B3.027 Chronic Infections Flashcards
what are chronic infections
infections that are not efficiently cleared by either the innate or adaptive immune response
examples of viruses that cause chronic/persistant diseases
HIV-retroviral integration into host
CMV- persistent infection of glands and kidneys
HSV- episomal latency in neuronal cells, inhibition of apoptosis
EBV- dormancy in B cells with reactivation
what are 6 major bacterial persistence mechanisms
antigenic variation or surface antigens (usually immunodominant/serotype defining)
colonization of immunopriveleged niches
modification of intracellular environment
host mimicry
resistance to immune effector mechanisms (opsonization or complement pathway inhibition)
selective gene deactivation
bacteria that uses antigenic variation of surface antigens as a mechanism
borrelia burgdorferi
bacteria that use modification of intracellular environment as a mechanism
facultative and obligate intracellular bacteria
deactivate lysosome or something else
bacteria that uses host mimicry as a mechanism
treponema pallidum (host proteins, limited antigens)
bacteria that use resistance to immune effector mechanisms as a mechanism
encapsulated pathogens borrelia burgdorferi (complement factor sequestration, prevent MAC formation)
spirochetal human diseases
syphilis: treponema pallidum
leptospirosis: leptospira interrogans
relapsing fever: several borrelia species
lyme borreliosis: borrelia burgdorferi
periodontal disease: treponema denticola
describe the spirochetal envelope structure
periplasmic flagella- hide flagella from the immune system within the periplasm
outer membrane and cytoplasmic membrane
thin and long
predestined for penetration
leptospira host-pathogen interface
LPS and lipoproteins
treponema pallidum host-pathogen interface
no major surface antigens, no LPS
stealth
borrelia host-pathogen interface
abundant lipoproteins which play major roles in pathogenesis
no LPS
t. pallidum virulence factors
no culture in medium (only in rabbit testicles)
hyaluronidase (sticks to extracellular matrix)
fibronectin coat
few surface proteins (Tromp1)
lipoproteins
stealth pathogen
what causes the symptoms of t.pallidum?
the immune responses to tissue damage
NOT toxicity of the pathogen itself
describe the stages of syphilis
primary at 2 weeks
secondary at 23 weeks
long latency before a tertiary stage
what are the symptoms associated with primary syphilis?
chancre at the site of pathogen entry
painless
heals spontaneously
what are the symptoms associated with secondary syphilis?
maculopapular, desquamative rash
alopecia
papules and plaques in groin
erythematous mucous patches in mouth
what are the symptoms associated with tertiary syphilis?
gummatous (benign gumma lesions in skin, bone, brain)
cardiovascular (aortic aneurysms)
neurosyphilis (syphilitic meningitis within 2 yrs of infection, vascular syphilis, general paresis, spinal cord damage with demyelination of dorsal roots)
what is congenital syphilis?
infection in utero after 4th month of gestation
stillborn
rhinitis, secondary and tertiary syphilis
Hutchinsonian teeth and saddleback nose
syphilis epidemiology
total US cases 88,000
incidence rising
8:1 males to females
microscopy diagnostics for syphilis
darkfield of fresh skin lesions (not oral) DFA staining (fluorescent delabeled antibody)
nontreponemal serology diagnostics for syphilis
VDRL
RPR (rapid plasma antigen)- tests for regain antibodies against cardiolipin (host cell wall component, released due to tissue damage and then an Ab is developed against it)
sensitive
treponemal serology diagnostics for syphilis
specific
FTA-ABS
TP-PA
DOC for syphilis
penicillin G (single shot IM) if allergy: doxycycline, tetracycline, azithromycin, ceftriaxzone
Jarisch Herxeheimer reaction
NOT penicillin allergy
happens in 25% of patients
abrupt onset of fever, chills, myalgias, tachycardia, vasodilation, with flushing, skin rash, or mild hypotension
due to massive release of proinflamm cytokines, triggered by release of endotoxin like substances from bacteremic organisms (lipoproteins)
describe the physical structure of leptospira interrogans
free living spirochetes
large genomes
several serovars
different LPS on surface
asymptomatic hosts of leptospira
rodents
dogs
animals
act as resevoirs and shed and contaminate soil/water
where do spirochetes persist in the body?
renal tubules
shed in urine
contamination of soil and water
pathogenesis of leptospirosis
- infection via intact mucosa or broken skin (via water uptake)
- septicemia
- damage of small blood vessel endothelium
- meningitis
- hepatitis
- nephritis
- hemorrhage - exit
leptospirosis epidemiology
<100 cases/ year worldwide occupational exposures peak in warm months no human to human transmission can be fatal
microscopy diagnostics for leptospirosis
insensitive, nonspecific bc number of spirochetes too low to see
except DFA
culture diagnostics for leptospirosis
special media, slow growth (2 wks to 4 mo)
blood, CSF: positive during first 10 days
urine: positive after first week
serology diagnostics for leptospirosis
gold standard: agglutination test
enzyme linked dot IgM immunoassay
DOC for leptospirosis
severe: IV penicillin oral doxycycline (preventative), ampicillin, amoxicillin
how are borrelia sp transmitted?
soft Ornithodoros ticks
B.hermsii in NW
B.turicatae in SW
differentiate between TBRF and LBRF
tick borne relapsing fever: endemic
louse borne relapsing fever: epidemic
TBRF transmission
tick infested rodents nests
Ornithodoros ticks are fast feeders, thus bites are usually not noticed
RF Borrelia are present in salivary glands and quickly transmitted with the saliva upon feeding
ID=1
LBRF transmission
crushing of louse (rub louse feces into bite wound)
humans the only host
describe the mechanism behind recurrent fever
recombination of silent genes into single expression site
different genes expressed every few weeks
each serotype is defined by the expression of a different single immunodominant surface lipoprotein
microscopy diagnostics for RF
detection of spirochetes in blood smears during febrile periods
sens 70%
culture diagnostics for RF
complex medium
slow growth
serology diagnostics for RF
western blot for B.turicatae
tests for other spirochetal diseases can show cross reactivity
DOC for RF
tetracycline (LBRF)
doxycycline (TBRF)
erythromycin
species causing Lyme disease
Borrelia burgdorferi
what types of ticks transmit B.burgdorferi
Ixodes
describe the epidemiology of Lyme in the uS
300,000 cases/year
most common vector borne disease
2 major foci: NE and Great Lakes
discuss the transmission of Lyme
humans are incidental dead end hosts
Ixodes ticks feed for several days
transmission within 48 hours unlikely
-spirochetes travel from midgut to salivary gland
early localized symptoms of Lyme disease
days to weeks at site of tick bite erythema migrans (EM) -bulls eye rash -expanding, self resolving -appears in most ->5 cm diagnostic
early diffuse symptoms of Lyme
malaise fever headache fatigue chills MSK pain lymphadenopathy
weeks to months disseminated Lyme symptoms
secondary EMs neuroborreliosis -bell's palsy (facial nerve paralysis) -meningitis -encephalitis -radiculopathy -cranial neuritis cardiac dysfunction -myocarditis -pericarditis -AV nodal block
Late disseminated Lyme symptoms
acrodermatitis chronicum atrophicans (paper like skin)
encephalopathy
oligoarticular arthritis (large joints, on only one side)
what are two major classes of B.burgdorferi virulence factors
tick colonization and survival
mammalian colonization/persistence
virulence factor associated with tick colonization and survival
OspA binds to tick midgut receptor and protects other bacterial proteins from tick proteases
virulence factors associated with mammalian colonization/ persistence
OspC binds immunomodulary tick saliva protein, blocks phagocytosis by macrophages, and binds complement component C4b
Adhesins
broad complement resistance family of proteins binding complement regulatory Factor H from different species
antigenic variation allows for persistent infection of reservoir hosts
CRASPs
complement regulator acquiring surface proteins
block MAC formation
render bacteria serum resistant
lyme arthritis pathogenesis
- invasion and colonization
- inflammatory host response to bacterial lipoproteins
- bacterial numbers are reduced
- persistence/immune evasion
- lipoproteins: constant source of inflammatory stimulus in joints (edema associated with neutrophil infiltration)
- antibiotic treatment-refractory arthritis: autoimmune response to OspA epitope
1st generation Lyme vaccine
recombinant lipidated OspA
was approved, but taken off market in 2002
transmission blocking vaccine: needs to generate high titers
