Bacterial Defense against Specific Immune Responses

Introduction

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 forces of antibody-mediated
immunity (AMI) and cell-mediated immunity (CMI) are brought into play during the presentation of bacterial antigens
to the immunological system.
Although AMI is the principal immunological response effective against extracellular bacteria, the major defensive and
protective response 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 epithelial surfaces have been penetrated,
however, the immune defenses of AMI and CMI are encountered.

If there is a way for an organism to successfully bypass or overcome the immunological defenses, then some bacterial
pathogen has probably "discovered" it. Bacteria evolve very rapidly in relation to their host, so that most of the feasible
anti-host strategies are likely to have been tried out and exploited. Consequently, pathogenic bacteria have developed
numerous ways to bypass or overcome the immunological defenses of the host, which contributes 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 Antigen

Tolerance is a property of the host in which there is an immunologically-specific reduction in the immune response to
a given antigen (Ag). Tolerance to a bacterial Ag does not involve a general failure in the immune response but a
particular deficiency in relation to the specific antigen(s) of a given bacterium. If there is a depressed immune response
to relevant antigens of a parasite, the process of infection is facilitated. Tolerance can involve either AMI or CMI or
both arms of the immunological response.

Tolerance to an Ag can arise in a number of ways, but three are possibly relevant to bacterial infections.

1. Fetal exposure to Ag. If a fetus is infected at certain stages of immunological development, the microbial Ag may
be seen as "self", thus inducing tolerance (failure to undergo an immunological response) to the Ag which may persist
even after birth.

Ex: Pregnant mom’s exposure to flu vaccine kick-starts fetal immune system.

The hypothesized that the fetus can be exposed to and mount an immune response against allergens to which the
mother has been exposed, and this may have an effect on the development of allergic sensitivity (e.g. eczema and
asthma) later in an infant’s life. However this hypothesis has remained controversial because of an inability to detect
antigen-specific T cells in cord blood. Recently, a newly developed technique known as MHC tetramer staining has
facilitated the detection of antigen-specific T cells.

2. High persistent doses of circulating Ag. Tolerance to a bacterium or one of its products might arise when large
amounts of bacterial antigens are circulating in the blood. The immunological system becomes overwhelmed.

3. Molecular mimicry. If a bacterial Ag is very similar to normal host "antigens", the immune responses to this Ag
may be weak giving a degree 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 that the immunological cells cannot distinguish between the two and an immunological response cannot be
raised. Some bacterial capsules are composed of polysaccharides (hyaluronic acid, sialic acid) so similar to host tissue
polysaccharides that they are not immunogenic.

Antigenic Disguises
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 immunolobulin molecules. In this way they are
able to hide their own antigenic surface components from the immunological system.

S. aureus produces cell-bound coagulase and clumping factor that cause fibrin to clot and to deposit on the cell
surface. It is possible that this disguises the bacteria immunologically so that they are not readily identified as antigens
and targets for an immunological response.

Protein A produced by S. aureus, and the analogous Protein G produced by Streptococcus pyogenes, bind the Fc
portion of immunoglobulins, thus coating the bacteria with antibodies and canceling their opsonizing capacity by the
disorientation.

The fibronectin coat of Treponema pallidum provides an immunological disguise for the spirochete.

E. coli K1, that causes meningitis in newborns, has a capsule composed predominantly of sialic acid providing an
antigenic disguise, as does the hyaluronic acid capsule of Streptococcus pyogenes.

Immunosuppression

Some pathogens (mainly viruses and protozoa, rarely bacteria) cause immunosuppression in their infected host. This
means that the host shows depressed immune responses to antigens in general, including those of the infecting
pathogen.

Suppressed immune responses are occasionally observed 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 antigens. After patients have been successfully treated, immunological reactivity reappears, suggesting that
general immunosuppression is in fact due to the disease.

In mild cases of leprosy there is frequently an associated immunological suppression that is specific for M. leprae
antigens. This is separate from tolerance, since unique antigens (proteins) of M. leprae have been associated as the
cause of this immunosuppression. This could be explained by (1) lack of costimulatory signals (interference with
cytokine secretion); (2) activation of suppressor T cells; (3) disturbances in TH1/TH2 cell activities.

At present, little is known of the mechanisms by which bacterial pathogens inhibit general immune responses. It seems
probable that it is due to interference with the functions of B cells, T cells or macrophages. Since many intracellular
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 value to an invading pathogen, but it is of no
particular significance (to the invader) if it merely promotes infection by unrelated microorganisms. Perhaps this is why
it does not seem to be a commonly used strategy of the bacteria.

Persistence of a Pathogen at Bodily Sites Inaccessible to Specific Immune Response

Some pathogens can avoid exposing themselves to immune forces. Intracellular pathogens can evade host
immunological responses as long as they stay inside of infected cells and they do not allow microbial Ag to form on
the cell surface. This is seen in macrophages infected with Brucella, Listeria or M. leprae. The macrophages support
the growth of the bacteria and at the same time give them protection from immune responses. Some intracellular
pathogens (Yersinia, Shigella, Listeria, E. coli) may take up residency in cells that are neither phagocytes nor APC's
and their antigens are not displayed on the infected cell's surface. They are virtually unseen by cells of the immune
system.

Some pathogens persist on the luminal surfaces of the GI tract, oral cavity and the urinary tract, or the lumen of the
salivary gland, mammary gland or the kidney tubule. If there is no host cell destruction, the pathogen may avoid
inducing an inflammatory response, and there is no way in which sensitized lymphocytes or circulating antibodies can
reach the site to eliminate the infection. Secretory IgA could react with surface antigens on bacterial cells, but the
complement sequence would be unlikely to be activated and the cells would not be destroyed. Conceivably, IgA
antibodies could immobilize bacteria by agglutination of cells or block adherence of bacteria to tissue or cell surfaces,
but it is unlikely that IgA would kill bacteria directly or inhibit their growth.

Some examples of bacterial pathogens that grow at tissue sites generally inaccessible to the forces of AMI and CMI are
given below.

Streptococcus mutans can initiate dental caries at any time after the eruption of the teeth, regardless of the immune
status of the host. Either the host does not undergo an effective immune response or secretory IgA plays little role in
preventing colonization and subsequent plaque development.

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 in preventing infection by these bacteria as demonstrated by the relative ineffectiveness of
the cholera vaccine prepared from phenol-killed vibrios.

The carrier state of typhoid fever results from a persistent infection by the typhoid bacillus, Salmonella typhi. The
organism is not eliminated 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 colonize the biliary tract (gall bladder) away from the immune forces, and be shed 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 the 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 bacterial 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 bacterial Ag are of low avidity, or if they are directed against
unimportant antigenic determinants, they may have only weak antibacterial action. Such "ineffective" (non-
neutralizing) Abs might even aid a pathogen by combining with a surface Ag and blocking the attachment of any
functional Abs that might be present.

In the case of Neisseria gonorrhoeae the presence of antibody to an outer membrane protein called rmp interferes with
the serum bactericidal reaction and in some way compromises the surface defenses of the female urogenital tract.
Increased susceptibility to reinfection is highly correlated with the presence of circulating rmp antibodies.

Antibodies Absorbed by Soluble Bacterial Antigens

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 surrounding fluids by Gram-negative bacteria.

Autolysis of Gram-negative or Gram-positive bacteria may release antigenic surface components in a soluble form.
Streptococcus pneumoniae and Neisseria meningitidis are known to release capsular polysaccharides during growth in
tissues. They are found in the serum of patients with pneumococcal pneumonia and in the cerebrospinal fluid of
patients with meningitis. Theoretically, these released surface antigens could "mop up" antibody before it reached the
bacterial surface which should be an advantage to the pathogen. These soluble bacterial cell wall components are
powerful antigens and complement 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 the staphylococcal cell surface or it may be released in a
soluble form. Protein A will bind to the Fc region of IgG. On the cell surface, protein A binds IgG in the wrong
orientation to exert its antibacterial activity, and soluble protein A agglutinates and partially inactivates IgG.
Local Interference with Antibody Activity

There are probably several ways that pathogens interfere with the antibacterial action of antibody molecules. Some
pathogens produce enzymes that destroy antibodies.

Neisseria gonorrhoeae, N. meningitidis, Haemophilus influenzae, Streptococcus pneumoniae and Streptococcus

mutans, 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 and partially inactivate IgG.

Antigenic Variation

One way bacteria can trick forces of the immunological response is to periodically 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 type (serotypes or serovars). Antigenic variation is an important mechanism used by
pathogenic microorganisms for escaping the neutralizing activities of antibodies.

Some types of antigenic variation during the course of an infection result from site-specific 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 antibodies.

Neisseria gonorrhoeae can change fimbrial antigens during the course of an infection. During initial stages of an
infection, adherence to epithelial cells of the cervix or urethra is mediated by pili (fimbriae). Equally efficient
attachment to phagocytes would be undesirable. Rapid switching on and off of the genes controlling pili are therefore
necessary at different stages of the infection, and N. gonorrhoeae is capable 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 genes for pili and surface proteins changes the adherence pattern to different
host cells, and increases resistance 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 which 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 disappear from the blood because of antibody mediated phagocytosis, lysis,
agglutination, etc., and the fever falls. Then an antigenically distinct mutant arises in the infected individual, multiplies,
and in 4-10 days reappears in the blood and there is another febrile attack. The immunological system is stimulated and
responds by conquering the new antigenic variant, but the cycle continues 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 a 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 types or serotypes, meaning that they are variant strains
of the same pathogenic species. For example, there are multiple serotypes of Salmonella enterica based on differences
in cell wall (O) antigens and/or flagellar (H) antigens. There are 80 different antigenic types of Streptococcus pyogenes
based on M-proteins on the cell surface. There are over one hundred strains of Streptococcus pneumoniae depending on
their capsular polysaccharide antigens. Based on minor differences in surface structure chemistry there are multiple
serotypes of Vibrio cholerae, Staphylococcus aureus, Escherichia coli, Neisseria gonorrhoeae and an assortment of
other bacterial pathogens. Antigenic variation is prevalent among pathogenic viruses as well.

If the immunological response is a critical defense against a pathogen, then being able to shed old antigens and present
new ones to the immune system might allow infection or continued invasion by the pathogen to occur. Furthermore, 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 explains why many successful
bacterial pathogens exist in a great variety of antigenic types.
Molecular mimicry. If a bacterial Ag is very similar to normal host "antigens", the immune responses to this Ag
may be weak giving a degree 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 "self" components that the immunological cells cannot distinguish between the two and an immune response
cannot be raised. Some bacterial capsules are composed of polysaccharides (hyaluronic acid, sialic acid) so
similar to host tissue polysaccharides that they are not immunogenic.

Antigenic Disguise

Bacteria may be able to coat themselves with host proteins (fibrin, fibronectin, antibody molecules) or with host
polysaccharides (sialic acid, hyaluronic acid) so that they are able to hide their own antigenic surface components
from the immunological system.

Immunosuppression

Some pathogens (mainly viruses and protozoa, rarely bacteria) cause immunosuppression in the infected host.
This means that the host shows depressed immune responses to antigens in general, including those of the
infecting pathogen. Suppressed immune responses are occasionally observed during chronic bacterial infections
such as leprosy and tuberculosis.

Persistence of a Pathogen at Bodily Sites Inaccessible to the Immune Response

Some pathogens can avoid exposing themselves to immune forces.

Intracellular pathogens can evade host immune responses as long as they stay inside of infected cells and they
do not allow microbial Ag to form on the cell surface. Macrophages support the growth of the bacteria and at the
same time give them protection from immune responses.

Some pathogens persist on the luminal surfaces of the GI tract, oral cavity and the urinary tract, or the lumen of
the salivary gland, mammary gland or the kidney tubule.

Induction of Ineffective Antibody

Many types of antibody are formed against a given Ag, and some bacterial 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 bacterial Ag are of low avidity, or if they are directed
against unimportant antigenic determinants, they may have only weak antibacterial action. Such "ineffective"
(non-neutralizing) Abs might even aid a pathogen by combining with a surface Ag and blocking the attachment of
any functional Abs that might be present.

Antibodies Absorbed by Soluble Bacterial Antigens

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 surrounding fluids by Gram-negative bacteria.

Antigenic Variation

One way bacteria can avoid forces of the immune response is by periodically changing antigens, i.e., undergoing
antigenic variation. Some bacteria avoid the host antibody response by changing from one type of fimbriae to
another, by switching fimbrial tips. This makes the original AMI response obsolete by using new fimbriae that do
not bind the previous antibodies. Pathogenic bacteria can vary (change) other surface proteins that are the
targets of antibodies. Antigenic variation is prevalent among pathogenic viruses as well.

Changing antigens during the course of an infection

Antigens may vary or change within the host during the course of an infection, or alternatively antigens may vary
among multiple strains (antigenic types) of a parasite in the population. Antigenic variation is an important
mechanism used by pathogenic microorganisms for escaping the neutralizing activities of antibodies. Antigenic
variation usually results from site-specific inversions or gene conversions or gene rearrangements in the DNA of
the microorganisms.
Changing antigens between infections

Many pathogenic bacteria exist in nature as multiple antigenic types or serotypes, meaning that they are variant
strains of the same pathogenic species. For example, there are multiple serotypes of Salmonella typhimurium
based on differences in cell wall (O) antigens or flagellar (H) antigens. There are 80 different antigenic types of
Streptococcus pyogenes based on M-proteins on the cell surface. There are over one hundred strains of
Streptococcus pneumoniae depending on their capsular polysaccharide antigens. Based on minor differences in
surface structure chemistry there are multiple serotypes of Vibrio cholerae, Staphylococcus aureus, Escherichia
coli, Neisseria gonorrhoeae and an assortment of other bacterial pathogens.