drug resistance.
Explain conjugative transposition.
A stable transposon carrying genes is part of the bacteria's chromosome.

The transposon becomes ring-like (similar to a plasmid).

One strand of the transposon-plasmid is transferred to the other cell in conjugation.

Both cells make complementary strands, and this double-stranded DNA is reincorporated into the chromosome.
How does Vibrio cholerae use transduction to its advantage?
Virulence can be transferred between Vibrio cholerae via a filamentous phage. It is non-lytic, so it essentially just churns out virulence-carrying phages that confer that virulence on other bacteria.
How does Corynebacterium diptheriae use phages to its advantage?
The beta phage carries genetic information that causes C. diphtheriae to become positive for diphtheria toxin.
What differentiates between pathogenic and non-pathogenic Neisseria meningitides?
Pathogenic N. meningitides has a filamentous phage that makes it pathogenic. Transduction allows this to spread.
How do Neisseria gonorrheae use variation in sex pili? What is the mechanism for transferring this variation?
Many antigenic variations in sex pili of Neisseria gonorrheae.

These variants can be transferred, so they acquire new antigenic variations from other Neisseria.

Transformation via uptake of naked DNA is one mechanism of this transfer.
What makes Bacillus anthracis different from other Bacillus species?
B. anthracis is different from other species (B. cereus, B. thuringiensis) in that it has a pXO2 plasmid.

The pXO2 plasmid is similar to other Bacillus plasmids, but pXO2 has a "small island of DNA" that makes it toxic.

Apparently, a few recent B. cereus infections have occurred because of transfer of this toxic plasmid from B. anthracis.
R. rickettsii
Rocky Mountain Spotted Fever.

Tick-borne.
Small, gram-negative bacillus.
Obligate intracellular parasite.
R. akari
Ricksettsialpox.

Mouse mites.
Small, gram-negative bacillus.
Obligate intracellular parasite.
R. typhi
Endemic murine typhus.

Flea-borne.
Small, gram-negative bacillus.
Obligate intracellular parasite.
R. prowazekii
Epidemic typhus.

Louse-borne.
Small, gram-negative bacillus.
Obligate intracellular parasite.
Ehrlichia chaffeensis
Human monocytic ehrlichiosis (HME).

Tick-borne.
Small, intracellular gram-negative bacteria that infect monocytes.
Anaplasma phagocytophilium
Human granulocytic anaplasmosis (HGA)

Tick-borne.
Small, intracellular gram-negative bacteria that infect granulocytes.
Borrelia burgdoferi
Lyme disease.

Hard tick-borne
Spirochetal (helical) gram-negative bacteria.
Borrelia recurrentitis
Louse-borne relapsing fever.

Spirochetal (helical) gram-negative bacteria.
Borrelia hermsii
Tick-borne relapsing fever.

Spirochetal (helical) gram-negative bacteria.
Borrelia turicatae
Tick-borne relapsing fever.

Spirochetal (helical) gram-negative bacteria.
What causes gonorrhea?
Neisseria gonorrhoeae.
About what percentage of patients infected with gonorrhea also have chlamydia?
About 30%.
Is there a vaccine available for meningococcal meningitis (N. meningiditis)?
Yes.

A quadrivalent vaccine (Menactra) exists against types A, C, Y, and W135.