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419 Cards in this Set

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  • Back
What are the characteristics of bacterial chromosomes?
-Borellia spp linear
Organized into ~ 50 domains
~1 mm long (500x length of the bacterium)
Domains are supercoiled (implications for gene expression, esp. virulence genes)
Extrachromosomal genetic elements
Capable of autonomous replication
lysogenic conversion
refers to when a nonvirulent strain of bacteria acquires a prophage encoding a virulence factor and therby converts to a virulent strain
What is the defining factor about transposons?
cannot replicate autonomously-Must be integrated into a replicating molecule (chromosome, plasmid or virus) to be maintained
IS element transposon
major cause of bacterial mutation
inactivate genes
catalyze DNA rearrangments(deletions, inversions, and replicon fusion)
What is necessary for a stable genetic exchange?
integration of the DNA fragment into the bacterial chromosome or plasmid via recombination
Uptake of DNA from the environment!!!
DNA bound by specific receptors and transported into the cytoplasm, one strand being degraded (Haemophilus, Bacillus)
May require specific DNA recognition sequences (Neisseria)
Transfer of DNA from donor to recipient requiring cell-cell contact!!!
Usually involves participation of a conjugal plasmid
Conjugal plasmids
Carry a set of genes necessary for conjugal transfer of DNA
Transfer begins at a specific site on the plasmid, the origin of transfer, and proceeds by rolling circle replication
Forming mating pairs in Gram NEGATIVE(Ecoli)
Sex pilus contacts recipient
Pilus retracts bringing donor and recipient into close contact
Formation of mating pore allowing transfer of DNA
Forming mating pairs in Gram Positive(E.faecalis)
Recipient secretes peptide pheromone to attract donors
Mating aggregates form
Hfr transfer
Conjugal plasmid integrates into chromosome
Transfer begins within integrated plasmid
Chromosomal DNA transferred to recipient
F prime plasmid formation
Occasionally an integrated plasmid excises carrying a fragment of chromosomal DNA
This F’ plasmid can transfer to recipient cells
The chromosomal fragment is maintained as part of the plasmid
No recombination with the recipient chromosome is required
Packaging of bacterial DNA into a viral particle
Conjugative transposons
Move from one site in the DNA to another – transposition
Move from donor to recipient during transposition – conjugation
What is diauxic growth?
ability of bacteria to preferentially use feul in an enviornment of multiple feuls
How does inducer exclusion work?
when glucose enters cell it is phosphorylate leaving a lot of IIeGLU that inhibits lactose permease
What happens in the absence of glucose?
Phosphorylated IIeP activates adenylate cyclase which produces cAMP which activate the lac operon via CAP
Describe global regulation of CAP
CAP works on many operons when activated but specific signals causes requisite catabolic genes.
Nitrogen uptake
glutamine synthetase converts NH3 and glutamate into glutamine in an ATP dependent reaction
How is glutamine synthetase transcription activated?
When there is a high ration of a-ketoglutarate/glutamine ration, NtrC is phosphorylated and activates transcription via sigma54
heat shock
sigma 32 activates genes which either refold of degrade unfolded proteins
how do bacteria monitor its population and environment?
through a general signal AI-2 and a species specific signal AI-1.
single stranded DNA virus
double stranded DNA virus
RNA + virus
RNA - virus
Double stranded RNA virus
Course of disease
Acute-common cold
Late complications-measles-SSPE
Chronic-hep B
Parvovirus examples
Papovirus examples
Herpesvirus examples
Poxvirus examples
What are the features of virus used in classification
virus genome structure
presence/absence of envelope
Which viruses are enveloped?
DNA-pox, herpes, hepadna
Which viruses are not enveloped?
DNA-parvo, papova (polyoma, papilloma), adeno
Characteristics of parvoviridiae
-replicate autonomously
-require cell to enter S phase of cell cycle for virus replication
-Only single strand DNA virus with + or - strand polarity
-B19 is the known only disease causing infectious family member in humans
B19 replication
-repilicates in RBC precursor
-genome has hairpin that act as primers for DNAP
-duplicated and transcribed in nucleus
-CAP and genome form caspid which is released upon lysis
Pathogenesis of B19
-mainly erythema infectiosum (“slapped cheek”, “fifth disease”)
-associated with arthritis
-Primary infection in 2nd trimester may manifest as fetal hydrops – severe fetal anemia causing cardiac failure with associated edema
What patients can B19 cause aplastic crisis and chronic anemia?
aplastic-sickle cell, thalassemia
Chronic-immunodeficient patients
What is the treatment for B19 induced fetal hydrops?
watchful waiting
high dose IG
intrauterine fetal transfusion

*no prophylaxis available
-polyomaviruses are able to manipulate host cell cycle to facilitate virus replication
-encode large T antigen, that is able through inactivation of pRB and p53.
T antigen
-helicase activity
-inactivates tumor suppressors
-tricks cells into entering S phase to aid viral replication
Human Polyoma Virus
Transmission -respiratory
Epidemiology -aquired during childhood
Pathogenesis-reactivated or primary infection during renal transplants can cause severe infection
Progressive multifocal leukoencephalopathy (PML)
Demyelinating disease, associated with 2-4% of AIDS patients

caused by polyoma virus
Transmission - direct contact
Primary infection - infects basal layer of epithelial cells
Latency - remains in basal epithelium
Reactivation - normally causes warts(virus forces warts to divide--tumor possible)
Tumor transformation in HPV
-viral genome disrupts E2 upon insertion which control E7-pRB binding
-E7-pRB binding helps release control of cell cycle
Common Wart
Members: HPV 1,2,4
Transmission: direct contact
Penetration: break in dead cell layer
Organ affected: skin
Clinical significance: common and superficial
Flat (planar) Warts
Members: HPV 1,3,4,9,10
Transmission: direct contact
Penetration: break in dead cell layer
Organ affected: skin - usually hands and feet
Clinical significance: nuisance and difficult to remove
Laryngeal HPV
Transmission: during birth
Penetration: none required
Organ affected: exposed epithelial cells of larynx
Clinical significance: grow rapidly, may affect speech, can be life threatening if airway becomes blocked
Epidermodysplasia Verruciformis
rare disease that is thought to involve an underlying dysfunction in cell mediated immunity (autosomal recessive)
-Eruptive, polymorphic,
warty papules and plaques
Gentital Warts
Members: HPV 6,11,16,18
Transmission: sexual
Penetration: break in dead cell layer
Organ affected: skin - genital area
Clinical significance: nuisance with occasional malignant conversion (HPV16,18)
What percentage of cervical cancer is associated with HPV?
HPV Tumor associations
5,8-skin carcinomas in EV pts
16,18,31,33-genital tract cancer
6,11-malignant prog. of respiratory carcinomas
Adenovirus replication
drives infected cell's cycle via E1A which binds to inactivate pRB and E1B which binds to inactivate p53
What is important about adenovirus' complicated replication?
many levels to target therapies
Transmission - aerosol, close contact, possibly oral-fecal
Primary infection- epithelial cells of mucous membranes of respiratory tract, gastrointestinal tract, or cornea/conjuctiva
Persistent (latent?) infection in lymphoid tissues (tonsils, adenoids)
epidemic keratoconjunctivitis (shipyard eye)--adenovirus
Virus serotypes: Ad8
Symptoms: tearing, inflammation, corneal infiltrates (can cause lasting visual impairment)
medical instruments
conjunctivitis, pharyngo-conjunctival fever--adenovirus
serotypes: Ad3, Ad7
Symptoms: mild pharyngitis, sore throat, mild inflammation of conjunctiva
Inadequate chlorination of swimming pools
infant respiratory disease--adenovirus
serotypes: Ad1, Ad2, Ad5, Ad6
Symptoms: fever, aches, sore throat, cough
Treatment: none
acute respiratory disease (ARD)--adenovirus
serotypes: Ad4 and Ad7
Symptoms: headaches, cough, pharyngitis, fever
Treatment: oral live virus vaccine
Only available to the military
Waht are the three classes of herpes virus?
Alpha-herpesviruses (neurotropic)
Gamma-herpesviruses (lymphotropic)
How long do herpesvirus infect their host?
Herpesvirus latency
-limited viral gene expression
-Viral genome exists as an episome in the nucleus of infected cell
-upon stimulation virus undergoes reactivation
Distinctive characteristics of alpha herpes
-acute disease of epithelial tissues
-latency in sensory ganglia
-recurrent infections of epithelial tissues result in lesions
-high prevalence
-transmitted by close contact
-causes mild epithelial lesions
-can cause encepalitis, neonatal herpes
-leading cause of blindness in US
HSV-1 primary infection
-Usually cold sores
Sore throat, fever, and -encephalitis (rare) are also seen
-Less frequently found as a genital infection
HSV-1 Latent infection
-Asymptomatic – little or no virus or virion proteins produced
-Viral DNA resides in sensory neurons of (usually) trigeminal ganglion
HSV-1 Recurrent infection
Virus replicates and travels down sensory nerve fiber to infect epithelial cells around the nose and mouth
Symptoms are usually a milder form of primary infection
-typically transmitted by sex
-usually causes relatively mild epithelial lesions
-can cause encephalitis
-major cause of neonatal herpes
HSV-2 primary infection
Usually vesicular eruptions on the genetalia
Spread by sexual contact
Affects both sexes
Less frequently found as herpes labialis (cold sores)
HSV-2 Latent infection
Little or no virus or virion proteins produced
Viral DNA resides in sensory neurons of (usually) sacral ganglia
HSV-2 Recurrent infection
Milder outbreak, usually in same location in genital area
Varicella Zoster virus (VZV)
Transmission is by close contact with vesicle fluid, and probably by an aerosol/respiratory route
primary-chicken pox
Varicella Zoster primary infection
Infection occurs in seasonal epidemics as chicken pox (Varicella)
Contracted from another infected individual, usually a child
Systemic infection resulting in a generalized, vesicular rash
Varicella Zoster Latent infection
Asymptomatic with no virus or virion proteins produced
Viral DNA resides in cells of sensory ganglia
Varicella Zoster Recurrent infection
Virus travels down sensory nerve fibers and infects epithelial cells enervated by the fiber
Infections are unilateral, painful vesicular eruptions localized to the dermatome, usually in the head or upper trunk
Severe systemic infections are observed in immunocompromised individuals
Herpes B virus
Herpes simplex of old world monkeys
Transmitted by bites; seen in animal handlers
80% fatality rate, causes encephalitis
Distinctive characteristics of beta herpesvirus
-Primary infection is usually asymptomatic
-Latency in lymphoid tissues ?
-Recurrent infection is usually asymptomatic (?)
-CMV can cross placenta and cause congenital birth defects
Infection ages 0-5 or >18
US seroprevalence 50%, worldwide >90%
Transmission by contact with virus in secretions, particularly breast milk
CMV pathogenesis
-when infected by breast milk, asymptomatic
-can be transmitted transplacentally during primary or recurrent infection of mother
-leading infectious cause of congenital birth defects in US
-primary infection of adults can cause infectious mononucleosis (EBV is most common cause of IM)
-AIDS: disseminated infections, including pneumonia, gastroenteritis, encephalitis, and retinitis
CMV primary, latent, and recurrent infection
Primary infection: epithelial tissues of oral mucosa, possibly STD
Latency: site unknown, probably macrophages
Recurrent infection: virus shed from saliva, urine, vaginal secretions, semen, breast milk, and feces
-Infection-children 0-2 years
-seroprevalence >70%
-primary infection causes exanthem subitum (roseola)
-site of latency unknown; reactivation not associated with any known disease
-recent association with non-HSV viral encephalitis
Infection 2-10 years
US seroprevalence >70%
Pathogenesis-recent association with non-HHV6 rash in children
Distinctive characteristics of gamma herpes virus
Latent infection of B cells + other cell types??
-EBV: infectious mononucleosis
-KSHV: ???
Recurrent disease asymptomatic
Associated with several cancers
Infection-early childhood or late teens/early 20s
seroprevalence 70%
Transmission-contact of oral mucosa with saliva containing virus
EBV Pathogenesis
primary infection usually asymptomatic in children; causes infectious mononucleosis in ~50% of adults
associated with several cancers in immunocompetent hosts
major problem in transplant patients, cause of malignant B cell lymphomas
AIDS: oral hairy leukoplakia
EBV primary, latent, and recurrent infections
-Primary infection in epithelial cells of oral mucosa, followed by infection of B lymphocytes?
-Latency in B lymphocytes
-Reactivation results in virus shedding in saliva
EBV associated tumors
Endemic Burkitt’s lymphoma (100%)
Nasopharyngeal carcinoma (100%)
Hodgkin’s lymphoma (30-50%)
Lymphoma in immunosuppressed patients (~50%)
Breast cancer ???
gamma Herpesvirus, found in Kaposi’s sarcoma of AIDS and non-AIDs patients
tightly associated with a rare B cell lymphoma, peritoneal effusion lymphoma (PEL), that occurs in AIDS patients
-Largest and most complex viruses known
-Oval or “brick-shaped” particles 200-400 nm in length
-Extracellular virus contains 2 membranes (EEV – extracellular enveloped virions)
-Intracellular particles only have an inner membrane (IMV – intracellular mature virions)
Poxvirus replication
-poxviruses replicate in the cytoplasm(unique for DNA virus
-Encodes all the necessary replication and transcription enzymes to autonomously replicate
-early and late gene expression
human infections of the poxvirus
Molluscum contagiosum-warty papule
Monkey pox
Small pox (variola virus)
Epidemiology: last natural case of smallpox was diagnosed in 1977
Source: only from close contact with infected persons
No animal reservoir or vector
No latency in humans
Spread: via droplet infection of pharyngeal secretions (ulcers in pharynx)
Incubation: 10-12 days
Major illness caused by small pox
rather similar to severe chicken pox
Abrubt onset of fever and prostration with macular rash on the third day
Progresses to vesicles which become pustular, ulcerated, scabbed, healed with scarring (“pock marked”)
16-30% mortality
what are the two varieties of small pox?
Variola minor 1% mortality
Variola major 5- 30% mortality
Small pox vs. chicken pox
fever 3 days before rash, slow development, centrifugal distribution, common on palms and soles
What is severe small pox like?
In severe disease patients became very toxemic and
- massive inflammatory response (cytokine release)
- capillary leak -> intravascular depletion
-multisystem organ failure
which has the most serotypes and what does this mean?
rhinoviruses have so many serotypes that it is hard to create a vaccine for it
what are the different types of enteroviruses?
Host range-Human viruses, no natural reserviors
Epidemiology-Worldwide distribution
-Asymptomatic infection common
-Primarily fecal-oral route of transmission, but examples of respiratory route exist
Pathology-Cause a wide range of syndromes
Poliovirus infection
90% asymptomatic
5% abortive - febrile illness - headache, sore throat, fever, malaise, vomiting
1-2% Non-paralytic poliomyelitis
.1-2% Paralytic
Salk polio vaccine advantages
dead virus
immunocomp safe
good systemic immunity
Salk polio vaccine disadvantages
multiple IM injections
*less intestinal immunity
Sabin polio vaccine advantages
both systemic and intestinal immunity
Sabin polio vaccine disadvantages
neurovirulent revertion
no immunocompromised
-Geographical barriers
-Long-term shedding of live vaccine viruses in immunocompromized individuals
-Laboratory stocks
-Virus construction
-Major cause of mild upper respiratory tract infection
-Temperature sensitive - 33°c
-Affects all age groups
-No vaccine - >100 serotypes
-No effective treatment
-Second most prevalent cause of the common cold
-Epidemic gastroenteritis
-Most important cause of diarrhea in adults
-Oral transmission
-Short duration, self-limiting
How fast do you see symptoms after ingestion of Norwalk virus?
24 hours
Negative sense RNA genome
**Segmented genome
RNA replication in nucleus
What are the three types of Influenza?
-Influenza A - 8 segments - humans, birds, pigs, horses, and aquatic mammals can all act as hosts
-Influenza B - 8 segments - humans
-Influenza C - 7 segments - humans
Influenza A
viruses generally cause greatest disease problems
Influenza B
causes similar disease symptoms and during occasional years are the most prevalent
Influenza C
causes mild disease symptoms by comparison
hemiagglutin (HA)
-responsible for initial interaction and plays role in uncoating the virus
-change in structure required to bind to membrane-due to fusion pH
Neuraminidase (NA)
occurs at the end of cycle and plays a role in release of the newly formed virus
protein channel that allows H+ in cell that lowers the pH and activates HA
who dies from the flu?
old and young
da FLU illness
Shaking chills
Secondary bacterial infection and pneumonia can seriously increase consequences
when do you see the flu and how many people are affected?
winter months
10% of the population
What is the incubation time for the flu?
Brief incubation period, ~2 days abrupt onset
2 - 5 days of maximum illness
What types of immune response does the flu trigger?
What are some serious complications of the flu?
secondary bacterial infection
primary viral pneumonia
CNS, muscle involvement
What are the major contributors to pathogenesis of flu?
1. aerosol inoculation
2. replication in respiratory tract
3. desquamation of mucus secreting cells
How do you detect flu early?
lab methods that detect virus in respiratory secretions
Why is it advantageous for the flu to occur in aquatic waterfowl?
Continuously circulate, many of the birds are migratory
Do not cause disease
Perfect natural reservoir
What flu subtypes have caused pandemics in humans?
H1 subtype - 1918 pandemic (h1n1)
H2 subtype - 1957 pandemic (h2n2)
H3 subtype - 1968 pandemic (h3n2
Antigenic drift
Mutation in surface proteins that enables virus to escape from currently circulating antibodies
Antigenic shift
Reassortment of segments of the viral genome
What is the mechanism of reassortment in flu?
duck and human virus combine in flu to make new strains in pigs that are transmitted to humans
Limited outbreak in hong kong
Highly pathogenic
18 confirmed cases
All required hospitalization
6 fatalities
2004 H5N1 outbreak in southeast Asia
Highly pathogenic
238 human cases confirmed - vietnam, thailand, china - 139 fatalities
Direct transmission from birds
Killed wild birds as well as chickens
Human incidence decreased recently
Why did the human incidence of H5N1 decrease recently?
Decrease in host population? - >100 million birds died due to natural exposure or slaughter
Normal decline due to seasonal variation
Defining Characteristics of Retroviruses
-2 enveloped RNA virus
-virion associated RT
-DNA Provirus integrated
-rapid evolution via error prone RT
what are the three main genome segments of HIV?
Which genome segment is a target for therapy?
pol- contians the top 3 targets for therapy RT, integrase, and protease
What genes do the env segment give rise to?
gp120-glycoprotein on the envelope
gp41-matrix protein
these would be primary targets for a vaccine
Flow of Genetic Information in Retroviruses
virion rna is reverse transcibed into provirus which is subsequently integrated into the genome. From here, everything is transcribed and such.
Simple Retroviruses
Contain only gag, pol, (pro) & env protein coding regions
e.g. Avian Leukosis Virus (ALV)
Complex Retroviruses
Contain additional accessory genes
Gene Regulation
Multiple mRNA splice sites
e.g. HIV
*ALL human retroviruses are complex
which retroviruses are responsble for human t cell leukemia?
HTLV-I, II (complex)
What genus is the HIV virus?
What types of disease can retrovirueses cause?
wasting and auto-immune diseases
immunodeficiency syndromes aplastic & haemolytic anaemias
what are the four human retroviruses known?
HTLV-1-T cell leukemia, tropical spastic paraparesis
HTLV 2-no known pathology
what triggered the discovery of human retrovirus?
ability to culture t cells in vitro-1980
What do all human retroviruses infect?
CD4 T cells
T-cell leukaemia/lymphoma
-Aggressive tumour of CD4 -cells infiltrates skin & brain
-only produced after a prolonged latent period. -Malignant change is the result of viral genome insertion changeing gene reg.
-Less than 1% develop this malignancy.
Tropical spastic paraparesis
Aggressive non-demyelinating spastic paraparesis.
Epedemiology of HTLV-1?
-Japan,Caribbean, West Africa
-prevalence increases with age
-family clustering
-spread via blood transfusion & sexual intercourse, breast feeding
How do you diagnose HTLV-1?
HTLV-1 specific antibody, ELISA
Lentiviruses & Persistence
ability of these viruses to evolve in response to biological, immunological & pharmacological selective pressures with a remarkable array of genetic & antigenic variations
How does the HIV envelope allow it to escape from effective antibody response?
sequence evolution
sheilding of receptor binding sites
extensive glycosylation
Gp120/ CD4/ Co-Receptor Interactions
gp120 binding sites are block for both CD$ and chemokine
Which viruses are responsible for the HIV epidemics?
HIV-1-SIV Chimp
HIV-2-SIV sooty mangabey
HIV Transmission
Inoculation in blood
Sexual Transmission
Perinatal transmission (intrauterine and brestfeeding)
What is the main predictor of risk of transmission?
HIV load
When is infectivity highest?
primary infection - high viremia
What factors enhance transmission?
Ulcerative STDs & lack of male circumcision
What are the stages of HIV infection?
HIV progression
What cells does HIV target?
Th cells
macrophages-facilitate persistence
dendritic cells-capture and present HIV
chemokine receptors CCR5 and CXCR-4
CCR5 ligands
Homozygous mutants of CCR5 are resistant to infection
CXCR4 ligands
what are the main sites of HIV replication?
Primary Lymphoid Organs
Secondary Lymphoid Organs
What are circumstances of immune activation that faciltate HIV replication?
proliferation of CD4 cells is a requirement for RT and nuclear transport
upregulation of CCR5 and enhanced expression of provirus in activated t cells
What things can you use to test for HIV
how can you test for antibodies?
Confirmation by Western Blot
Traditionally done with serum; may be done with saliva
how can you test for antigens?
ELISA based assay for p24 which is detected in blood before antibodies
used with ELISA to screen lood supply
how can you test for virus?
Quantitative RT-PCR(standard)
Qualitative PCR for DNA
Virus isolation by culture used infrequently
How would you recognize a primary HIV infection?
symptoms of influenza infection or acute mononucleosis
high transient viremia
What resolves the primary peak in the primary infection and how long does it last?
peak is resolve by CD8 cells
antibody response in 3-5 weeks
Quasi-steady state set-points in viral load are reached in 3-12 months
After seroconversion, what predicts variable progression to AIDS?
set point HIV RNA values
What is the relationship between CD4 count and HIV replication?
What is the clinical importance of viral load measures?
strongly predictive of disease progression
standard of care for decisions regarding initiation of therapy
essential for monitoring therapy
Clinical ‘Latency’ Period
Approximately constant viral loads
CD4+ T cells decline slowly
No apparent symptoms
highly dynamic state with high levels of turnover
How long does is take on average for people to progress to AIDS?
about 10 years
when do you see onset of symptoms and what are they?
mucosal candidiasis
herpes infection
What do you see with full blown AIDS?
Severe CMV(<40)
Dementia, malignancies
Protozoal indicators of AIDS
Toxoplasmosis of the brain
Cryptosporidiosis with diarrhea
Isoporiasis wih diarrhea
Fungal indicators of AIDS
Candidiasis of the esophagus, trachea, and lungs
Pneumocystis carinii pneumonia
Viral indicators of AIDS
Progressive multifocal leukoencephalopathy
Hairy oral leukoplakia caused by EBV
Bacterial indiators of AIDS
Mycobacterium avium (MAC) Tuberculosis
Salmonella septicemia
Pyrogenic bacterial infections
Kaposi’s sarcoma
Primary lymphoma of the brain
Other non-Hodgkin’s lymphomas
Other indicators of AIDS
HIV wasting syndrome
HIV encephaolpathy
Lymphoid interstitial pneumonia
What are the most likely indicator conditions in AIDS?
Severe HIV-related immunosuppression-85
HIV wasting syndrome-8
Esophageal candidiasis-6
M. Tuberculosis infection-3
How does HIV directly cause AIDS?
Lysis of infected cells(virus effect)
How does HIV indirectly cause AIDS
Host response-
-Apoptosis of bystander cells
-Impaired T cell regeneration
-Disruption of lymph nodes
-CTL killing of infected cells
How much is virus turnover in the clinical latency period?
10^10 virions produced each day
Besides CD4, what are the other immune perturbations in HIV?
CD8 T cell activation: inc. CD38, dec. CD28
Apoptosis of CD4 and CD8 T cells
Naïve T cell loss, effector memory T cell increase
Altered lymph node, thymus and bone marrow
Altered T cell kinetics: inc destruction, dec. production
What is the exception to CD4 count and viral load being inversely related?
SIV infection in sooty mangabeys the CD4 count stays high regardless of high viremia
What leads to increased destruction of CD4?
direct effect of virus and increased bystander cell death as a result of inappropriate apoptosis
Anti-HIV immune responses
Total antibody
Neutralizing Antibody
Inhibition of viral entry by b-chemokines
Pro-inflammatory cytokines (IFN-g, TNF-a)
Basic Principle 1
Infectious diseases are caused by microorganisms that differ from us both structurally and functionally
Basic Principal 2
Structural and functional differences of microbes provide targets for antimicrobial chemotherapy
Koch’s postulates
Isolate the pathogen in pure culture
Introduce the pathogen into a susceptible animal host and observe the disease
Isolate the pathogen in pure culture from experimentally infected animal
Always isolate the pathogen from humans with the disease
Koch’s molecular postulates
Phenotype should be more often associated with pathogenic strains of a species
Specific inactivation of the gene should decrease virulence or result in loss of a property in a cell or animal model system
Restoration of the wild-type gene restores virulence
What is the leading cause of bacterial meningitis in the United States ?
Streptococcus pneumoniae
Which form of bacterial meningitis shows the highest mortality in the US?
Streptococcus pneumoniae
How do we identify bacteria?
differential staining
biochemical characteristics
-streptococci-division in one plane and grows in chains
-staphylococci-division in multiple planes
-bacillus anthracis-appear as single rods
-listeria monocytogenes-oval coccobacilli
Gram Stain
1.crystal violet
2. iodine
3. alcohol wash
4. safranin
+ dark blue
- pink
Acid fast stain
Red dye carbol fuchsin applied to fixed smear
Slide heated
acid/alcohol mixture
-Acid fast organisms retain dye because it is more soluble in the cell wall lipids than in the acid/alcohol mixture
Acid fast stain is used to identify which bacteria?
mycobacteria spp.
What are hemolysis reactions?
performed by doing a liquid or solid culture onto a petri dish and checking for a response.
“alpha” hemolysis
Green due to the production of biliverdin from heme. S. pneumonia will give this result
“beta” hemolysis
The complete lysis of RBCs around the colony
“gamma” hemolysis
absence of any hemolytic activity
selection test
selects for particular bacteria of interest and selects against those that we don’t care about (ex: antibiotics in the media that kill sensitive bacteria while resistant bacteria grow)
Differential/selection for S. aureus
Mannitol salt agar has a very high concentration of NaCl so that only Staphylcocci grow.
To distinguish S. aureus from all of the other Staphylococcal species add mannitol (a sugar) and a pH indicator. S. aureus will ferment mannitol while secreting lactic acid causing the pH to become acidic and the indicator will change color (from red to yellow). On the left is S. aureus and on the right is some other type of Staphylococcal bacteria.
MacConkey agar
Bile salts select for growth of enteric bacteria, lactose plus pH indicator identify lactose fermentation (red) indicating Escherichia coli
Polymerase chain reaction
rapid and sensitive identification of bacteria without having to do a culture.
Can be done for speices or strain
Also can be used to compare sequences
DNA – DNA hybridization
defines bacterial species
If DNA preparations from two bacteria show 70% hybridization and half the hybridizing DNA melts within a 5°C increase in temperature, the bacteria belong to the same species
virus definition
-Sub-microscopic, obligate intracellular parasite
small (200-400 nucleotides) circular RNAs with a rod-like secondary structure which possess no capsid or envelope and are associated with certain plant diseases
satellite viroid-like molecules, slightly larger, which are dependent on the presence of virus replication for multiplication, which allow them to be packaged into virus capsids as passengers
infectious agents believed to consist of a single type of protein molecule with no nucleic acid component (e.g., Creutzfeldt-Jakob disease)
viral capsid
encloses viral genome
protects genome from physical(shear), chemical(UV), and enzymatic damge(nuceases or antiviral).
protein subunits are redundant
outer envelope
lipid bilayer containing viral glycoproteins (and in some cases cellular glycoproteins – e.g., HIV) – however, many viruses lack an envelope
outer surface
involved in binding/recognition of the host cell
viral structure is icosahedral
naked viruses tend to be stable and to resist dessication, acid, and detergent
Geometry determines the size of the genome that can be packaged inside the capsid
What determines viral classification?
morphology including size, shape, capsid symmetry, envelope, and viron properties
What are the top two factors to classify a virus?
what is the difference between positive and negative RNA?
negative contains the complement RNA and must be copied by a viral RNA plymerase in order to produce mRNA
Which DNA viruses have an envelope?
Which DNA viruses are NAKED?
Which RNA viruses have an envelope?
Which RNA viruses are NAKED?
Which RNA virus has a double capsid?
What are the stages of viral growth?
Why would catheterization predispose to infection?
Provide access to defended site, introduce infecting organisms, block defenses
Where did the infecting microorganisms come from?
Normal flora, nosocomial infection
What is sepsis and what is its cause?
Clinical condition due to systemic effects of inflammatory responses, bacterial toxin esp. endotoxic products
How does sepsis cause death?
Vasodilation, DIC, organ failure
How did the pope die?
Organ failure due to sepsis following urinary tract infection
Virulent bacteria
Have the capacity to grow at the expense of the host
Opportunistic bacteria
Exploit preexisting conditions in the host
Virulence factors
Enhance the ability of the bacteria to cause disease
Not all strains of a particular species express the same virulence factors
what factors prevent entry and spread of bacteria?
Integrity of skin
Ciliary action
Fluid flow
Secretions (lysozyme, bile)
What factors affect colonization, adhesion, and invasion?
Invasins/manipulation of actin cytoskeleton
Biofilm formation
what determines the disease a bacteria causes?
how the bacteria gained entry and where it ended up
How does bacteria cause tissue destruction?
Hemolysins, lipases (membranes)
Collagenase, protease, hyaluronidase (CT)
Provision of nutrients?
Is LPS an endotoxin or exotoxin?
Is diptheria toxin an endo or exotoxin?
How does diptheria toxin cause disease?
b unit allow translocation where the catalytic subunit A causes cell death by inactivatiing EF-2
Is cholera an endo or exotoxin?
How do cholera work?
cholera releases its toxin wbinds to a ganglioside receptor triggering a cAMP dependent loss of cell nutrients leading to diarrhea
Is tetanus endo or exo?
How does tetanus work
toxin is a n endopeptidase that inhibits release of inhibitory transmitter allowing only contiuouw stimulation by excitatory transmitters leading to spastic paralysis
Is botylism endo or exo?
How does botylism work?
toxin blocks the release of ACH vesicles causing flaccid paralysis
What is the most important virulence factor enabling bacteria to escape host defenses?
capsules because they inhibit phagocytosis and opsonization by hiding surface antigens from antibodies.
what causes gas gangrene?
Clostridium perfringens
What determines tropism in viral infection?
receptor specificity
What is the most common route of viral infection?
it is not a virus but implies spread by arthropod vector
Outcome of infection of a cell
Failure to infect
cell death
syncytia formation
What are the ways viruses can be oncogenic?
remove growth inhibition
activate growth stimulation
prevent apoptosis
Flu-like systemic symptoms
Interferon, cytokines, C3
Respiratory viruses
Delayed type hypersensitivity
T cell responses
Enveloped viruses
Immune complex disease
Antibody, complement
Hepatitis B
Hemorrhagic disease
T cell, antibody, complement
HIV, cytomegalovirus, measles, influenza
Susceptibility/severity of disease depends on what?
Nature of exposure
Immune status
Viral dose
T or F Most viral infections cause disease
how do bacterial cells differ from eukaryotic cells?
Transcription, translation and DNA replication all take place in the same intracellular compartment
smaller, no mitochodria, 70/50/30 ribosomes, no sterols, and respiration takes place in cytoplasmic membrane
Bacterial chromosome
Organized into ~ 50 domains
~1 mm long (500x length of the bacterium)
Domains are supercoiled
what bacteria has a linear chromosome?
borellia spp
Extrachromosomal genetic elements
Capable of autonomous replication
how do gram +/- membranes differ?
negative-has an outer membrane with less murein underneath

the outer membrane block the cresyl violet stain
What gives bacteria their shape
Peptidoglycan: glycan chains joined by peptide crosslinks

Murein: peptidoglycan containing muramic acid
Gram-positive cell wall
Single membrane
Multiple layers of peptidoglycan (murein)
Teichoic and lipoteichoic acids: polyribitol and glycerol phosphates
(antigenic determinants, adherence, movement of cations, gram-positive sepsis)
Gram-negative cell wall
Outer and inner membrane
Single layer of peptidoglycan
Lipoprotein (attaches outer membrane to peptidoglycan)
Porins (small compounds diffuse across outer membrane)
Mycobacterial cell wall
Mycolic acids
Porins (aid diffusion through hydrophobic
Gram + tetrapeptides and cross links
pentapeptide precursor: L-ala – D-glu – L-lys – D-ala – D-ala
cross link: L-lys – (gly)5 - D-ala
Gram - tetrapeptides and cross links
pentapeptide precursor: L-ala – D-glu – dap – D-ala – D-ala
cross link: dap – D-ala
Extremely toxic
Causes fever and shock
Blocks diffusion of hydrophobic and hydrophilic compounds(requirement for porins)
O antigen side chains are major surface antigens (no teichoic acids)
e.g. E. coli O157:H7
movement of flagella
What are the types of pili?
Common pili or fimbriae-carry adhesins, mediate attachment, twitching motility
Sex pili-mediate attachment to other bacteria during conjugation
What is important about pili?
facilitate bacterial protein secretion
Usually made of polysaccharide
Produced by both gram-positive and gram-negative bacteria
Resistance to phagocytosis
Quellung reaction
What is the quelling reaction?
capsule specific antibody that causes capsule to swell forming a white halo on slide
General term for substances that surround cells
What are the functions of glycocalices?
Adherence – biofilm formation, adherence to tissues
Protection from phagocytosis
What is the glycocalx called when it is attached to the cell wall?
capsule--slime if not
formed by + rods
Small, dehydrated, metabolically quiescent
can withstand extemes, chemicals, and radiation
external layer is made of lipoprotein/carb)
What are the steps of endospore formation?
1. septum isolates DNA
2. plasma membrane forms
3.septum surrounds spore
4.peptidoglycan layer forms
5.spore coat
6. endospore released
In rich broth, how often do bacteria double?
every 30 minutes
Bacterial growth curve
Log phase
Exponential growth in the presence of excess nutrients
Stationary phase
Nutrient exhaustion leading to many complex adaptations
-Competence for genetic transformation
-Survival under starvation
Aerobic respiration
1 molecule of glucose generates 2 ATP molecules by glycolysis and 2 ATP molecules from the TCA cycle
The NADH and FADH2 lead to the production of 34 ATP molecules by electron transport and chemiosmosis
Toxic forms of oxygen
Singlet oxygen (O2)
Superoxide free radicals (O2.-)
Peroxide anion (O2 2-)
Singlet oxygen
Molecular oxygen in a high energy state (phagocytic cells)
superoxide free radicals
Produced when oxygen is terminal electron acceptor
Requires superoxide dismutase (SOD) for neutralization
Peroxide anion
Catalase-h2o and o2
Peroxidase-just h2o
What determines whether oxygen is useful to a bacteria?
enzymes present
Obligate anaerobes
O2 required
catalase and SOD
facultative anaerobes
greater growth in the presence of oxygen
catalase and SOD
obligate anaerobe
oxygen stops growth
lacks enzymes
aerotolerant anaerobes
only anaerobic growth but continues in the presence of oxygen
only aerobic growth in low conc of oxygen
produce too much toxic oxygen
What is the purpose of fermentation?
Fermentation restores NAD+
How do bacteria acquire nutrients?
Secretion of degradative enzymes
Transport into the cell
Secretion of compounds that bind nutrient followed by uptake
Iron uptake
Concentration of free iron vanishingly small (transferrin, lactoferrin, ferritin)
Bacteria obtain iron either by chelating agent or by special receptors that extract iron from cells and transport it into cells.
destruction of all forms of life
ususally done under pressure or with ethylene oxide
commercial sterilization
sufficient heat to kill endospores of clostridium botulinum in canned food
destruction of vegetative pathogens
can use phyiscal or chemical methods
destruction of vegetative pathogens on living tissue
always by antimicrobial chemicals
removal of microbes form limited area such as skin around infection
mostly mechanical with alcohol swab
treatment intended to lower microbial count on eating and drinking utensils
high temp washing or by dipping into chemical disinfectant
Disinfection of living tissue
handwashing-<1 log
hand disinfection(more effective
presurgical skin disinfection-iodine is only one approved, friction greatly increases difference in killing
Thermal death point (TDP)
Lowest temperature at which all organisms in a liquid sample will be killed in 10’
Thermal death time (TDT)
Minimum for everything to die at a given temperature
Decimal reduction time (DRT or D value)
Time in which 90% of a population will be killed at a given temperature
What factors affect effectiveness of antimicrobials?
Number of organisms – larger number, longer to eliminate the population
Environmental factors – organic materials reduce effectiveness, serum binding proteins, biofilms,temperature
Time of exposure
Pasteurization-High temperature short time (HTST) pasteurization
High temperature short time (HTST) pasteurization
72ºC, 15” for milk – milk must still be refrigerated
Ultra high temperature (UHT) treatment
140ºC, 1” – milk can be stored without refrigeration
disk diffusion assay
used to evaluate disinfectants by plating them with various bugs and measuring the zone of inhibition
why are phenols modified?
to reduce irritation or increase antibacterial action in combination with a detergent
what is the main ingredient in lysol?
O-phenylphenol (cresol) main ingredient in Lysol
What can kill staphylococci and streptococci?
Hexachlorophene – pHisohex
Quaternary ammonium compounds
Hydrogens of the ammonium ion replaced
Zephiran – benzalkonium chloride
Cepacol – cetylpyridinium chloride
Neutralized by soaps and and anionic detergents
Pseudomonas actively grow on quaternary ammonium compounds
iodine and chlorine
tincture (solution in aqueous alcohol)
iodophore (combination of iodine and organic compound) Betadine
Chlorine + water yields hypochlorous acid (strong oxidizing agent)
Sodium hypochlorite – Clorox
Sodium dichloroisocyanurate – Chlor-Floc (chlorine + flocculating agent)
Chloramines – water treatment
Ozone – supplement to chlorination
Hydrogen peroxide – not good on open wounds (catalase), effective on surfaces
Benzoyl peroxide – acne medication, anaerobic bacteria
Peracetic acid – liquid sporicide
List bugs in order of most to least resistant?
endospores, mycobacteria, protozoa, gram -, fungi, nonenveloped virus, gram +, enveloped virus
What works best on endospores?
chlorines and glutaraldehyde
What works best on mycobacteria?
phenolics, iodine, alchohols, and glutaraldehyde
Therapeutic index
ratio of toxic to therapeutic dose
which are easier to kill--bacteria or virus?
bacteria-bc they are different
What are unique targets that make things easier to kill?
Cell wall biosynthesis
Different ribosomes
Different RNA polymerase
Different DNA polymerases
Selective toxicity
kills the bugs without killing us
only effective in infected cells
Must be metabolized by viral encoded thymidine kinase
Not a substrate for the cellular thymidine kinase
Bactericidal drugs
(e.g. beta-lactams) kill bacteria (only growing bacteria) without the action of the humoral or cellular immune response
Bacteriostatic drugs
prevent growth of susceptible bacteria, but they must be killed by the host’s defenses
What effect does biofilm growth have on effectivness of antibiotic therapy?
can dramatically reduce it
Minimal inhibitory concentration (MIC)
Least amount of antibiotic required to prevent growth of the bacteria under standard
How is MIC measured?
Serial dilutions of antibiotic each with a standard inoculum
Disk diffusion assays
Diameter of the zone of inhibition related to the MIC
Minimum lethal concentration (MLC)
Least amount of antibiotic required to kill a predetermined fraction of the bacteria (99.9%) in a given time
What is the key for an effective antibiotic therapy?
levels of antibiotic at the site of infection must be above the MIC
What factors determine the MIC at the site of infection?
Absorption from the upper gastrointestinal tract
Is the compound excreted or concentrated in the urine
How rapidly is the compound metabolized
How strongly does the compound bind to protein
serum binding of antibiotic
leads to a more prolonged but lower concetration
Spectrum of activity
The spectrum of an antibiotic activity is the range of organisms against which the antibiotic is effective
benzyl penicillin
narrow spectrum
active against gram-positive and gram-negative cocci but not gram-negative bacilli
chloramphenicol or tetracycline
broad spectrum
active against a wide range of gram-positive and gram-negative bacteria
How do penicillin and aminoglycosides synergistically work against enterococci?
Penicillin affects cell wall synthesis, increasing penetration of the aminoglycoside (protein synthesis inhibitor)
Why do bacteriostatic drugs and penicillin antagonize each other?
Penicillin only active against growing cells
when do you use dual therapy?
high numbers (pulmonary TB)
resistance to a single drug at 10^-6-frequency of resistance to 2 drugs is rare
How would you treat pulmonary TB?
isoniazid and rifampicin
what are the most important drugs that inhibit peptidoglycan synthesis?
The most important are the beta-lactams (penicillins and cephalosporins) and the glycopeptides (vancomycin)
Inhibit cell wall bisynthesis
Low toxicity (except for hypersensitivity reactions)
Example of beta-lactam antibiotics
Susceptible to cleavage by penicillinases (beta-lactamases)
Action of penicillin
Penicillin inhibits transpeptidation
Structure of penicillin very similar to terminal D-ala-D-ala of peptidoglycan precursor
Narrow spectrum (penicillin V)
active against gram-positive organisms, some gram-negative cocci, some spirochetes (treponema)
not active against Gram-negative bacilli (outer membrane)
Penicillinase-resistant (nafcillin, oxacillin)
active against beta-lactamase producing S. aureus
Extended spectrum (ampicillin, carbenicillin)
Active against some gram-negative bacteria
Inactivated by staphylococcal beta-lactamase
Greater activity against enteric bacteria and Pseudomonas spp
β-lactam plus β-lactamase inhibitor (ampicillin/sulbactam)
Improved activity against beta-lactamase producing S. aureus
Contain beta-lactam ring
Resistant to staphylococcal beta-lactamases
First generation (narrow spectrum)Cephalosporins
some gram-negative activity (E. coli, Klebsiella, Proteus mirabilis)
susceptible to gram-negative beta-lactamases
Second generation (expanded spectrum)Cephalosporins
extend spectrum to anaerobes and more gram-negatives (Haemophilus)
Third generation (broad spectrum)Cephalosporins
extended gram-negative spectrum (Neisseria, Pseudomonas)
Fourth generation (extended spectrum)Cephalosporins
Most Enterobacteriaciae and Pseudomonas
Carbapenems(beta lactam)
Highly resistant to most beta-lactamases
Very wide spectrum of activity
Rapidly hydrolyzed by renal tubular dehydropeptidase
Therefore administered with inhibitor (cilastatin)
Monobactams (beta lactams)
Little activity against gram-positives, anaerobes
Highly resistant to gram-negative beta-lactamases
Anaerobic superinfections and distortions of bowel flora less commmon than with broad spectrum beta-lactamases
Binds to terminal D-ala - D-ala of peptidoglycan precursor
Inhibits transglycosylation and transpeptidation
Treatment of methicillin-resistant S. aureus (bacteria are resistant to penicillinase-resistant penicillins such as oxacillin) and of resistant enterococcal infections
Inhibitors of protein synthesis
Synergistic effects with beta-lactam antibiotics
Tetracyclines and chloramphenicol
Protein synthesis inhibitors
Broad spectrum
Pass through eukaryotic cell membranes
Active against intracellular bacteria (Rickettsia, Chlamydia)
Macrolides (e.g. erythromycin)
Protein synthesis inhibitors

Newer macrolides such as azithromycin and clarythromycin are active against Mycobacterium avium and Toxoplasma gondii
Inhibitors of nucleic acid sythesis
Quinolones (e.g. ciprofloxacin)
DNA gyrase inhibitors

Rifampicin (important antimycobacterial agent)
RNA polymerase inhibitor
Folate inhibitors-Sulphonamides
Useful for urinary tract infections
Structural analogues of para-aminobenzoic acid (folate precursor)
Folate inhibitors-Trimethoprim
Active against Pneumocystis carinii
Inhibits dihydrofolate reductase
What is the mutation rate of HIV?
Mutation rate: ~1 mutation per 10,000 bp genome/replication cycle
What is the recombination rate of HIV?
Recombination rate: ~1 in 3 genomes arising from cells infected with 2 genetically distinct genomes
Why is it challenging to find an effective antiviral against HIV?
Extensive replication in vivo generates many viral variants, including those that differ in susceptibility to antiviral drugs, immune responses
Drug resistant variants may be present before therapy is initiated, ditto for immune escape variants
antiviral agents
Combination Nucleosides
Protease inhibitors
Non-nucleoside RT inhibitors
Fusion inhibitor
What are the benefits of early HIV therapy?
-Control of viral replication easier to achieve/maintain
-Delay or prevention of immunodeficiency
-Lower risk of resistance
-Possible decreased risk of HIV transmission
What are the risks of early HIV therapy?
-Drug-related reduction in quality of life
-Greater cumulative drug-related adverse events
-Earlier development of drug resistance
-Limitation of future treatment options
What are the benefits of delayed HIV therapy?
-Avoid negative effects on quality of life
-Avoid drug-related adverse events
-Delay development of drug resistance
-Preserve treatment options for the future
What are the risks of delayed HIV therapy?
-Possible risk of immune system depletion
-Possible greater difficulty in suppressing viral replication
-Possible increased risk of HIV transmission
Realities of ART
Eradication of HIV not possible
Toxicities of HAART potentially limit therapy
Viral suppression rates not uniformly excellent
Possible Causes of Treatment Failure
Poor adherence
Pharmacologic factors
Limited drug/regimen potency
Host factors
Drug resistance
Antiretroviral Drug Toxicities-Immediate
Immediate: headaches, GI intolerance, rash, stomatitis, hypersensitivity reactions
Antiretroviral Drug Toxicities-short term
Short term: neutropenia, anemia, peripheral neuropathy, renal stones, hepatitis
Antiretroviral Drug Toxicities-long term
Hyperlipidemia,Hyperglycemia/ diabetes mellitus, Fat redistribution, lipodystrophy
Lactic acidosis/ hepatic steatosis, Avascular necrosis of hip, osteopenia, Thrombotic events, ischemic heart disease
how do you decide when begin antiretroviral therapy?
virologic and immunologic crit.
pt understands need for requirements, circumsances, and commitment involved
first chance is best chance
Patient is symptomatic..tx?
initiate rx
patient is asymtomatic with CD4 less than 350
offer rx
patient is asymtomatic with viral load of >60,000
offer rx
patient is asymtomatic with viral load of <60,000 and >350 CD4
Criteria for Changing Therapy
-<0.5 - 0.75 log10 reduction in plasma HIV RNA within 4 weeks or <1.0 log10 reduction within 8 weeks of initiating therapy
-Failure to suppress HIV RNA to undetectable levels within 4-6 months of initiating therapy
-Repeated detection of virus in plasma after initial suppression to undetectable levels, suggesting the development of resistance
-Any reproducible increase, 3-fold or greater, from the lowest point of HIV RNA not attributable to intercurrent infection, vaccination, or test methodology
-Persistently declining CD4 cell numbers, as measured on at least two separate occasions
-Clinical deterioration
Influenza antivirals-Amantadine and rimantadine
Acts at the level of viral entry by preventing acidification of virus interior in the endosome - dissociation of nucleocapsids from protein
Very effective antiviral
Doesn’t act on all strains
Mutants selected
Influenza antivirals- Neuraminidase inhibitors – oseltamivir (Tamiflu)
Acts at the level of virus release by inhibiting virus disemination
Reduces severity of infection, but only if administered early on
Drug-resistant mutants are rare
What are the 2 categories of antivirals for herpes?
1.affect viral DNA polymerase directly: foscarnet (PFA)- active against all herpesviruses
2.nucleoside analogs that require phosphorylation by viral enzymes before being utilized by, and inhibiting, viral polymerase (acyclovir, gancyclovir, vidarabine, idoxuridine)
What are the antivirals used for herpes?
HSV1,2: all nucleoside analogs
VZV: vidaribine
CMV: gancyclovir
EBV: none
Herpes B virus: acyclovir
Vaccine for herpes?
only vaccine currently licensed is live attenuated VZV
subunit vaccines for HSV currently in human trials
What memory responsed enable vaccines to work?
Antibody-for acute infection
Cytotoxic T lymphocytes, T Cell Help-Needed to control chronic intracellular pathogens (Viruses,Gram-positive) bacteria
B cell memory responses
T-dependent B cells - Persisting Ab plus anamnestic expansion.
T-independent B cells - Anamestic expansion
T cell memory response
Protection by anamnestic expansion
What 3 types of CD4 T cell help support the establishment and expansion of memory responses
What are the three things need for a vaccine response?
Antigen to provide specificity and memory
Innate immunity to provide danger signals
Co-stimulation to provide energy
How does the innate immunity provide danger signals?
What does costimulation provide energy for?
provides nutrients for rapid differentiation and division by activating AKT (glucose transporter) and Tor and Pim 1/2 which are amino acid transporters
What forms can the antiden be delivered as?
Live attenuated vaccine
Killed whole Vaccine
Purified protein or polysaccharide
Conjugated polysaccharide
Genetically engineered protein
Recombinant viral or bacterial vector
Heterologous prime/boost
Heterologous Prime/Boost Vaccines
DNA priming and live vector boosting
Priming with one live vector followed by boosting with another live vector
Priming with DNA or a live vector followed by protein boosting

Power: Immunity to the prime does not interfere with the boost
Assays used for Vaccine Development
Challenge infection (death and morbidity)
Antibody (use ELISA to detect bound antibodies to measure neutralization.)
Assays used for Cellular Responses
CFSE Proliferation
Which vaccines have been withdrawn?
Inactivated measles
Inactivated respiratory syncytial virus
Links between Vaccines and adverse events that have been disproved
MMR - autism
Thimerosol – autism
Hepatitis B - multiple sclerosis
Haemophilus influenzae type B conjugate and hepatitis B - diabetes
Links that are unsubstantiated by research
Anthrax – Gulf War syndrome
DTP – Atopy
Pediatric vaccines – sudden infant death
Cancers that could be prevented by vaccines
Liver-hep b and c
stomach-H pylori
diseases that need vaccines
Respiratory Diseases
Diarrheal Diseases
bench to clinic
GMP/GLP manufacture
FDA – IND (investigational new drug approval)
Phase I – Safety/Dose escalation
Phase II – Regimen and dose to elicit the correlate for protection
Phase III – Efficacy in at risk population
Phase IV – Continued post licensure monitoring