Pathogenic Neisseriae: Gonorrhea, Neonatal Ophthalmia and Meningococcal Meningitis (page 7)
(This chapter has 7 pages)
© Kenneth Todar, PhD
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.
END OF CHAPTER
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