ICL 2.10: Treponema

Question 1

what’s the micriobiology of treponema?

Answer 1

spirochete

NOT all spiral shaped bacteria are spirochetes

Question 2

what diseases do spirochetes cause?

Answer 2

1. gonorrhea
2. syphilis
3. salmonella
4. shigellosis

Question 3

which bacteria are spirochetes?

Answer 3

1. borrelia
2. leptospira
3. treponema

Question 4

how is syphilis spread?

Answer 4

sexual contact

~60% of US cases are men who have sex with men (CDC)

no known animal reservior!!

Question 5

how can syphilis be grown?

Answer 5

It will grow in rabbit testes, and can be isolated that way, but no disease results in the infected rabbit. There is no animal model

Question 6

is syphilis incidence increasing or decreasing?

Answer 6

increasing…

Easily detected and treated, so no good reason for this situation

Question 7

where did syphilis come from?

Answer 7

MAY have origins in Africa or South America as a skin disease called Yaws

the causative agents of syphilis and of yaws are nearly indistinguishable

T. pallidum pallidum vs. T. pallidum pertenue

there appears to be cross immunity between the two

Question 8

what’s the progression of syphilis vs. yaws?

Answer 8

YAWS
primary lesion in yaws –> ulcerating papule (small solid conical elevation of the skin)

localized scarring, even some bone destruction, but almost never involves viscera or nervous system

not transmitted transplacentally

SYPHILIS
primary syphilis –> chancre

MUCH more invasive and damaging

can involve ANY part of the body with a blood supply….

Question 9

where on the range of bacterial mechanisms of pathogenesis does treponema pallidum fall?

Answer 9

nontoxic

highly invasive

damage from immune system

Question 10

how many stages of syphilis are there?

Answer 10

3

Question 11

what is primary syphilis?

Answer 11

painless ulcer with heaped up edges

occur in most indivs. within 3-6 weeks

may be hidden and since they’re painless, sometimes people don’t even know they’re there

high number of spirochetes

vaginal chancres common – whatever the site though, it’s a local infection

disappears after a few weeks

Question 12

what is the immune response to primary syphilis?

Answer 12

TH1-skewed response

spirochetes surrounded by CD4+ and CD8+ T cells, plasma cells, macrophages producing IL-2 and IFN-γ

chancres disappear after a few weeks

Question 13

what happens during secondary syphilis?

Answer 13

dissemination from initial site(s) of infection

distribution via blood throughout body because it traverses the tight junctions between endothelial cells

may also use transcytosis to spread through the endothelium

Question 14

what are the symptoms of secondary syphillis?

Answer 14

fever, malaise, arthralgia
and arthritis common

hepatosplenomegaly

new cutaneous lesions usually after 3 months = condylomata lata

rash includes palms and soles

aka “great pox”

Question 15

what is tertiary syphilis?

Answer 15

occurs in ~30% of untreated cases, following latent phase

during the latent phase, no symptoms but Ab titers remain high because treponemes are still present

tertiary syphilis has severe consequences = granulomatous lesions called gummas in skin, bones and liver

literally looks like rotting flesh….

you can also get neurosyphilis or cardiovascular syphilis

Question 16

what is one of the serious side effects of tertiary syphilis?

Answer 16

nerosyphilis with:

1. general pareisis: brain damage leads to dementia and paralysis
2. tabes dorsalis: loss of myelinated axons in posterior columns of spinal cord which is marked by wasting, pain, lack of coordination and disorders of sensation, nutrition and vision = locomotor ataxia

Question 17

what is cardiovascular syphilis?

Answer 17

can lead to aortic aneurysm or aortic valve insufficiency

Question 18

what is one of the main effects of tabes dorsalis?

Answer 18

tabes dorsalis is a condition that is caused by neurosyphilis

Argyll Robertson Pupil

these are small, irregularly shaped pupils that do not react to light but do accommodate

Question 19

what is the Tuskegee study?

Answer 19

it was a study of syphilis-infected african american men on how the syphilis disease progressed to try and improve AA health

it started before antibiotics when there wasn’t a safe and effective treatment for syphilis

but then when the program went bankrupt it turned into a study of what happens when syphilis is untreated….

they didn’t tell the patients they had syphilis and the patients weren’t told about arsphenamine

even when antibiotics came about in the 40-50s and could safely cure syphilis, the study wasn’t canceled and patients that moved away were denied treatment!

now AA don’t trust doctors…

Question 20

what did genome sequencing of treponema pallidum tell us?

Answer 20

that treponema pallidum lacks most genes for synthesis of AA, nucleotides, and lipids (LPS)

but it does have genes for large number of transport proteins that is uses for scavenging

Question 21

how does treponema pallidum evade the immune system?

Answer 21

virtually no protein exposed on the surface for the immune system to detect!!

exposed proteins very rare; called TROMPs = treponemal rare outer membrane proteins

immunodominant proteins are hidden in periplasm (LP1/LP2)

Question 22

is there a syphilis vaccine?

Answer 22

nope

immunization with recombinant T. pallidum antigens has (so far) yielded only partial protection

Question 23

what are the different ways we can detect T. pallidum?

Answer 23

culturing is rarely used because doubling time is 33 hours

darkfield microscopy of lesion exudate may show treponemes but some are part of normal flora…

so we tend to rely on serological methods

Question 24

what’s the main way we detect T. pallidum?

Answer 24

a nonspecific but inexpensive blood test based on a big mistake

Wasserman was looking for an antigen associated with serum from syphilis patients

he found one but it was actually cardiolipin which is from mammalian mitochondrial membranes and gets released when mammalian cells lyse = not specific

so serum cardiolipin levels are usually zero but after widespread tissue damage levels rise

it appears that the treponemes bind cardiolipin and an Ab response follows!

Question 25

what are flocculation tests?

Answer 25

it’s when purified cardiolipin is mixed with dispersants

if there are cardiolipin-specific IgG, IgA or IgM, visible clumps appear

these tests give negative results about a year after successful treatment (unlike specific anti-treponemal Ab tests)

Question 26

what are the most commonly used floculation tests?

Answer 26

1. VDRL = venereal disease research labs
2. RPR = rapid plasma reagin
3. TRUST = toluidine red unheated serum test

Question 27

what’s the drawback to cardiolipin-based tests?

Answer 27

MANY diseases that lead to tissue damage can lead to a positive result!

ex. malaria, leprosy, measles, lupus, even pregnancy!

also, these tests can give negative results during the latent phase of syphilis and in 1/3 of tertiary patients

anti-treponemal protein tests are better!

Question 28

which tests are done to specifically confirm T. pallidum infections?

Answer 28

1. FTA = fluorescent treponemal Ab
2. EIA = enzyme immunoassay
3. TPPA = T. pallidum partilcle aggulination
4. PCR

Question 29

how does an FTA test work?

Answer 29

FTA = fluorescent treponemal Ab

The patient’s serum sample + drop of T. pallidum + fluorescently-labeled 2°Ab

requires flurescnece microscope

Question 30

how does EIA test work?

Answer 30

EIA = enzyme immunoassay

Patient’s
serum sample into microtiter wells coated
with recombinant treponemal Ags

enzyme-linked anti-human IgG/IgM

Question 31

how does TPAA test work?

Answer 31

uses gelatin microbeads coated with recombinant treponemal proteins

but be careful people with periodontal disease carry oral treponemes that can
be detected with antibodies to the same antigen used in many tests. These people have detectable antibodies to this and other T. pallidum antigens

also these treponeme-specific tests remain positive for years, even if the patient has been successfully treated; they are useful to confirm that an infection has occurred in the past, but not for assessing current status

Question 32

how does PCR for T. pallidum work?

Answer 32

T. pallidum can be identified by PCR in the bloodstream of patients with all stages of syphilis

the quantity of treponemes in blood is highest during early syphilis

in latency, treponemes persist in many tissues without causing clinical signs or symptoms; other tests may be negative

Question 33

what is congenital syphilis?

Answer 33

caused by infection in utero with Treponema pallidum

wide spectrum of severity

kids under 2 may have hepatosplenomegaly, confyloma lata, jaundice, rash, snuffles, anemia

older kids may have interstitial keratitis, mulberry molars, saddle nose, nerve deafness, frontal bossing, Hutchinson teeth etc.

Question 34

how is congenital syphilis transmitted?

Answer 34

mother-to-child

treponemal reservoir was mother

transplacental infection does not occur in the first ~10 wks of pregnancy, so there was a treatment window

mother was probably infected late in the pregnancy

transplacental infection early in pregnancy generally –> miscarriages and stillbirths

late-pregnancy infections generally –> bone and tooth deformation, heart and brain damage

Question 35

how do you treat a pregnant woman with syphilis?

Answer 35

only penicillin!!

even if they’re allergic, you should desensitize them and treat them with penicillin

for a nonpregnant patient that’s allergic to penicillin, you can treat with doxycycline

Question 36

what do you use to treat syphilis?

Answer 36

penicillin G benzathine

it’s the first line treatment for all stages of syphilis except neurosyphilis because it doesn’t cross the BBB

Question 37

KEY CONCEPTS syphilis

Answer 37

caused by the spirochete treponema pallidum

can be transmitted from mother to fetus = congenital

initial diagnosis via RPR with confirming test for +s

readily treated with penicillin

could be eliminable

three stages:
1. primary = localized to chancre

2. secondary = disseminated
3. tertiary = immune response –> tissue damage

Question 38

FLASHCARD: micropathology, pathology, epidemiology, clinical, diagnosis and treatment for treponema pallidum?

Answer 38

MICROBIOLOGY:Spirochete; subsp. pallidum cannot grow on any known culture medium

PATHOLOGY: Extremely invasive (especially subsp. pallidum; affects all tissues with blood supply); “stealth” pathogen with few surface proteins

EPIDEMIOLOGY: (subsp. pallidum) spread sexually and congenitally

CLINICAL: Depends on subsp:

T. p. pallidum – syphilis, chancre –> dissemination / condylomata –> gummas / neurosyphilis

T. p. pertenue – yaws, ulcerating papule –> dissemination to skin & bones

T. p. endemicum – bejel, intertriginous areas & facial bone, destructive lesions of nose & palate

T. carateum – pinta, spread in skin only, local patches of hypo-achromia

DIAGNOSIS: T. p. pallidum – semispecific test for Ab against cardiolipin (Wasserman / VDRL / RPR / TRUST), with positives followed by FTA / TPHA / TPPA (or, increasingly, PCR)

TREATMENT: T. p. pallidum – typically single large dose of benzylpenicillin ( for 1°or 2°syphilis)