Pathogenic Neisseriae: Gonorrhea, Neonatal Ophthalmia and Meningococcal Meningitis (page 2)
(This chapter has 7 pages)
© Kenneth Todar, PhD
caused by N. gonorrhoeae
The disease gonorrhea is a specific type of urethritis
practically always involves mucous membranes of the urethra, resulting
in a copious discharge of pus, more apparent in the male than in the
The first usage of the term "gonorrhea", by Galen in the second
implied a "flow of seed". For centuries thereafter, gonorrhea and
were confused, resulting from the fact that the two diseases were often
present together in infected individuals. Paracelsus (1530) thought
gonorrhea was an early symptom of syphilis. The confusion was further
by the classic blunder of English physician John Hunter, in 1767.
intentionally inoculated himself with pus from a patient with symptoms
of gonorrhea and wound up giving himself syphilis! The causative agent
of gonorrhea, Neisseria gonorrhoeae, was first described by A.
in 1879, in the pustular exudate of a case of gonorrhea. The organism
grown in pure culture in 1885, and its etiological relationship to
disease was later established using human volunteers in order to
the experimental requirements of Koch's postulates.
is generally limited to superficial mucosal
lined with columnar epithelium. The areas most frequently involved are
the urethra, cervix, rectum, pharynx, and conjunctiva. Squamous
which lines the adult vagina, is not susceptible to infection by the N.
gonorrhoeae. However, the prepubescent vaginal epithelium, which
not been keratinized under the influence of estrogen, may be infected.
Hence, gonorrhea in young girls may present as vulvovaginitis.
infections are usually characterized by a purulent discharge.
gonorrhea in the adult male is an inflammatory and
infection of the mucous membranes of the anterior urethra. The most
symptom is a discharge that may range from a scanty, clear or cloudy
to one that is copious and purulent. Dysuria (difficulty in
often present. Inflammation of the urethral tissues results in the
redness, swelling, heat, and pain in the region. There is intense
and pain upon urination.
infection is the most common form of uncomplicated
in women. Such infections are usually characterized by vaginal
and sometimes by dysuria. About 50% of women with cervical infections
asymptomatic. Asymptomatic infections occur in males, as well. Males
asymptomatic urethritis are an important reservoir for transmission and
are at increased risk for developing complications. Asymptomatic males
and females are a major problem as unrecognized carriers of the
disease. In the United States alone, according to the Centers for
Disease Control and Prevention, the number of cases is estimated at
about 700,000 a year.
In the male, the
organism may invade the prostate resulting in prostatitis,
or extend to the testicles resulting in orchitis. In the
cervical involvement may extend through the uterus to the fallopian
resulting in salpingitis, or to the ovaries resulting in ovaritis.
As many as 15% of women with uncomplicated cervical infections may
inflammatory disease (PID). The involvement of testicles,
tubes or ovaries may result in sterility.
occur. The most common forms of disseminated infections are a dermatitis-arthritis
syndrome, endocarditis and meningitis.
Rectal infections (proctitis)
with N. gonorrhoeae occur
in about one-third of women with cervical infection. They most often
from autoinoculation with cervical discharge and are rarely
Rectal infections in men that have sex with men usually result from
and are more often symptomatic. Partners must be treated as well to
Ocular infections by
N. gonorrhoeae can have serious
of corneal scarring or perforation. Ocular infections (ophthalmia
occur most commonly in newborns who are exposed to infected secretions
in the birth canal. Part of the intent in adding silver nitrate or an
to the eyes of the newborn is to prevent ocular infection by N.
Gonorrhea in adults is almost invariably transmitted by sexual
The bacteria adhere to columnar epithelial cells, penetrate them, and
on the basement membrane. Adherence is mediated through pili
and opa (P.II) proteins. although nonspecific factors
as surface charge and hydrophobicity may play a role. Pili undergo
both phase and antigenic variation. The bacteria attach only to
of nonciliated columnar epithelial cells. Attachment to ciliated cells
does not occur.
Most of the
information on bacterial invasion comes from studies
tissue culture cells and human fallopian tube organ culture. After the
bacteria attach to the nonciliated epithelial cells of the fallopian
they are surrounded by the microvilli, which draw them to the surface
the mucosal cell. The bacteria enter the epithelial cells by a
called parasite-directed endocytosis. During endocytosis the
of the mucosal cell retracts and pinches off a membrane-bound vacuole
contains the bacteria. The vacuole is transported to the base of the
where the bacteria are released by exocytosis into the subepithelial
The neisseriae are not destroyed within the endocytic vacuole, but it
not clear whether they actually replicate in the vacuoles as
A major porin
protein, P.I (Por), in the
membrane of the bacterium is thought to be the invasin that mediates
of a host cell. Each N. gonorrhoeae strain expresses only one
of Por; however, there are several variations of Por that partly
for different antigenic types of the bacterium.
gonorrhoeae can produce one or several outer
proteins called Opa (P.II) proteins . These proteins are
subject to phase variation and are usually found on cells from colonies
possessing a unique opaque phenotype called O+. At any
time, the bacterium may express zero, one, or several different Opa
and each strain has 10 or more genes for different Opas.
is an outer membrane protein found in all
strains of N. gonorrhoeae. It does not undergo antigenic
and is found in a complex with Por and LOS. It shares partial homology
with the OmpA protein of Escherichia coli. Antibodies to
either by a neisserial infection or by colonization with E. coli, tend
to block bactericidal antibodies directed against Por and
LOS. In fact,
anti-Rmp antibodies may increase susceptibility to infection by
bacterial lipooligosaccharide (LOS) and
are released by autolysis of cells. Both LOS and peptidoglycan activate
the host alternative complement pathway, while LOS also stimulates the
production of tumor necrosis factor (TNF) that causes cell damage.
are immediately attracted to the site and feed on the bacteria. For
reasons, many gonococci are able to survive inside of the phagocytes,
least until the neutrophils themselves die and release the ingested
Neisserial LOS has a
profound effect on the virulence and
of N. gonorrhoeae. The bacteria can express several antigenic
of LOS and can alter the type of LOS they express by some unknown
Gonococcal LOS produces mucosal damage in fallopian tube organ cultures
and brings about the release of enzymes, such as proteases and
that may be important in pathogenesis. Thus, gonococcal
LOS appears to
have an indirect role in mediating tissue damage. Gonococcal
LOS is also
involved in the resistance of N. gonorrhoeae to the
activity of normal human serum. Specific LOS oligosaccharide types are
known to be associated with serum-resistant phenotypes of N.
can utilize host-derived N-acetylneuraminic
(sialic acid) to sialylate the oligosaccharide component of its LOS,
a serum-sensitive organism to a serum-resistant one. Organisms with
LOS are more invasive than those with sialylated LOS but organisms with
sialylated LOS are more resistant to bactericidal effects of serum.
is also antigenic similarity between neisserial
LOS and antigens present
on human erthyrocytes. This similarity to "self" may preclude an
immune response to these
LOS antigens by maintaining the immunotolerance
of the host.
is highly efficient at utilizing
iron for in vitro growth;
many strains can also utilize
iron. The bacteria bind only human transferrin and lactoferrin. This
is thought to be, in part, the reason these bacteria are
Strains of N.
gonorrhoeae produce two distinct extracellular
proteases which cleave the heavy chain of the human immunoglobulin
at different points within the hinge region. Split products of IgA1
been found in the genital secretions of women with gonorrhea,
that the bacterial IgA1 protease is present and active during genital
It is thought that the Fab fragments of IgA1 may bind to the bacterial
cell surface and block the Fc-mediated functions other immunoglobulins.
described above, invading Neisseria gonorrhoeae
enter the bloodstream causing a Gram-negative bacteremia which may lead
to a disseminated bacterial infection. Asymptomatic infections of the
or cervix usually serve as focal sources for bacteremia. Strains of N.
gonorrhoeae that cause disseminated infections are usually
to complement and the serum bactericidal reaction. This accounts for
ability to persist during bacteremia. In Gram-negative
of this sort, the effect of bacterial endotoxin can be exacerbated by
lyis of bacterial cells which may simply liberate soluble LOS.
Figure 3. Pathogenesis of
gonorrhea adapted from Morse, in Baron, Chapter 14, Neisseria,
Branhamella, Moraxella and Eikenella. See text for details.