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