Chapter 24, Syphilis: Disease with a History from Mechanisms of Microbial Disease, 1993

Syphilis: Disease with a History

Edward N. Robinson, Jr., Penelope J. Hitchcock, and Zell A. McGee

Ch. 24 of Mechanisms of Microbial Disease, 2nd ed.

Ed. Moselio Schoechter, Gerald Medoff, Barry I. Eisenstein.

Baltimore, 1993

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The agent of syphilis is a spirochete, a group of bacteria with a

highly characteristic appearance.  Spirochetes are helical, slender, relatively

long cells (Fig. 24.2).  Spirochetes are widespread in nature; only

a few cause disease in humans and animals.  The principal human spirochetoses

are syphilis, Lyme disease (Chapter 25), relapsing fever

(caused by members of the genus Borrelia), and leptospirosis (due to

Leptospira).  The treponeme of syphilis has some close relatives that

cause other diseases (e.g., yaws, pinta, bejel), found mostly in tropical


T. pallidum is so thin (0.1-0.2um) that it cannot be seen by standard

microscopic techniques.  It can be visualized by special stains (silver

impregnation or immunofluorescence) or with special lighting (dark-field

microscopy).  When observed in a freshly prepared wet mount

using a dark-field microscope, it exhibits a characteristic corkscrew-like

movement and flexion.  The organisms resemble Gram-negative

bacteria in having an outer membrane, which, although lipid rich, does

not contain classical lipopolysaccharide.  Unlike the flagella of other

bacteria, which protrude freely into the medium, those of spirochetes

are contained within the periplasm.

The amount of information regarding the mechanisms by which T.

pallidum causes disease has been limited both by the inability to cultivate

the organisms serially in artificial media and by the lack of a suitable

animal model.  In artificial media, these bacteria can be kept alive

for only short periods of time—for a few divisions at the most.  To bypass

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these constraints, efforts have focused on producing and characterizing

specific proteins of T. pallidum using genes cloned into E. coli



T. pallidum is very sensitive to drying, disinfectants, and heat (as low

as 42°C).  Therefore, they are unlikely to be acquired by means other

than by personal contact.  Neither the toilet seat nor the hot tub can be

blamed.  The two major routes of transmission are sexual and transplacental. 

Sexual exposure to a person with an active chancre carries a

high probability of acquiring syphilis. 

The organisms enter a susceptible host through the mucous membranes

or the minute abrasions in the skin surface that occur during

sexual intercourse.  Once in the subepithelial tissues, the organisms

replicate locally in an extracellular location (Fig. 24.3).  In culture,

they adhere to cells by their tapered ends and probably stick to cells in

tissue by the same means.  Not all of them stick, and many are soon carried

through lymphatic channels to the systemic circulation.  Thus,

even if the initial manifestation of the disease consists of an isolated

skin lesion, syphilis is a systemic disease almost from the outset. 

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Treponemes can cross the placental barrier from the bloodstream of

an infected mother and cause disease in the fetus.  It is not known how

the organisms cross this barrier.  Chapter 68 has a general discussion of

this issue.


Initially, neutrophils migrate to the area of inoculation, and are later

replaced by lymphocytes and macrophages.  The result of the battle

between the locally replicating treponemes and the cellular defenses

of the host is the lesion of primary syphilis, a painless ulcer—the syphilitic

chancre (Fig. 24.4).  The time between the initial introduction of

the organisms and the appearance of the ulcer depends on the size of

the inoculum.  The more treponemes enter, the earlier the chancre appears. 

This lesion heals spontaneously in 2-6 weeks, but by this time

the spirochetes have spread through the bloodstream and may be causing

lesions in other parts of the body.  It is these diverse lesions that

comprise the cluster of findings that characterize “secondary syphilis”

such as that manifested in Mr. B.

The syphilitic chancre and other genital ulcer diseases are associated

with increased risk of human immunodeficiency virus (HIV)

transmission.  Patients who have genital ulcers are estimated to have a

three- to five-fold increase risk of acquiring HIV infection.  Furthermore,

recent studies have demonstrated that HIV can be isolated from

genital ulcers, which increases the likelihood of transmitting the virus. 

The possible role of the chancre in facilitating the transmission of

AIDS underscores the importance of recognizing and promptly treating

primary syphilis. 

Three to six weeks after the ulcer heals, the secondary form of the

disease occurs in about 50% of the cases.  Secondary syphilis is the systemic

spread of the infection, and is the manifestation of replication of

the treponemes in the lymph nodes, the liver, joints, muscles, skin, and

mucous membranes distant from the site of the primary chancre.  The

signs and symptoms of secondary syphilis may be so varied, and involve

such different tissues and organs, that the disease has been called “the

great imitator.”  The rash and other manifestations of secondary syphilis

resolve in the course  of weeks to months, but recur within 1 year or

so in about one-fourth of affected individuals (Fig. 24.3).

This biphasic course of the disease is puzzling for various reasons. 

Why does the primary chancre heal?  (We do not even understand how

spirochetes kill so many epidermal cells to create a chancre.)  Why do

the defense mechanisms that are so successful in resolving the primary

chancre not function as well systemically during secondary syphilis? 

How does the organism survive in the body for long periods of time? 

Where are the organisms located—intracellularly or extracellularly? 

What is the role of the specific immune response to the organism in the

disease process?  Or, when penicillin therapy of syphilis results in fever

and sometimes shock (the so-called Jarisch-Herxheimer reaction), the

clinical events strongly suggest the release of interleukin-1 (IL-1,

which causes fever), and the release of tumor necrosis factor/cachectin

(TNF, which causes shock—see Chapters 6 and 7).  If this hypothesis is

correct, which molecules do the spirochetes release to stimulate the

production of these potent cytokines?  We do not have answers to these

questions or to others regarding other aspects of syphilis.  It remains

one of the more fascinating and puzzling of infectious diseases. 


The mechanisms whereby treponemes evade host defenses over a

period of years are not well understood.  Recently, it has been demonstrated

that the proteins in the outer layer of the bacterium are not exposed

to the surface.  In other words, antibodies specific for these

proteins cannot bind the organism’s surface.  It is not known whether

the proteins are obscured by some sort of undefined “coat,” such as a

capsule, or whether they protrude from the surface only part of the


The mystery deepens with the resolution of the secondary phase.  In

about one-third of individuals, the organisms disappear and the person

is spontaneously cured.  In the remaining two-thirds, the treponemes

remain latent for years without causing signs or symptoms (Fig. 24.3). 

In about one-half of this group, the manifestations of tertiary syphilis

eventually develop, sometimes years or even decades after the primary


In adults, tertiary syphilis is responsible for a majority of the morbidity

and mortality associated with the disease.  Fortunately, tertiary

syphilis is very uncommon in the U.S., where routine serological

screening identifies most cases before this stage can develop.  The hallmark

of tertiary syphilis is the destruction of tissue from a response to

the presence of treponemal antigens.  The clinical-pathological manifestations

are those of vasculitis and chronic inflammation.  Soft

masses, the gummas, composed of few treponemes and inflammatory

cells, are lesions that commonly destroy bone and soft tissue (“late benign

syphilis”), but may involve vital organs, such as the liver as well.  In

cardiovascular syphilis, vasculitis involves the nutrient arteries supplying

the thoracic aorta.  Destruction of the elastic tissue in the aorta

media leads to dilatation of the wall and to aortic valve insufficiency, or

to the formation of aortic aneurysms with resultant rupture of the

aorta.  The central nervous system may also be involved, either by direct

invasion of the parenchyma by treponemes or by brain infarction

caused by vasculitis. 

The clinical findings of neurosyphilis can be subtle.  The severity of

the manifestations depends on the location of the lesions.  Involvement

of the dorsal columns of the spinal cord results in loss of position sensation,

a classic condition known as tabes dorsalis.  It is often manifested

as ataxic gait; in turn, this usually results in trauma to the knee and

ankle joints, which results in bone overgrowth, and misalignment of

the knee, or occasionally the ankle, the so-called “Charcot’s joint.”

There may also be cutaneous sensory loss over the lower chest, inner

aspects of the arms, and lower legs.  A generalized involvement of the

brain leads to impaired motor function (paresis) as well as to gradual

loss of higher integrative functions and personality changes.  This clinical

picture is known as general paralysis of the insane.  A physical sign

of neurosyphilis is the Argyll-Robertson pupil—the pupil fails to react

to light but accommodates when an object is moved from far to near

the eye.  If left untreated, neurosyphilis may ultimately lead to death of

the patient. 

The lesions of tertiary syphilis usually contain few or no treponemes. 

What then causes lesions in the tissues?  Researchers have demonstrated

that the immune system likely plays a deleterious role in the

development of the syphilitic lesions.  Is it an exaggerated hypersensitivity? 

Or, could it be a cross-reaction between treponemal and tissue

antigens, in  other words, an autoimmune response?  Once again, the

answer is not known.  However, cross-reactive antibodies are elicited

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and are the basis for the most widely utilized tool to detect the disease,

the serological test for syphilis. 

Congenital Syphilis

Despite the availability of serological tests that can detect latent

forms of syphilis, despite the availability of inexpensive and safe antibiotics,

and despite the (welcome) persistent antibiotic sensitivity of the

causative organisms, about 2000-3000 babies were born with congenital

syphilis in the U.S. in 1990.  But this number under-represents the

problem; the majority of infected fetuses likely die in utero.  Among

those who make it to term, the manifestations are varied, ranging from

life-threatening organ damage to silent infections.  They can also include

congenital malformations that are immediately apparent as well

as developmental abnormalities that become manifest only as the child

gets older.  These congenital anomalies include premature birth, intrauterine

growth retardation, and multiple organ failure (e.g., central

nervous system infection, pneumonia, enlargement of the liver and

spleen).  The most common manifestations of syphilis become evident

at about 2 years of age and include facial and tooth deformities (the so-called Hutchinson’s incisors and “mulberry” molars).  Other less common

findings include deafness, arthritis, and “saber shins.”  Congenital

syphilis is especially tragic because it is completely preventable by

penicillin therapy of women found to have a positive serological test

for syphilis early in pregnancy…if they get prenatal care.