Pathogenic Neisseriae: Gonorrhea, Neonatal Ophthalmia and Meningococcal Meningitis
(This chapter has 7 pages)
© 2008 Kenneth Todar, PhD
The family Neisseriaceae consists of Gram-negative
bacteria from fourteen genera (Bergey's 2001), including Neisseria,
Chromobacterium, Kingella, and Aquaspirillum. The
contains two important human pathogens, N. gonorrhoeae and N.
meningitidis. N. gonorrhoeae
causes gonorrhea, and N. meningitidis
is the cause of meningococcal meningitis. N. gonorrhoeae
have a high prevalence and low mortality, whereas N. meningitidis
infections have a low prevalence and high mortality.
Neisseria gonorrhoeae infections are acquired by sexual
and usually affect the mucous membranes of the urethra in males and the
endocervix and urethra in females, although the infection may
to a variety of tissues. The pathogenic mechanism involves the
of the bacterium to nonciliated epithelial cells via pili (fimbriae)
the production of lipopolysaccharide endotoxin. Similarly, the
of Neisseria meningitidis is highly toxic, an it has an
virulence factor in the form of its antiphagocytic capsule. Both
produce IgA proteases which promote virulence. Many normal individuals
may harbor Neisseria meningitidis in the upper respiratory
but Neisseria gonorrhoeae is never part of the normal flora
is only found after sexual contact with an infected person (or direct
in the case of infections in the newborn).
In the vocabulary of the public health and medical
N. gonorrhoeae is often referred to as the "gonococcus", while N.
meningitidis is known as the "meningococcus"and one form of the
it causes is called meningococcemia.
Figure 1. Left: Neisseria
gonorrhoeae Gram stain of pure culture; Right: Neisseria
Gram stain of a pustular exudate.
Neisseria gonorrhoeae is a Gram-negative coccus, 0.6 to 1.0
in diameter, usually seen in pairs with adjacent flattened sides
1 Left and Fig 2 below). The organism is frequently found
in polymorphonuclear leukocytes (neutrophils) of the gonorrhea pustular
exudate (Figure 1 Right). Fimbriae, which play a major role in
extend several micrometers from the cell surface (Figure 2 below).
Figure 2. Neisseria
Neisseria gonorrhoeae possesses a typical Gram-negative outer
membrane composed of proteins, phospholipids, and lipopolysaccharide
However, neisserial LPS is distinguished from enteric LPS by its
basal oligosaccharide structure and the absence of repeating O-antigen
subunits. For these reasons, neisserial LPS is referred to as lipooligosaccharide
(LOS). The bacterium characteristically releases outer membrane
fragments called "blebs" during growth. These blebs contain LOS
probably have a role in pathogenesis if they are disseminated during
course of an infection.
N. gonorrhoeae is a relatively fragile organism, susceptible
to temperature changes, drying, uv light, and other environmental
Strains of N. gonorrhoeae are variable in their cultural
so that media containing hemoglobin, NAD, yeast extract and other
are needed for isolation and growth of the organism. Cultures are grown
at 35-36 degrees in an atmosphere of 3-10% added CO2.
PAGE 2 STARTS HERE
Infections 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.
Gonorrheal infection 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.
Uncomplicated 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.
Endocervical 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
which occurs in the U.S. at an estimated rate of over 700,00 cases
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. Occasionally, disseminated
occur. The most common forms of disseminated infection 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 homosexual men usually result from anal
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 fimbriae
and opa (P.II) proteins. although nonspecific factors
as surface charge and hydrophobicity may play a role. Fimbriae 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.
Neisseria 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.
Rmp (P.III) 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
During infection, bacterial lipooligosaccharide (LOS) and
are released by autolysis of cells. Both bacterial polysaccharides
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 a serum-resistant phenotypes of N.
N. gonorrhoeae 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.
N. gonorrhoeae 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.
Occasionally, as 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 in the 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 LPS.
Figure 3. Pathogenesis of
gonorrhea according to Morse in Baron, Chapter 14, Neisseria,
Branhamella, Moraxella and Eikenella
PAGE 3 STARTS HERE
Like the other pyogenic bacteria, Neisseria gonorrhoeae has a
range of virulence determinants, although it does not produce any
The first stages of infection, involving adherence and invasion, are
by surface components of the gonococci. The bacterium first attaches to
epithelial cells by means of its fimbriae, specifically N-methylphenylalanine
(Type 4) pili, the main subunit of which is PilE. After
attachment, the bacteria enter a second stage of binding mediated by
outer membrane protein
(also known as Opa) which is
needed for tight binding and invasion of epithelial cells. Also, P.II
from one bacterium will bind to LOS of an adjacent bacterium, which
for the construction of a microcolony which may be functionally
to a biofilm. However, the invasion of a cell involves a single
not whole microcolonies.
Neisseria gonorrhoeae also produces an
IgA1 protease that probably play a role in the colonization stage.
The outer membrane porin of N. gonorrhoeae P.I (also
as Por) is equivalent to the ompC and ompF porins of E.
that are involved in the passage of solutes through the outer
However, P.I apparently has a role in virulence that allows the
to survive inside of phagocytes. Purified P.I has been shown to inhibit
the ability of phagocytes to kill ingested bacteria.
The lipooligosaccharide (LOS) of the outer membrane is thought to be
responsible for most of the symptoms of gonorrhea. Gonococcal LOS
an intense inflammatory response. Subsequent activation of complement,
attraction and feeding by phagocytes, and the lysis of the phagocytes
contributes to the purulent discharge. The local production of TNF,
by LOS, is thought to be the main cause of damage to the fallopian
In addition, in strains that cause systemic infection, LOS binds sialic
acid from the serum forming a microcapsule of sialylated LOS,
allows the gonococci to resist the host immune response and serum
Nonsialyated LOS and P.I (Por) on the bacterial surface are known to
be effective targets for bactericidal antibodies. However, if
produced against P.III (also known as Rmp) react with
antigenic site on the gonococcal surface, the effect is to block
antibodies against LOS and P.I and to protect the bacterium from
Finally, Neisseria gonorrhoeae has a well-developed iron
system that permits it to extract iron from its host during growth,
is necessary to support bacterial invasion. Basically, the bacterium is
able to form two transferrin receptors (Tbp1 and Tbp2)
one lactoferrin receptor (Lbp) in its outer membrane, which are
induced under low-iron conditions, and which are able to directly
iron from transferrin and lactoferrin, respectively. The proteins can
extract iron from heme and hemoglobin.
Table 1. Surface
components of N.
gonorrhoeae that may play a role in virulence
||major fimbrial protein
||initial binding to epithelial cells
||outer membrane protein
||contributes to invasion
||outer membrane porin
||may prevent phagolysosome formation in
neutrophils and/or reduce oxidative
||outer membrane lipooligosaccharide
||elicits inflammatory response, triggers
release of TNF
||outer membrane protein
||elicits formation of ineffective antibodies
that block that block bactercidal
antibodies against P.I and LOS
|Tbp1 and Tbp2
||outer membrane receptors for transferrin
||iron acquisition for growth
||outer membrane receptor for lactoferrin
||iron acquisition for growth
PAGE 4 STARTS HERE
Infection stimulates inflammation and a local immune (IgA) response.
focuses the host defenses but also becomes the pathology of the
It is not known whether the secretory immune response is protective.
antibodies also appear, and IgG and complement may be components of the
inflammatory exudate. But whether the immune defenses provide much
against reinfection has not been clearly shown. In any case, immunity
expected to be strain specific so that reinfection may occur.
Not everyone exposed to N. gonorrhoeae acquires the disease.
may be due to variations in the size or virulence of the inoculum, to
resistance, or to specific immunity. A 50% infective dose (ID50)
of about 1,000 bacteria has been determined based on experimental
inoculation of male volunteers. No data is available for females.
Nonspecific factors have been implicated in natural resistance to
infection. In women, changes in the genital pH and hormones may
resistance to infection at certain times of the menstrual cycle. Urine
contains bactericidal and bacteriostatic components against N.
Factors in urine that may be important are pH, osmolarity, and the
of urea. The variability in the susceptibility of gonococcal strains to
the bactericidal and bacteriostatic properties of urine is thought to
one of the reasons some males apparently do not develop a gonorrhea
Most uninfected individuals have serum antibodies that react with
antigens. These antibodies probably result from colonization or
by various Gram-negative bacteria that possess cross-reactive antigens.
Such "natural antibodies" may be important in individual natural
resistance or susceptibility to infection, but this has not been
Infection with N. gonorrhoeae stimulates both mucosal and
antibodies to a variety of gonococcal antigens. Mucosal antibodies are
primarily IgA and IgG. In genital secretions, antibodies have been
that react with Por, Opa, Rmp and LOS. Vaccine trials have suggested
specific anti-fimbrial antibodies inhibit the fimbrial-mediated
of the homologous gonococcal strain. In general, the IgA response is
and declines rapidly after treatment; IgG levels decline more
Anti-Por antibodies apparently are bactericidal for the gonococcus. IgG
that reacts with Rmp blocks the bactericidal activity of antibodies
against Por and LOS. Genital infection with N. gonorrhoeae
a serum antibody response against the LOS of the infecting strain.
gonococcal infection results in much higher levels of anti-LOS antibody
than do genital infections.
Strains that cause uncomplicated genital infections usually are
by normal human serum and are termed serum sensitive. This
activity is mediated by IgM and IgG antibodies that recognize sites on
the LOS. Strains that cause disseminated infections are not killed by
normal human serum and are referred to as serum resistant.
is mediated, in part, by IgA that blocks the IgG-mediated
activity of the serum. Serum from convalescent patients with
infections contains bactericidal IgG to the LOS of the infecting
Individuals with inherited complement deficiencies have a markedly
risk of acquiring systemic neisserial infections and are subject to
episodes of systemic gonococcal and meningococcal infections,
that the complement system is important in host defense. Gonococci
complement by both the classic and alternative pathways. Complement
by gonococci leads to the formation of the C5b-9 complex (membrane
complex) on the outer membrane. In normal human serum, similar numbers
of C5b-9 complexes are deposited on serum-sensitive and serum-resistant
organisms, but the membrane attack complex is not functional on
The recommended treatment for uncomplicated infections is a
cephalosporin or a fluoroquinolone plus an antibiotic (e.g.,
or erythromycin) effective against possible coinfection with Chlamydia
trachomatis. Sex partners should be referred and treated. The
Treatment Guidelines recommend treatment of all gonococcal
with antibiotic regimens effective against resistant strains. The
antimicrobial agents are ceftriaxone, cefixime, ciprofloxacin, or
There is no effective vaccine to prevent gonorrhea. Candidate vaccines
consisting of PilE protein or Por are of little
The development of an effective vaccine has been hampered by the lack
a suitable animal model and the fact that an effective immune response
has never been demonstrated. Condoms are effective in preventing the
The evolution of antimicrobial resistance in N. gonorrhoeae
ultimately affect the control of gonorrhea. Strains with multiple
resistance to penicillin, tetracycline, erythromycin, and cefoxitin
been identified in the United States and most other parts of the world.
Sporadic high-level resistance to spectinomycin and fluoroquinolones
been reported. Penicillinase-producing strains of N. gonorrhoeae
were first described in 1976. Five related ß-lactamase plasmids
different sizes have been identified. Their prevalence
strains has increased dramatically in the United States since 1984.
Plasmid-mediated resistance of N. gonorrhoeae to
was first described in 1986 and has now been reported in most parts of
the world. This resistance is due to the presence of the streptococcal
tetM determinant on a gonococcal conjugative plasmid.
The only natural host for N. gonorrhoeae is humans. Gonorrhea
has all but disappeared in Scandinavia and several other European
countries. However, the disease is very common in the United States.
CDC estimates that more than 700,000 persons in the U.S. get new
gonorrheal infections each year. Only about half of these infections
are reported to CDC. In 2002, 351,852 cases of gonorrhea were reported
to CDC. In the period from 1975 to 1997, the national gonorrhea rate
declined, following the implementation of the national gonorrhea
control program in the mid-1970s. After a small increase in 1998, the
gonorrhea rate has decreased slightly since 1999. In 2002, the rate of
reported gonorrheal infections was 125.0 per 100,000 persons.
Gonorrhea is transmitted almost exclusively by sexual contact. Any
sexually active person can be infected with gonorrhea. In the United
States, the highest reported rates of infection are among sexually
active teenagers, young adults, and African Americans. Persons who have
multiple sex partners are at highest risk. Rates of gonorrhea are
higher in males and in minority
and inner-city populations.
Gonorrhea is usually contracted from a sex partner who is either
or has only minimal symptoms. It is estimated that the efficiency of
after one exposure is about 35 percent from an infected woman to an
man and 50 to 60 percent from an infected man to an uninfected woman.
than 90 percent of men with urethral gonorrhea will develop symptoms
5 days; fewer than 50 percent of women with genital gonorrhea will do
Women with asymptomatic infections are at higher risk of developing
inflammatory disease and disseminated gonococcal infection.
PAGE 5 STARTS HERE
The bacterium Neisseria meningitidis, the meningococcus,
is identical in its staining and morphological characteristics to Neisseria
gonorrhoeae. However, at the ultrastructural level, N.
has a prominent antiphagocytic polysaccharide capsule. N.
strains are grouped on the basis of their capsular polysaccharides,
12 serogroups, some of which are subdivided according to the presence
outer membrane protein and lipopolysaccharide antigens.
Neisseria meningitidis is usually cultivated in a
base medium in a moist chamber containing 5-10% CO2. All
must be warmed to 37 degrees prior to inoculation as the organism is
susceptible to temperatures above or below 37 degrees. This trait is
unique among bacteria. Also, the organism tends to undergo rapid
after death, both in vitro and in vivo. This accounts for the
of lipopolysaccharide (endotoxin) during septicemia and meningitis.
The organism tends to colonize the posterior nasopharynx of humans,
and humans are the only known host. Individuals who are colonized are
of the pathogen who can transmit disease to nonimmune individuals. The
bacterium also colonizes the posterior nasopharynx in the early stages
of infection prior to invasion of the meninges. Most individuals in
contact with a case of meningococcal meningitis become carriers of the
organism. This carrier rate can reach 20 percent of the contact group
the first case is recognized, and may reach as high as 80 percent at
height of an epidemic.
Structure and Classification
The only distinguishing structural feature between N. meningitidis
and N. gonorrhoeae is the presence of a polysaccharide capsule
the former. The capsule is antiphagocytic and is an important virulence
Meningococcal capsular polysaccharides provide the basis for grouping
organism. Twelve serogroups have been identified (A, B, C, H, I, K, L,
X, Y, Z, 29E, and W135). The most important serogroups associated with
disease in humans are A, B, C, Y, and W135. The chemical composition of
these capsular polysaccharides is known. The prominent outer membrane
of N. meningitidis have been designated class 1 through class
The class 2 and 3 proteins function as porins and are analogous to
Por. The class 4 and 5 proteins are analogous to gonococcal
and Opa, respectively. Serogroup B and C meningococci have been
subdivided on the basis of serotype determinants located on the class 2
and 3 proteins. A handful of serotypes are associated with most cases
meningococcal disease, whereas other serotypes within the same
rarely cause disease. All known group A strains have the same protein
antigens in the outer membrane. Another serotyping system exists based
on the antigenic diversity of meningococcal LOS.
The term meningitis refers to inflammation the meninges
the brain or spinaL cord. Meninges are any of the three membranes that
envelope the brain and spinal cord. The disease meningitis is
by a number of different bacteria and viruses. Bacterial causes include
influenzae, Escherichia coli, Streptococcus
pyogenes, Staphylococcus aureus, and Neisseria
Although a variety of cocci cause meningitis, the term
is reserved for the Gram-negative, bean-shaped diplococcus, Neisseria
meningitidis. Like its relative N. gonorrhoeae, the
tends to occur intracellularly in the cytoplasm of neutrophils which
attracted to the site of inflammation in the mininges, so this type of
infection is called pyogenic (pus-forming).
Marchiafava and Celli were the first to report observing
diplococci in cerebrospinal fluid of a fatal case of meningitis in
In 1887, Weichselbaum isolated the bacterium from six cases of
and established the isolates as a distinct species and proven to be the
cause of meningitis.
Infection with N. meningitidis has two presentations, meningococcemia,
characterized by skin lesions, and acute bacterial meningitis.
fulminant form of disease (with or without meningitis) is characterized
by multisystem involvement and high mortality.
Infection is by aspiration of infective bacteria, which attach to
cells of the nasopharyngeal and oropharyngeal mucosa, cross the mucosal
barrier, and enter the bloodstream. If not clear whether blood-borne
may enter the central nervous system and cause meningitis.
The mildest form of disease is a transient bacteremic illness
by a fever and malaise; symptoms resolve spontaneously in 1 to 2 days.
The most serious form is the fulminant form of disease complicated by
The manifestations of meningococcal meningitis are similar to acute
meningitis caused by other bacteria such as Streptococcus
Haemophilus influenzae, and E. coli. Chills, fever,
and headache are the usual manifestations of infection. Signs of
meningeal inflammation are also present.
PAGE 6 STARTS HERE
Clinical manifestations of N. meningitidis
The onset of meningococcal meningitis may be abrupt or insidious.
with meningococcal meningitis rarely display signs of meningeal
Irritability and refusal to take food are typical; vomiting occurs
in the disease and may lead to dehydration. Fever is typically absent
children younger than 2 months of age. Hypothermia is more common in
As the disease progresses, apnea, seizures, disturbances in motor tone,
and coma may develop.
In older children and adults, specific symptoms and signs are
present, with fever and altered mental status the most consistent
Headache is an early, prominent complaint and is usually very severe.
vomiting, and photophobia are also common symptoms.
Neurologic signs are common; approximately one-third of patients
convulsions or coma when first seen by a physician. Signs of meningeal
irritation such as spinal rigidity, hamstring spasms and exaggerated
Petechiae (minute hemorrhagic spots in the skin) or purpura
into the skin) occurs from the first to the third day of illness in 30
to 60% of patients with meningococcal disease, with or without
The lesions may be more prominent in areas of the skin subjected to
such as the axillary folds, the belt line, or the back.
Fulminant meningococcemia occurs in 5 to 15% of patients with
disease and has a high mortality rate. It begins abruptly with sudden
fever, chills, myalgias, weakness, nausea, vomiting, and headache.
restlessness, and delirium occur within the next few hours. Widespread
purpuric and ecchymotic skin lesions appear suddenly. Typically, no
of meningitis are present. Pulmonary insufficiency develops within a
hours, and many patients die within 24 hours of being hospitalized
appropriate antibiotic therapy and intensive care.
Figure 4. The characteristic
skin rash (purpura) of meningococcal septicemia, caused by Neisseria
For a time, the virulence of Neisseria meningitidis was
to the production of an "exotoxin" that could be recovered from culture
filtrates of the organism. But when studies revealed that antitoxin
equally well with washed cells as culture filtrate, it was realized
the bacteria underwent autolysis during growth and released parts of
cell walls in a soluble form. Hence, the major toxin of N.
is its lipooligosaccharide,LOS, and its mechanism is endotoxic.
The other important determinant of virulence of N. meningitidis
is its antiphagocytic polysaccharide capsule.
The human nasopharynx is the only known reservoir of N.
Meningococci are spread via respiratory droplets, and transmission
aspiration of infective particles. Meningococci attach to the
columnar epithelial cells of the nasopharynx. Attachment is mediated by
and possibly by other outer membrane components. Invasion of the
cells occurs by a mechanism similar to that observed with gonococci.
involved after bloodstream invasion are unclear and how the
enters the central nervous system is not known.
Purified meningococcal LOS is highly toxic and is as lethal for mice
as the LOS from E. coli or Salmonella typhimurium;
meningococcal LOS is 5 to 10 times more effective than enteric LPS in
a dermal Shwartzman phenomenon (a characteristic type of inflammatory
in rabbits. Meningococcal LOS has been shown to suppress leukotriene B4
synthesis in human polymorphonuclear leukocytes. The loss of
B4 deprives the leukocytes of a strong chemokinetic and chemotactic
PAGE 7 STARTS HERE
N. mengingitidis establishes systemic infections only in
who lack serum bacterial antibodies directed against the capsular or
(cell wall) antigens of the invading strain, or in patients deficient
the late-acting complement components.
The integrity of the pharyngeal and respiratory epithelium appears
be important in protection from invasive disease. Chronic irritation of
the mucosa due to dust or low humidity, or damage to the mucosa
from a concurrent upper respiratory infection, may be
factors for invasive disease.
The presence of serum bactericidal IgG and IgM is probably the most
important host factor in preventing invasive disease. These antibodies
are directed against both capsular and noncapsular surface antigens.
antibodies are produced in response to colonization with carrier
of N. meningitidis, as well as N. lactamica, and other
species that are normal inhabitants of the upper respiratory tract.
antibodies are also stimulated by cross-reacting antigens on other
species such as Escherichia coli. The role of bactericidal
in prevention of invasive disease explains why high attack rates are
in infants from 6 to 9 months old, the time at which maternal
are being lost. Individuals with complement deficiencies (C5, C6, C7,
C8) may develop meningococcemia despite protective antibody. This
the importance of the complement system in defense against
The meningococcus usually inhabits the human nasopharynx without
detectable disease. This carrier state may last for a few days to
and is important because it not only provides a reservoir for
infection but also stimulates host immunity. Between 5 and 30% of
individuals are carriers at any given time, yet few develop
disease. Carriage rates are highest in older children and young adults.
Attack rates highest in infants 3 months to 1 year old. Meningococcal
occurs both sporadically (mainly groups B and C meningococci) and in
(mainly group A meningococci), with the highest incidence during late
and early spring. Whenever group A strains become prevalent in the
the incidence of meningitis increases markedly.
Penicillin is the drug of choice to treat meningococcemia and
meningitis. Although penicillin does not penetrate the normal
barrier, it readily penetrates the blood-brain barrier when the
are acutely inflamed. Either chloramphenicol or a third-generation
such as cefotaxime or ceftriaxone is used in persons allergic to
Meningococcal disease is contracted through association with
individuals, as evidenced by the 500- to 800-fold greater attack rate
household contacts than among the general population. Because such
members are at high risk, they require chemoprophylaxis. Sulfonamides
the chemoprophylactic agent of choice until the emergence of
meningococci. At present, approximately 25 percent of clinical isolates
of N. meningitidis in the United States are resistant to
nowadays, rifampin is the chemoprophylactic agent of choice.
Groups A, C, AC, and ACYW135 capsular polysaccharide vaccines are
However, the polysaccharide vaccines are ineffective in young children
(in children under 1 year old, antibody levels decline rapidly after
and the duration of protection is limited in children vaccinated at 1
4 years of age. Routine vaccination is not currently recommended
because the risk of infection is low. The group B capsular
is a homopolymer of sialic acid and is not immunogenic in humans. A
B meningococcal vaccine consisting of outer membrane protein antigens
recently been developed, but is not licensed in the United States.
Search for a universal vaccine for meningococcal meningitis
There is an obvious need for a universal vaccine for meningococcal
but the development of an effective vaccine against all forms of
meningitidis has been hampered by the high degree of variation in
proteins on the surface of the bacterium which leads to the occurrence
of many different antigenic types.
More than 10% of the population may be carrying the bacterium at any
one time on the mucosal surfaces of the nose and throat. The majority
these carriers will not have any symptoms of the disease, but this
exposure to the immune system puts pressure on the bacterium to mutate
its surface components in order to survive. Thus, natural selection is
the driving force for the emergence of new antigenic variants.
Among the class 2 and 3 outer membrane proteins of N.
Por A has been considered a primary target for a vaccine-induced
PorA is a major component of the outer membrane of N. meningitidis,
and anti-PorA antibodies are thought to be a critical component in
Interactions between antibodies and PorA have been studied.
strains of the bacterium have different PorA amino acid sequences
the region of the protein that specifically binds to antibody
PorA has several large amino acid "loop" regions that protrude
the surface, and it is these loops that are targets for antibody
In the laboratory, the antigen-binding fragment (Fab) of anti-PorA
can be crystallized and reacted with the antigenic loop regions of
in order to determine the specificity of binding between antigen and
Slight changes in PorA amino acid sequence have been shown to cause
in the ability to bind to antibody molecules. In nature, the
mutates to insert new amino acid residues into the tip of the loop,
alters or eliminates many of the interactions with antibody and
the bacterium to bypass previous immune responses.
Figure 5. Image of the
(Fab) molecular surface, with the PorA antigen superimposed. The dark
groove on the surface of the antibody matches precisely the shape of
PorA antigen; hence any changes in the sequence of PorA in this region
can disrupt antibody binding. Jeremy Derrick, UMIST. SRS
Hence, by introducing changes into portions of the PorA protein that
are exposed at the surface, the bacterium can evade the attention of
immune system. These alterations are apparently introduced without
the biological function of PorA, as a pore-forming protein. Designing
that are able to take into account these changes is a huge challenge,
as more information of this type becomes known, it leads to a more
approach to design of a universal vaccine for meningococcal meningitis.