B3.027 Chronic Infections

Question 1

what are chronic infections

Answer 1

infections that are not efficiently cleared by either the innate or adaptive immune response

Question 2

examples of viruses that cause chronic/persistant diseases

Answer 2

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

Question 3

what are 6 major bacterial persistence mechanisms

Answer 3

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

Question 4

bacteria that uses antigenic variation of surface antigens as a mechanism

Answer 4

borrelia burgdorferi

Question 5

bacteria that use modification of intracellular environment as a mechanism

Answer 5

facultative and obligate intracellular bacteria

deactivate lysosome or something else

Question 6

bacteria that uses host mimicry as a mechanism

Answer 6

treponema pallidum (host proteins, limited antigens)

Question 7

bacteria that use resistance to immune effector mechanisms as a mechanism

Answer 7

encapsulated pathogens
borrelia burgdorferi (complement factor sequestration, prevent MAC formation)

Question 8

spirochetal human diseases

Answer 8

syphilis: treponema pallidum
leptospirosis: leptospira interrogans
relapsing fever: several borrelia species
lyme borreliosis: borrelia burgdorferi
periodontal disease: treponema denticola

Question 9

describe the spirochetal envelope structure

Answer 9

periplasmic flagella- hide flagella from the immune system within the periplasm
outer membrane and cytoplasmic membrane
thin and long
predestined for penetration

Question 10

leptospira host-pathogen interface

Answer 10

LPS and lipoproteins

Question 11

treponema pallidum host-pathogen interface

Answer 11

no major surface antigens, no LPS

stealth

Question 12

borrelia host-pathogen interface

Answer 12

abundant lipoproteins which play major roles in pathogenesis

no LPS

Question 13

t. pallidum virulence factors

Answer 13

no culture in medium (only in rabbit testicles)
hyaluronidase (sticks to extracellular matrix)
fibronectin coat
few surface proteins (Tromp1)
lipoproteins
stealth pathogen

Question 14

what causes the symptoms of t.pallidum?

Answer 14

the immune responses to tissue damage

NOT toxicity of the pathogen itself

Question 15

describe the stages of syphilis

Answer 15

primary at 2 weeks
secondary at 23 weeks
long latency before a tertiary stage

Question 16

what are the symptoms associated with primary syphilis?

Answer 16

chancre at the site of pathogen entry
painless
heals spontaneously

Question 17

what are the symptoms associated with secondary syphilis?

Answer 17

maculopapular, desquamative rash
alopecia
papules and plaques in groin
erythematous mucous patches in mouth

Question 18

what are the symptoms associated with tertiary syphilis?

Answer 18

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)

Question 19

what is congenital syphilis?

Answer 19

infection in utero after 4th month of gestation
stillborn
rhinitis, secondary and tertiary syphilis
Hutchinsonian teeth and saddleback nose

Question 20

syphilis epidemiology

Answer 20

total US cases 88,000
incidence rising
8:1 males to females

Question 21

microscopy diagnostics for syphilis

Answer 21

darkfield of fresh skin lesions (not oral)
DFA staining (fluorescent delabeled antibody)

Question 22

nontreponemal serology diagnostics for syphilis

Answer 22

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

Question 23

treponemal serology diagnostics for syphilis

Answer 23

specific
FTA-ABS
TP-PA

Question 24

DOC for syphilis

Answer 24

penicillin G (single shot IM)
if allergy: doxycycline, tetracycline, azithromycin, ceftriaxzone

Question 25

Jarisch Herxeheimer reaction

Answer 25

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)

Question 26

describe the physical structure of leptospira interrogans

Answer 26

free living spirochetes large genomes several serovars different LPS on surface

Question 27

asymptomatic hosts of leptospira

Answer 27

rodents dogs animals act as resevoirs and shed and contaminate soil/water

Question 28

where do spirochetes persist in the body?

Answer 28

renal tubules shed in urine contamination of soil and water

Question 29

pathogenesis of leptospirosis

Answer 29

1. infection via intact mucosa or broken skin (via water uptake) 2. septicemia 3. damage of small blood vessel endothelium - meningitis - hepatitis - nephritis - hemorrhage 4. exit

Question 30

leptospirosis epidemiology

Answer 30

``` <100 cases/ year worldwide occupational exposures peak in warm months no human to human transmission can be fatal ```

Question 31

microscopy diagnostics for leptospirosis

Answer 31

insensitive, nonspecific bc number of spirochetes too low to see except DFA

Question 32

culture diagnostics for leptospirosis

Answer 32

special media, slow growth (2 wks to 4 mo) blood, CSF: positive during first 10 days urine: positive after first week

Question 33

serology diagnostics for leptospirosis

Answer 33

gold standard: agglutination test | enzyme linked dot IgM immunoassay

Question 34

DOC for leptospirosis

Answer 34

``` severe: IV penicillin oral doxycycline (preventative), ampicillin, amoxicillin ```

Question 35

how are borrelia sp transmitted?

Answer 35

soft Ornithodoros ticks B.hermsii in NW B.turicatae in SW

Question 36

differentiate between TBRF and LBRF

Answer 36

tick borne relapsing fever: endemic | louse borne relapsing fever: epidemic

Question 37

TBRF transmission

Answer 37

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

Question 38

LBRF transmission

Answer 38

crushing of louse (rub louse feces into bite wound) | humans the only host

Question 39

describe the mechanism behind recurrent fever

Answer 39

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

Question 40

microscopy diagnostics for RF

Answer 40

detection of spirochetes in blood smears during febrile periods sens 70%

Question 41

culture diagnostics for RF

Answer 41

complex medium | slow growth

Question 42

serology diagnostics for RF

Answer 42

western blot for B.turicatae | tests for other spirochetal diseases can show cross reactivity

Question 43

DOC for RF

Answer 43

tetracycline (LBRF) doxycycline (TBRF) erythromycin

Question 44

species causing Lyme disease

Answer 44

Borrelia burgdorferi

Question 45

what types of ticks transmit B.burgdorferi

Answer 45

Ixodes

Question 46

describe the epidemiology of Lyme in the uS

Answer 46

300,000 cases/year most common vector borne disease 2 major foci: NE and Great Lakes

Question 47

discuss the transmission of Lyme

Answer 47

humans are incidental dead end hosts Ixodes ticks feed for several days transmission within 48 hours unlikely -spirochetes travel from midgut to salivary gland

Question 48

early localized symptoms of Lyme disease

Answer 48

``` days to weeks at site of tick bite erythema migrans (EM) -bulls eye rash -expanding, self resolving -appears in most ->5 cm diagnostic ```

Question 49

early diffuse symptoms of Lyme

Answer 49

``` malaise fever headache fatigue chills MSK pain lymphadenopathy ```

Question 50

weeks to months disseminated Lyme symptoms

Answer 50

``` secondary EMs neuroborreliosis -bell's palsy (facial nerve paralysis) -meningitis -encephalitis -radiculopathy -cranial neuritis cardiac dysfunction -myocarditis -pericarditis -AV nodal block ```

Question 51

Late disseminated Lyme symptoms

Answer 51

acrodermatitis chronicum atrophicans (paper like skin) encephalopathy oligoarticular arthritis (large joints, on only one side)

Question 52

what are two major classes of B.burgdorferi virulence factors

Answer 52

tick colonization and survival | mammalian colonization/persistence

Question 53

virulence factor associated with tick colonization and survival

Answer 53

OspA binds to tick midgut receptor and protects other bacterial proteins from tick proteases

Question 54

virulence factors associated with mammalian colonization/ persistence

Answer 54

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

Question 55

CRASPs

Answer 55

complement regulator acquiring surface proteins block MAC formation render bacteria serum resistant

Question 56

lyme arthritis pathogenesis

Answer 56

1. invasion and colonization 2. inflammatory host response to bacterial lipoproteins 3. bacterial numbers are reduced 4. persistence/immune evasion 5. lipoproteins: constant source of inflammatory stimulus in joints (edema associated with neutrophil infiltration) 6. antibiotic treatment-refractory arthritis: autoimmune response to OspA epitope

Question 57

1st generation Lyme vaccine

Answer 57

recombinant lipidated OspA was approved, but taken off market in 2002 transmission blocking vaccine: needs to generate high titers