SPIROCHETES I: TREPONEMA

LEARNING OBJECTIVES: At the end of the lecture, the students can:

1. Characterize the genus Treponema.
2. Describe the basic morphology of the members of the genus.
3. Explain the virulence factors of Treponema.
4. Differentiate the various species of Treponema as to mode of transmission, clinical manifestations,
treatment and prevention.

TREPONEMAL SPECIES:
Treponema pallidum
◦ T. pallidum subspecies pallidum (Syphilis)
◦ T. pallidum subspecies endemicum (Bejel)
◦ T. pallidum subspecies pertenue (Yaws)
Treponema carateum (Pinta)

TREPONEMA PALLIDUM

GENERAL CHARACTERISTICS
• Gram negative, actively motile
• Slender spirals regularly spaced at a distance of 1 μm from one another
o Seen only with immunofluorescent stain or darkfield microscope
• With pointed tapering ends
• Stain with difficulty except with Giemsa’s or silver stain
• No tricarboxylic acid cycle in the bacteria  failure to grow in vitro
o Dependent on host cells for all purines, pyrimidines and most amino acids

STRUCTURE:
• Outer sheath: glycosaminoglycan coating (mucoid layer)
• Outer membrane – inside the sheath; contains peptidoglycan; maintain structural integrity
• Endoflagella or axial filaments – within periplasmic space; encased by outer membrane
• Inner or cytoplasmic membrane – within endo-flagella; osmotic stability; cover protoplasmic
cylinder
• Cytoplasmic tubules (body fibrils) – near inner membrane

CULTURE:
• Pathogenic T. pallidum never been cultured continuously on artificial media
o Usually cultured in testes of rabbits
• Microaerophilic (1% - 4% oxygen)
• In whole blood or plasma stored at 40C  remain viable for at least 24 hours
• Non-pathogenic or saprophytic strains (Reiter strain)
o Anaerobic culture in vitro  30 hours doubling time
o Defined medium containing amino acids, vitamins, minerals, salts and serum albumin

GROWTH:
• Slow replication  30-33 hours doubling time
• In presence of reducing substances  remain motile for 3 – 6 days at 250C

OTHER CHARACTERISTICS:
• Rapidly killed or immobilized by
o Drying
o High temperature (420C)
 o Trivalent arsenical, mercury & bismuth
• Metabolic inactivity + slow multiplication rate of organism  slow rate of killing using penicillin

VIRULENCE FACTORS:
Virulence Factor Function
Outer membrane proteins covalently bound Lipids: keep the proteins inaccessible to antibodies
to lipids Proteins: promote adherence to host cell
Hyaluronidase Facilitate perivascular infiltration; enhance invasiveness
Coating of fibronectin Protect against phagocytosis
Species-specific Ag on cell surface Evasion of immune system

PATHOGENESIS:
1. Adherence to skin or mucosal membranes  produce hyaluronidase  promote tissue invasion
2. Organism becomes coated with host fibronectin  protect against phagocytosis and immune
recognition
 Treponemes spread to other skin sites & to other organs hematogenously soon after infection
 Skin lesions of primary syphilis  represent the primary site of initial replication

Phases of Disease:
1. Primary phase
 Chancres at site of penetration  primary site of initial replication
 Endarteritis and periarteritis; PMNs & macrophages
2. Secondary Phase
 (+) clinical signs of disseminated disease
 Skin lesions
3. Late Phase
 Systemic spread  virtually all tissues involved

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IMMUNITY
• Tissue destruction primarily due to host’s immune response to infection

CLINICAL MANIFESTATIONS:
• MOT:
1. Sexual contact during primary stage
2. Skin contact with disseminated rash during secondary stage
3. Transfusion of contaminated blood
4. In utero from infected mother
 • Local multiplication at initial site of entry
1. Infectious lesions on the skin or mucous membranes of genitalia
2. 10% - 20%; initial lesion intra-rectal, perianal, or oral
• Some spread to nearby LN  blood

Acquired Syphilis: Primary Stage

• Chancre: painless, ulcerated skin lesion at the site of inoculation; 10-90 days after initial infection
• Painless LAD 1 – 2 weeks after appearance of chancre
• Spontaneous healing of the chancre within 3 to 6 weeks  does not indicate a cure
• Highly infectious
• Initial infection – 10-90 days  papule  painless ulcer with raised border (chancre) 
spontaneous healing within 2 months
o Abundant spirochetes present in the chancre  disseminate via lymphatics or blood stream
o Secondary lesions appear 2 – 10 weeks after resolution of primary lesion

Acquired Syphilis: Secondary Stage

• Clinical evidence of disseminated disease
• “Flu-like” syndrome + lymphadenopathy
• Some with alopecia areata
• Lesions: highly infectious
1. Generalized mucocutaneous rash
o Red maculopapular rash anywhere in the body including the hands & feet
2. Condylomata lata
o Moist, pale papules in anogenital region, axillas, and mouth
• Other manifestations:
o Syphilitic meningitis
o Chorioretinitis
o Hepatitis
o Nephritis (immune complex type)
o Periostitis
• Lesions also rich in spirochetes  highly infectious
• Rash & symptoms gradually resolve spontaneously within 6 to 8 months of infection
o 30% complete cure without Tx
o Others become dormant in liver and spleen

Acquired Syphilis: Latent Stage

• Clinically inactive stage but with (+) serologic tests
• 30% of untreated infection

Acquired Syphilis: Tertiary (Late) Stage

• 1/3 of untreated patients
• Activation of dormant treponemes 3 – 30 years later in untreated cases
• Diffuse, chronic inflammation
• Characteristics:
1. Granulomatous lesions (gummas) in skin, bones, and liver
2. Degenerative CNS changes (neurosyphilis) – meningovascular SY, paresis, tabes dorsalis
3. CV lesions – aortitis, aortic aneurysm, aortic valve insufficiency
https://www.medical-institution.com/tabes-dorsalis-mnemonic/

Argyll Robertson Pupil (Light-Near Dissociation)

• Bilateral small pupils
• (+) constriction on accommodation
• (-) constriction when exposed to bright light

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Congenital Syphilis
• Transmission: beginning in the 10th – 15th weeks AOG
• Early congenital: rhinitis + desquamating maculopapular rash
• Late congenital: interstitial keratitis, Hutchinson’s teeth, saddle nose, mulberry molars, periostitis,
CNS anomalies, saber shins, symmetrical joint swelling (Clutton’s joints)

DIAGNOSIS:
Diagnostic Test Method of Examination
Microscopy Darkfield
Direct fluorescent antibody staining (DFTA)
Culture Not available
Serology NONTREPONEMAL TESTS
Venereal Disease Research Laboratory (VDRL)
Rapid Plasma Reagin Test (RPR)
Unheated Serum Reagin (USR) Test
Toluidine Red Unheated Serum Test (TRUST)
TREPONEMAL TESTS
Fluorescent Treponemal Antibody Absorption (FTA-ABS)
Treponema pallidum Particle Agglutination (TP-PA)
Enzyme Immunoassay
Specimen: tissue fluid from early surface lesions; blood serum for serology
Dark-Field Examination
• Typical motile spirochetes
• Exudates from skin lesion; primary, secondary and congenital syphilis
Immunofluorescence
• Fluorescent spirochetes; more useful
Nucleic Acid-Based Tests (PCR):
• For detecting T. pallidum in:
1. Genital lesions
2. Infant blood
3. CSF
Serologic Tests (Antibody Tests): Nontreponemal Tests
• Screening tests; not sensitive in early syphilis
• Antigens: measured amounts of cardiolipin (from beef heart), cholesterol & purified lecithin
• Antibodies: syphilitic IgG and IgM reaginic antibodies
• VDRL ((Venereal Dse. Research Lab.) – standardized for use on CSF
• USR (Unheated Serum Reagin) test
• RPR (Rapid Plasma Reagin)
• Only the VDRL test should be used to test CSF from patients with neurosyphilis
• Sensitivity: 70% - 85% for primary disease
100% for secondary disease
70% - 75% for late syphilis
• Specificity: 98% - 99%
• (+) after 2-3 weeks of untreated syphilis  revert to negative in 6-18 months and by 3 years after
effective treatment
• (+) in high titer in secondary syphilis
• If (+) late after treatment  ineffective Tx

Serologic Tests: Treponemal Tests

• Measure Ab’s vs. T. pallidum antigens
• Used to confirm if a (+) result from nontreponemal test is truly (+) or falsely (+)
• Serial dilution of serum not done
• Report as reactive or non-reactive
• T. pallidum Particle Agglutination (TP-PA) – most widely used in U.S.
• T. pallidum Hemagglutination (TPHA) & micro-hemagglutination (MHA-TP)
• Fluorescent Treponemal Antibody Absorbed (FTA-ABS) – most commonly used
• If (+) IgM FTA in blood of newborn  (+) in utero infection
• Not helpful in diagnosis of neurosyphilis but if (-), exclude neurosyphilis

Conditions with false (+) nontreponemal test Conditions with false (+) treponemal test
1. Viral infection 1. Pyoderma
2. Rheumatoid arthritis 2. Rheumatoid arthritis
3. SLE 3. SLE
4. Acute or chronic illness 4. Psoriasis
5. Pregnancy 5. Crural ulceration
6. Recent immunization 6. Skin neoplasm
7. Drug addiction 7. Drug addiction
8. Leprosy 8. Mycoses
9. Malaria 9. Lyme disease
10. Multiple blood transfusions 10. Acne vulgaris
 • Diagnosis of neurosyphilis and congenital syphilis based on clinical symptoms and laboratory
findings
o VDRL test on CSF highly specific but not sensitive  (-) test does not rule out
o (+) FTA-ABS CSF test consistent with neurosyphilis but not diagnostic
• (+) serologic test results in infants may represent passive transfer of Ab’s from mothers
o Measure antibody titers in sera for 6 months  Ab titers in non-infected infants decrease to
undetectable levels within 3 months of birth; remain elevated in infants with congenital
syphilis

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https://miphidic.com/2015/03/26/interpreting-syphilis-serological-tests/

TREATMENT:

DOC: Penicillin
• Long-acting benzathine PEN for early stages
• Penicillin G for congenital and late syphilis (only PEN for neurosyphilis & pregnant patients)
• Alternatives: tetracycline & doxycycline
• No available vaccine

TREPONEMA PALLIDUM SUBSPECIES ENDEMICUM (BEJEL)

• Endemic syphilis or bejel
• Distribution: Chiefly Africa; also Middle East, SE Asia, and elsewhere; usually children
• MOT: person-to-person (contaminated eating utensils)
• Lesions:
o Secondary: oral papules & mucosal patches
o Late: gummas of skin, bones, and nasopharynx
• Treatment:
o Benzathine penicillin
o Children < 10 y/o: 600,000 U benzathine penicillin IM
 o > 10 y/o: 1.2 million U IM
o Single dose azithromycin 30 mg/kg not to exceed 2 grams (WHO recommendation)

TREPONEMA PALLIDUM SUBSPECIES PERTENUE (YAWS)

• Endemic among children (<15 y/o) in humid, hot tropical countries
• MOT: direct contact with infected skin lesions
• Primary lesion: ulcerating papule, usu. on arms or legs
• Late destructive lesions of the skin, LN, and bones  scar formation common
• (+) cross-immunity with syphilis
• Diagnosis & treatment same as syphilis
• Dramatic improvement with PEN

TREPONEMA CARATEUM (PINTA)

• Endemic in all age groups in Mexico, Central & South America, the Philippines, and some areas of
the Pacific
• Restricted to dark-skinned races
• MOT: direct contact OR through flies or gnats
• Primary lesion: non-ulcerating, small pruritic papule on exposed areas
o Months later  flat, hyperpigmented lesions on skin  depigmentation & hyperkeratosis
years after