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Salmonella typhimurium and E. coli O157: H7
- food/water borne pathogens
- S. typhimurium used by cults to try to sway votes (bioterrorism)
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LD50=Lethal Dose 50
- number of pathogens that will kill 50% of an experimental group of hosts
- lower LD50=more virulent
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Viral infection steps
- 1. host contact/entry
- 2. replication
- 3. spread
- 4. cellular injury
- 5. host immune response.
- 6. clearance, persistance, or death of host
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syncytia
large mass/fusion of cells; multinucleated. forms in response to viral infection
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tropism
- specific site of infection (cell/tissue/organ)
- receptor dependent
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viral attachment and spread: roles of N and H on the influenza virus
- H=hemaglutinin=attachment
- N=neuraminidase=spread; cleaves host lipids and glycoproteins
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ways viruses avoid immune recognition and host response
- 1. block cytokine (interferon) synthesis
- 2. breakdown complement proteins
- 3. block production of complement proteins
- 4. block antigen processing of MHC export
- 5. antigenic variation (i.e changing the a.a. sequence in virion spikes)
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Interferons
- antiviral cytokines: important in viral resistance during early stages of infection
- destroy viral mRNA
- shut down viral translation
- stimulate CTLs and NKs
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bacterial adherence factors
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coagulase
- virulence factor that clots sera, forms a shield that protects pathogens from phagocytosis
- ex) S. aureus
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streptokinase/fibrinolysin
- Virulence factor that binds plasminogen and digests fibrin clots. Allows movement and spread
- ex) Staphylococcus, Streptococcus
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hemolysins
- virulence factors that lyse RBCs and make Fe available to bacteria
- ex) staphylococcus, streptococcus, E. coli
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collagenase
- virulence factor that breaks down collagen and allows bacterial spread
- ex) Clostridium sp.
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IgA protease
- virulence factor that cleaves IgA into Fc/Fab fragments
- ex) Streptococcus pneumoniae
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bacteremia vs. septicemia
- bacteremia=presence of bacteria in the bloodstream
- septicemia=growth/division of bacteria in the bloodstream
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M protein (2 roles)
- 1. adhesion of bacteria to host cell
- 2. block adhesion of phagocytes to bacterium
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Bacterial evasion of host defenses (4 methods)
- 1. Resist the complement system: cleave c5a, lengthen LPS, capsules
- 2. avoid specific immune responses: capsules, antigenic variation, IgA proteases
- 3. avoid phagocytosis: capsule, proteins that block adherence (M protein), leukocidines, coagulase
- 4. survival inside phagocytic cells: phagosome escape or resistance to ROS and NO, prevent phagosome-lysosome fusion
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3 intracellular pathogens
- 1. Listeria monocytogenes
- 2. Legionella pneumophila3. Mycobacterium tuberculosis
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Listeria monocytogenes
- intracellular pathogen
- uses host cell actin polymerization
- doesn't enter extracellular space or illicit an immune response
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Legionella pneumophila
- intracellular pathogen
- inhibits phagosome-lysosome fusion
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Mycobacterium tuberculosis
- intracellular pathogen
- inhibits phagosome-lysosome fusion
- can escape phagosome to cytoplasm
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Biofilms
- microbial communities attached to a surface and covered by a polysaccharide matrix
- protected from immune response and antibiotics
- produce virulence factors under QS control
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otitis media
- infection of the inner ear
- Streptococcus pneumoniaerecurring infections due to biofilm protection from antibiotic treatment
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cystic fibrosis
Pseudomonas biofilms in the lungs
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Endocarditis
Staphylococcus or Enterococcus biofilms on heart valves
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Types of exotoxins (4)
- 1. Membrane disrupting
- 2. AB exotoxins
- 3. superantigens
- 4. specific host site exotoxins
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pore forming exotoxins
- membrane disrupting exotoxin that forms pores which cause host swelling and lysis
- ex) hemolysins release Fe
- ex) leukocidins kill macrophages
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phospholipases
- membrane disrupting exotoxin
- cleaves host lipid bilayer between head and tail, leading to instability
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superantigens
- exotoxins that interact with and lock MHCII receptors to TCR, which overstimulates Tcell response even in the absence of peptide
- increases cytokines and inflammation
- ex) Staphylococcus and toxic shock syndrome toxin
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AB exotoxins
- transmembrane, 2 subunits
- A= toxic effect
- B= binds to target cell
- ex) Shiga toxin
- ex) E. coli O157: H7
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Diptheria toxin
- AB exotoxin that does not form a pore via the B subunit
- instead, it enters the host via receptor mediated endocytosis
- at ph <5, the vesicle and A and B subunits diffuse to cytoplasm
- A affects ADP ribosyl transferase, B goes back to membrane
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specific host site exotoxins
- often AB
- enterotoxins
- neurotoxins
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enterotoxins
- specific host site exotoxins that stimulate host adenylate cyclase which increases cAMP which causes ion imbalance and H20 loss.
- ex) cholera toxin of Vibrio cholerae
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neurotoxins
- specific host site exotoxins that block the release of Ach from the neuromuscular junctions, causing flaccid paralysis because the muscle can't contract
- ex) botulinum toxin of Clostridium botulinum (used in Botox)
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toxoid
- inactivated toxin that still illicits the immune response
- part of vaccines
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DTaP
vaccine for Diptheria, Tetanus, and Pertussis
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Endotoxin
- LPS from gram (-) bacteria
- more general effects: fever, shock, inflammation
- causes: release of endogenous pyrogens, TNF
- ex) meningitis, petechia--due to gram (-) shock
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Type III Secretion Systems (TTSS)
- for gram (-) pathogens
- inject effectors via injectisome
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injectisome parts
needle, pore, basal body
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pathogenicity islands
- large, often chromosomal DNA regions of the pathogen that encode many virulence genes (often in operons)
- encodes: injectisome for TTSS
- G and C content often differs from the rest of the pathogen genome...evidence for HGT
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Targets for TTSS
- host cell cytoskeleton- actin
- host cell signalling- NFkB
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EPEC
- Enteropathogenic E. coli: cause of infantile diarrhea
- ex) Type III secretion System
- binds host cells using bundle forming pili, assembles injectisome and delivers effectors
- *one effector is Tir-Translocated intimin receptor
- Tir is presented on the host cell surface to bind EPEC intimin and serve as a docking station
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Paul Ehrlich
- magic bullets
- selective toxicity (to germ rather than host)
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Who cultured >10,000 strains of soil bacteria and isolated Streptomyces?
Selman Waksman
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Alexander Fleming (1928)
- accidentally discovered penicillin
- Staphylococcus and Penicillium on same plate
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Who purified penicillum, proved its efficacy against infected animals, and shared the nobel prize with Fleming?
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cidal vs. static
- cidal: kills pathogen
- static: inhibits growth
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Antimicrobial Targets (5)
- 1. Cell wall synthesis
- 2. Plasma membrane
- 3. Nucleic acid synthesis
- 4. Protein synthesis
- 5. metabolic enzymes
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Antimicrobials that target cell wall synthesis
- betalactams (penicillin)
- Vancomycin
- Bacitracin
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Antimicrobials that target the Plasma Membrane
- Polymyxins
- Imidazole
- Nystatin
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Antimicrobials that target nucleic acid synthesis
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Antimicrobials that target Protein Synthesis
- Aminoglycosides (streptomycin, kanamycin)
- Tetracycline
- Macrolides (erythromycin, azithromycin)
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Antimicrobials that target metabolic enzymes
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Penicillins (beta lactams)
- target PBPs (penicillin binding proteins) for transpeptidation
- transpeptidation: energy used to cross-link NAG and NAM residues with the terminal D-Ala
- penicillinase attack the beta lactam ring
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Vancomycin
- CELL WALL SYNTHESIS INHIBITOR
- glycopeptide antibiotic
- binds terminal D-Ala and prevents peptidoglycan synthesis
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Bacitracin
- CELL WALL SYNTHESIS INHIBITOR
- inhibits carrier for peptidoglycan subunits
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Polymyxins
- PLASMA MEMBRANE INHIBITOR
- disrupt lipid bilayer
- cidal against narrow spectrum gram-
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Imidazole
- PLASMA MEMBRANE INHIBITOR
- blocks synthesis of membrane sterols
- treats athletes foot
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Nystatin
- PLASMA MEMBRANE INHIBITOR
- binds membrane sterols
- treats Candida infections
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Quinolones (definition and two types)
- NUCLEIC ACID SYNTHESIS INHIBITOR
- inhibits DNA gyrase
- **synthetic antimicrobials
- ex)Nalidixic acid
- ex)Ciprofloxacin
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Rifampin
- NUCLEIC ACID SYNTHESIS INHIBITOR
- inhibits RNA polymerase (and therefore transcription)
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Aminoglycosides (definition and two types)
- PROTEIN SYNTHESIS INHIBITORS
- prevent 30S and 50S binding
- ex) Streptomycin
- ex) Kanamycin
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Tetracycline
- PROTEIN SYNTHESIS INHIBITOR
- binds 30S, distorts A site, prevents amino-acyl tRNA binding
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Macrolides (definition and two types)
- PROTEIN SYNTHESIS INHIBITORS
- bind 50S rRNA, block elongation
- ex) Erythromycin
- ex) Azithromycin
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Sulfonamide
- METABOLIC ENZYME INHIBITOR
- metabolic analogs that inhibit folic acid synthesis
- also inhibit purine and pyrimidine synthesis
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Triclosan
- METABOLIC ENZYME INHIBITOR
- present in plastics, toothbrushes, etc.
- binds enoyl reductase (an enzyme for fatty acid synthesis)
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Acyclovir
- ANTIVIRAL
- inhibits DNA polymerase of herpes virus
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Tamiflu
- ANTIVIRAL
- inhibits neuraminidase to prevent spread of influenza virus
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HAART
highly active antiretroviral therapy
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Azidothymidine (AZT)
- HAART antiviral for HIV
- targets reverse transcriptase
- nucleoside analog, causes DNA chain termination
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Ritonavir
- HAART anti-HIV drug
- protease inhibitor (prevents viral assembly)
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Mechanisms of drug resistance
- 1. prevent access to or alter the drug target
- 2. create an enzyme to degrade antibiotic (ex. penicillinase)
- 3. Alter antibiotic (ex. phosphorylation)
- 4. efflux pumps
- 5. resistance genes from HGT
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Which superbug replaces the terminal D-Ala of peptidoglycan with another amino acid?
Vancomycin resistant Enterococcus
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MRSA
has a mecA gene which encodes mutant PBP, creates low affinity for penicillins
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Varicella-Zoster virus
- Herpes family
- dsDNA, icosahedral, enveloped
- causes Chickenpox and Shingles
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types of vaccines (3)
- attenuated (live): specific genes inactivated, activates humoral and cellular immune responses, may revert
- inactivated (killed): chemicals or irradiation, activates humoral response, requires a booster
- VLP (Virus Like Particle): noninfectious, naked, capsid (no genome) of a virus ex) Gardisil
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MMR
- Measles, Mumps, Rubella
- all caused by RNA viruses
- MMR vaccine=attenuated
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Antigenic SHIFT vs. DRIFT
SHIFT: major antigenic changes, often the result of different strains resorting via a reservoir (ex. Swine flu)
DRIFT: minor antigenic changes, due to mutations in N (or H) of influenza virus (ex. seasonal changes and increases in flu outbreaks)
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3 conditions for (influenza) pandemic
- 1. new antigenic influenza subtype
- 2. infects humans, and causes serious illness
- 3. spreads easily
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Arboviruses
- =arthropod-borne viruses
- insects=vectors
- ex) Yellow Fever-mosquito
- ex) West Nile Fever-mosquito and birds
- RNA flavoviruses
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Zoonotic viruses cause ________
ex)
- hemorrhagic fevers
- ex) fruit bats and the Ebola virus (filamentous morphology)
- viral proteins cause blood clotting, interferon blocks, and hemorrhaging
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A disease of animals that can be transmitted to humans is a _______ disease.
zoonotic
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direct contact diseases (4)
- HIV/AIDS
- Common Cold
- Mononucleosis
- Hepatitis
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HIV
- enveloped, icosahedral, RNA retrovirus
- enzymes and proteins: gp120, protease, reverse transcriptase, integrase
- life cycle: in a CD4+ Th cell, genome integrates (provirus), uses host machinery to assemble capsid
- pathogenesis: depletion of T cells and APCs (dendritic cells)
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CDC definition of AIDS
- Acquired Immune Deficiency Syndrome
- HIV infected individual with <200 CD4+ T cells per uL of blood
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Rhinovirus
- Major cause of the common coldssRNA+, naked, icosahedral
- >100 different serotypes
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ICAM-1
- cell-surface receptor for Rhinoviruses
- Intracellular Adhesion Molecule-1
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EBV=Epstein-Barr Virus
- type of herpesvirus; cause of Mononucleosisinfects epithelial cells and then B cells
- icosahedral, enveloped, dsDNA
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What virus causes Mononucleosis?
Epstein Barr Virus
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Hepatitis
- 11 viral causes (2=herpesviruses, 9=hepatotropic viruses)
- inflammation of the liver
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Hepatotropic Viruses
- multiple modes of transmission
- cause Jaundice, hepatitis
- treatment: vaccines, recombinant interferon therapy
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Rotavirus
- (1 of 2) viral gastroenteritis
- NSP4=viral enterotoxin that promotes fluid secretion
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Norovirus
- (1 of 2) viral gastroenteritis
- naked, RNA
- outbreaks on cruise ships, at oscar parties
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Poliovirus
- causes polio (infantile paralysis)
- naked, icosahedral, +ssRNA
- stable in food and water
- targets motor nerve cells in spinal cord, creates paralysis
- treatement: attenuated and inactivated vaccines available
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Mycobacterium tuberculosis (TB)
treatment?
- cause of TB (intracellular pathogen)
- waxy coat/cell wall that allows identification by acid fast staining
- treatment: iconiazid and rifampin
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Streptococcal diseases/pathogens?
Treatment?
- Streptococcus pyrogenes and Streptococcus pneumoniaeinfections of the skin, throat, lungs
- Treatment: penicillins, macrolides (erythromycin)
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flesh eating bacteria
- necrotizing fasciitis
- Invasive Streptococcus pyrogenes infection
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Whooping cough
- Bordetella pertussis (Gram -)
- virulence factors: pili, siderophores, Ptx
- Ptx: targets adenylate cyclase (increases secretions, mucus)
- treatment: Augmentin
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Augmentin
- Rx for Whooping Cough/Bordetella pertussisAmoxicillin component inhibits cell wall synthesis
- Clavalanate component impedes beta lactamases
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Meningitis microbes (3)
- Haemophilus influenzae
- Streptococcus pneumoniae
- Neisseria meningitidis**
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Neisseria meningitidis
- one cause of meningitis
- gram (-): LPS->TLR4->TNF->PMNs from blood vessels
- virulence factors: endotoxin, pili, capsule
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The Plague
- Yersinia pestis
2 types: Bubonic and Pneumonic - Bubonic: fleas spread, lymph nodes to rest of body forming bubos
- Pneumonic: humans, flu-like initially but 100% fatal if untreated
- Uses a Type III secretion system
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Lyme Disease (organism, stages, treatment)
- Borrelia burgdorferi
stages: 1-localized, 2-disseminated, 3-late - treatment: Tetracyclines, Penicillins
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Anthrax (organism, toxin type, treatment)
- Bacillus anthracis
Toxin: AB but three parts - cutaneous vs. respiratory
- Treatment: Quinolone (ciprofloxacin)
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Anthrax toxin (Bacillus anthracis)
- AB but three parts:
- PA=protective antigen (B)
- EF=edema factor (A)
- LF=lethal factor (A)
- encoded on plasmid and enter cell when the three toxins associate
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receptor interference
Concept that viruses are selfish and prevent superinfection by removing entry receptors from the cell surface once they have infected it
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Cholera
- Vibrio cholerae gram (-)
- cholera toxin increases adenylate cyclase, causes ion imbalance and H20 hypersecretion
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Botulism
- Clostridium botulinum
botulinum toxin: prevents Ach release from neuromuscular junctions, causes flaccid paralysis and cardiac failure
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Food and water-borne pathogens (2)
- Salmonella typhimurium: causes acid stress response in stomach, activates a specific set of genes in the human GI system
- E. coli 0157:H7: carried by cattle, produces shiga-like AB toxin, that cleaves rRNA. Encoded on a temperate phage (which makes treatment difficult)
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Major fermentations (3)
- Lactic (cheese and yogurt)
- Propionic
- Ethanolic (alcohol)
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Lactic acid fermentation pathway
balances with glycolysis (NAD+-->NADH reduction, ADP-->ATP)
2 pyruvate-->2 lactate. NADH-->NAD+ oxidation, no ATP required
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yogurt bacteria
- Lactobacillus and/or Streptococcus (Starter Culture)
- "Lactic Acid Bacteria" gram (+)
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Bio-based plastic
- "polylactide"
- E. coli and Lactobacillus
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Cheese Production
milk--1-->curd--2-->cheese
- 1=Lactococcus starter culture and renin
- 2=ripening by microbial action (microbe varies for each type of cheese)
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Microbe for swiss cheese (step 2)
Propionibacterium
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Microbe for bleu cheese (step 2)
Penicillium roqueforti
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Pro-Biotics (brand names, microbes, benefits)
- Brand names: Serovera, Activia, Bifantis
- Microbes: Lactobacillus, Bifidobacterium
Benefits: compete with unwanted organisms, produce antimicrobial compounds, etc.
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Steps/microbes for wine production (2)
- Sacchromyces ferments the must (from grapes/juice)
- Leuconostoc sp. undergo malolactic fermentation (malic acid to lactic acid)
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Secondary metabolite
- compound that accumulates during period of nutrient limitation following active growth (aka stationary phase)
- ex) Penicillin G and other ANTIBIOTICS
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Bioremediation
Using microbes to degrade pollutants
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alkane hydroxylase
enzyme (from microbes) to use to clean up oil spills--some microbes can use that carbon as a source of energy
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