To search the entire book, enter a term or phrase in the form below
Defense against Specific Immune Responses
© Kenneth Todar, PhD
The inflammatory and phagocytic responses of the host to invading
bacteria are immediate and nonspecific. A second, specific immune
response is soon encountered by invasive bacteria. The adaptive immune
antibody-mediated immunity (AMI) and cell-mediated immunity (CMI) are
brought into play during the presentation of bacterial antigens to the
Although AMI is the principal immunological response
effective against extracellular bacteria, the major defensive and
against intracellular bacteria is CMI. On epithelial surfaces, the main
specific immune defense of the
host is the protection afforded by secretory IgA antibodies. Once the
have been penetrated, however, the immune defenses of AMI and CMI
If there is a way for an organism to successfully bypass or overcome
the immunological defenses, then some bacterial pathogen has probably
it. Bacteria evolve very rapidly in relation to their host, so that
of the feasible anti-host strategies are likely to have been tried out
and exploited. Consequently, pathogenic bacteria have developed
ways to bypass or overcome the immunological defenses of the host,
to the virulence of the microbe and the pathology of the disease.
PATHOGEN STRATEGIES TO DEFEND AGAINST
THE SPECIFIC IMMUNE DEFENSES
Immunological Tolerance to a Bacterial
Tolerance is a property of the host in which there is an
reduction in the immune response to a given antigen (Ag). Tolerance to
Ag does not involve a general failure in the immune response but a
deficiency in relation to the specific antigen(s) of a given bacterium.
If there is a depressed immune response to relevant antigens of a
the process of infection is facilitated. Tolerance can involve either
or CMI or both arms of the immunological response.
Tolerance to an Ag can arise in a number of ways, but three are
relevant to bacterial infections.
1. Fetal exposure to Ag. If a fetus is infected at certain
of immunological development, the microbial Ag may be seen as "self",
inducing tolerance (failure to undergo an immunological response) to
the Ag which may persist even after birth.
2. High persistent doses of circulating Ag. Tolerance to a
or one of its products might arise when large amounts of bacterial
are circulating in the blood. The immunological system becomes
3. Molecular mimicry. If a bacterial Ag is very similar to
host "antigens", the immune responses to this Ag may be weak giving a
of tolerance. Resemblance between bacterial Ag and host Ag is referred
to as molecular mimicry. In this case the antigenic determinants of the
bacterium are so closely related chemically to host tissue components
the immunological cells cannot distinguish between the two and an
response cannot be raised. Some bacterial capsules are composed of
(hyaluronic acid, sialic acid) so similar to host tissue
that they are not immunogenic.
Some pathogens can hide their unique antigens
from opsonizing antibodies or complement. Bacteria may be able to coat
themselves with host proteins such as fibrin, fibronectin, or even
In this way they are able to hide their own antigenic surface
from the immunological system.
S. aureus produces cell-bound coagulase and clumping
factor that cause fibrin to clot and to deposit on the cell
It is possible that this disguises the bacteria immunologically so that
they are not readily identified as antigens and targets for an
Protein A produced by S. aureus, and the analogous Protein
G produced by Streptococcus pyogenes, bind the Fc portion
immunoglobulins, thus coating the bacteria with antibodies and
their opsonizing capacity by the disorientation.
The fibronectin coat of Treponema pallidum provides
disguise for the spirochete.
E. coli K1, that causes meningitis in newborns, has a capsule
composed predominantly of sialic acid providing an antigenic
as does the hyaluronic acid capsule of Streptococcus pyogenes.
Some pathogens (mainly viruses and protozoa, rarely bacteria)
immunosuppression in their infected host. This means that the host
depressed immune responses to antigens in general, including those of
Suppressed immune responses are occasionally
during chronic bacterial infections such as leprosy and tuberculosis.
This is significant considering a third of the world population is
infected with Mycobacterium tuberculosis.
In extreme forms of leprosy, caused by Mycobacterium leprae,
there is poor response to leprosy antigens, as well as unrelated
After patients have been successfully treated, immunological reactivity
reappears, suggesting that general immunosuppression is in fact due to
In mild cases of leprosy there is frequently an associated
suppression that is specific for M. leprae antigens. This is
from tolerance, since unique antigens (proteins) of M. leprae
been associated as the cause of this immunosuppression. This could be
explained by (1) lack of costimulatory signals
with cytokine secretion); (2) activation of suppressor T cells; (3)
in TH1/TH2 cell activities.
At present, little is known of the mechanisms by which bacterial
general immune responses. It seems probable that it is due to
the functions of B cells, T cells or macrophages. Since many
bacteria infect macrophages, it might be expected that they compromise
the role of these cells in an immunological response.
General immunosuppression induced in a host may be of immediate
to an invading pathogen, but it is of no particular significance (to
invader) if it merely promotes infection by unrelated microorganisms.
this is why it does not seem to be a commonly used strategy of the
Persistence of a Pathogen at Bodily Sites
to Specific Immune Response
Some pathogens can avoid exposing themselves to immune forces.
pathogens can evade host immunological responses as long as they stay
infected cells and they do not
allow microbial Ag to form on the cell
This is seen in macrophages infected with Brucella,
or M. leprae. The macrophages support the growth of the
and at the same time give them protection from immune responses. Some
pathogens (Yersinia, Shigella, Listeria, E. coli) may
take up residency in cells
are neither phagocytes nor APC's and their antigens are not displayed
the infected cell's surface. They are virtually unseen by cells of the
Some pathogens persist on the luminal surfaces of the GI tract, oral
cavity and the urinary tract, or the lumen of the salivary gland,
gland or the kidney tubule. If there is no host cell destruction, the
may avoid inducing an inflammatory response, and there is no way in
sensitized lymphocytes or circulating antibodies can reach the site to
eliminate the infection. Secretory IgA could react with surface
on bacterial cells, but the complement sequence would be unlikely to be
activated and the cells would not be destroyed. Conceivably, IgA
could immobilize bacteria by agglutination of cells or block adherence
of bacteria to tissue or cell surfaces, but it is unlikely that IgA
kill bacteria directly or inhibit their growth.
Some examples of bacterial pathogens that grow at tissue sites
inaccessible to the forces of AMI and CMI are given below.
Streptococcus mutans can initiate dental
at any time after the eruption of the teeth, regardless of the immune
of the host. Either the host does not undergo an effective immune
or secretory IgA plays little role in preventing colonization and
Vibrio cholerae multiplies in the GI tract where the bacteria
elaborate a toxin which causes loss of fluids and diarrhea in the host
which is characteristic of the disease cholera. IgA antibodies against
cellular antigens of the cholera vibrios are not completely effective
preventing infection by these bacteria as demonstrated by the relative
ineffectiveness of the cholera vaccine prepared from phenol-killed
The carrier state of typhoid fever results from a persistent
by the typhoid bacillus, Salmonella typhi. The organism is not
during the initial infection and persists in the host for months, years
or a life time. In the carrier state, S. typhi is able to
the biliary tract (gall bladder) away from the immune forces, and be
into urine and feces.
Some bacteria cause persistent infections in the lumen of glands. Brucella
abortus persistently infects mammary glands of cows and is shed in
the milk. Leptospira multiplies persistently in the lumen of
kidney tubules of rats and is shed in the urine and remains infectious.
Bacteria causing infections of the hair follicles, such as acne,
seldom encounter the immunological tissues.
Induction of Ineffective Antibody
Many types of antibody (Ab) are formed against a given Ag, and some
components may display various antigenic determinants. Antibodies tend
to range in their capacity to react with Ag (the ability of specific Ab
to bind to an Ag is called avidity). If Abs formed against a
Ag are of low avidity, or if they are directed against unimportant
determinants, they may have only weak antibacterial action. Such "ineffective"
(non-neutralizing) Abs might even aid a pathogen by combining with a
Ag and blocking the attachment of any functional Abs that might be
In the case of Neisseria gonorrhoeae the presence of
to an outer membrane protein called rmp interferes with the serum
reaction and in some way compromises the surface defenses of the
female urogenital tract. Increased susceptibility to reinfection is
correlated with the presence of circulating rmp antibodies.
Antibodies Absorbed by Soluble Bacterial
Some bacteria can liberate antigenic surface components in a soluble
form into the tissue fluids. These soluble antigens are able to combine
with and "neutralize" antibodies before they reach the bacterial cells.
For example, small amounts of endotoxin (LPS) may be released into
fluids by Gram-negative bacteria.
Autolysis of Gram-negative or Gram-positive bacteria may release
surface components in a soluble form. Streptococcus pneumoniae
meningitidis are known to release capsular polysaccharides during
in tissues. They are found in the serum of patients with pneumococcal
and in the cerebrospinal fluid of patients with meningitis.
these released surface antigens could "mop up" antibody before it
the bacterial surface which should be an advantage to the pathogen.
soluble bacterial cell wall components are powerful antigens and
activators so they contribute in a major way to the pathology observed
in meningitis and pneumonia.
Protein A, produced by S. aureus may remain bound to
staphylococcal cell surface or it may be released in a soluble form.
A will bind to the Fc region of IgG. On the cell surface, protein A
IgG in the wrong orientation to exert its antibacterial activity, and
protein A agglutinates and partially inactivates IgG.
Local Interference with Antibody Activity
There are probably several ways that pathogens interfere with the
action of antibody molecules. Some pathogens produce enzymes that
Neisseria gonorrhoeae, N. meningitidis, Haemophilus
influenzae, Streptococcus pneumoniae and Streptococcus
which can grow on the surfaces of the body, produce IgA proteases that
inactivate secretory IgA by cleaving the molecule at the hinge region,
detaching the Fc region of the immunoglobulin.
Soluble forms of Protein
A produced S. aureus agglutinate immunoglobulin molecules
partially inactivate IgG.
One way bacteria can trick forces of the immunological response is
change antigens, i.e., to undergo antigenic variation. Antigens may
vary or change in the host during the course of an
infection, or an organism can exist in nature as multiple antigenic
(serotypes or serovars). Antigenic variation is an
mechanism used by pathogenic microorganisms for escaping the
activities of antibodies.
Some types of antigenic variation during the course of an
inversions or gene conversions or gene rearrangements in the DNA of the
microorganisms. Such is the case with some pathogens that change
antigens during infection by switching from one fimbrial type to
another, or by switching fimbrial tips. This makes the original AMI
response obsolete by using new fimbriae that do not bind the previous
Neisseria gonorrhoeae can change fimbrial antigens during the
course of an infection. During initial stages of an infection,
to epithelial cells of the cervix or urethra is mediated by pili
Equally efficient attachment to phagocytes would be undesirable. Rapid
switching on and off of the genes controlling pili are therefore
at different stages of the infection, and N. gonorrhoeae is
of undergoing this type of "pili switching" or phase variation.
Genetically controlled changes in outer membrane proteins also occur in
the course of an infection. This finely controlled expression of the
for pili and surface proteins changes the adherence pattern to
host cells, and increases
to phagocytosis and immune lysis.
The "relapses" of relapsing fever caused by the spirochete, Borrelia
recurrentis, are a result of antigenic variation by the organism.
The disease is characterized by episodes of fever
relapse (come and go) for a period of weeks or months. After infection,
the bacteria multiply in tissues and cause a febrile illness until the
onset of an immunological response a week or so later. Bacteria then
from the blood because of antibody mediated phagocytosis, lysis,
etc., and the fever falls. Then an antigenically distinct mutant arises
in the infected individual, multiplies, and in 4-10 days reappears in
blood and there is another febrile attack. The immunological system is
and responds by conquering the new antigenic variant, but the cycle
such that there may be up to 10 febrile episodes before final recovery.
With each attack a new antigenic variant of the spirochete appears and
new set of antibodies is formed in the host. Thus, this change in
antigens during the infection contributes significantly to the course
of the disease.
Many pathogenic bacteria exist in nature as multiple antigenic
or serotypes, meaning that they are variant strains of the same
species. For example, there are multiple serotypes of Salmonella
based on differences in cell wall (O) antigens and/or flagellar (H)
There are 80 different antigenic types of Streptococcus pyogenes
based on M-proteins on the cell surface. There are over one hundred
of Streptococcus pneumoniae depending on their capsular
antigens. Based on minor differences in surface structure chemistry
are multiple serotypes of Vibrio cholerae, Staphylococcus
coli, Neisseria gonorrhoeae and an assortment of other
pathogens. Antigenic variation is prevalent among pathogenic viruses as
If the immunological response is a critical defense against a
being able to shed old antigens and present new ones to the immune
might allow infection or continued invasion by the pathogen to occur.
the infected host would seem to be the ideal selective environment for
the emergence of new antigenic variants of bacteria, providing the
organism's other virulence determinants remain intact. Perhaps this
why many successful bacterial pathogens exist in a great variety of
Textbook of Bacteriology Index