StealthDeath
05-21-2006, 06:00 PM
Copyright Notice:
The following research is the property of StealthDeath. This information has been obtained utilizing standard search engines on documents available to public view on the Internet. However, you may not use this research beyond my postings here as I am claiming copyright to my library of information, which has taken 8 years to assemble. These abstracts, document sections and narration are provided here on FreeConservatives.com for criticism, news reporting, and education as a documentary presentation. Your participation is greatly appreciated and needed to help direct which information will be used to create a DVD presentation exposing fraudulent medical care in America.
Want to see something really scary?
For all those that believe that bacteria cannot routinely stealth, live and travel through the bloodstream to create organ infections, I present the following as a representative summary of hundreds of papers on the topic. This is how a human can be sick and not know it. No elevated white blood counts or fevers are present in many cases. Chlamydia is just one example of a stealth infection that medical dogma refuses to acknowledge as a multi-organ invading organism. They have also failed to recognize the numerous transmission pathways.
If there is a way for an organism to successfully bypass or overcome the immune 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 immune defenses of the host, which contribute to the virulence of the microbe and the pathology of the disease.
Bacteria that are not killed and lysed in serum by the complement MAC are said to be serum resistant. As might be expected many of the Gram-negative bacteria that cause systemic infections, (bacteremia or septicemia) are serum resistant. Gram-positive bacteria are naturally serum-resistant since their cells are not enclosed in an outer membrane.
(MECHANISMS OF BACTERIAL PATHOGENICITY: Bacterial Defense against the Host Immune Responses, 2002 Kenneth Todar University of Wisconsin-Madison Department of Bacteriology)
Serum resistance is a crucial virulence factor for the development<SUP> </SUP>of systemic infections, including bacteraemia, by many pathogenic<SUP> </SUP>bacteria. (Identification of the outer-membrane protein PagC required for the serum resistance phenotype in Salmonella enterica serovar Choleraesuis, Miki Nishio, Nobuhiko Okada, Tsuyoshi Miki, Takeshi Haneda and Hirofumi Danbara, Department of Microbiology, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan )
This textbook has evolved from lectures presented in my bacteriology courses at the University of Wisconsin-Madison. Its contents are suitable for reading or presentation in courses or course modules concerning general microbiology and medical bacteriology at the college and advanced high school levels of education.
Todar's Online Textbook of Bacteriology http://www.textbookofbacteriology.net/ (http://www.textbookofbacteriology.net/)
SEE THIS DOCUMENT BETTER AT: http://textbookofbacteriology.net/antiimmuno.html
Kenneth Todar
University of Wisconsin
Department of Bacteriology
Madison, Wisconsin 53706
MECHANISMS OF BACTERIAL PATHOGENICITY: Bacterial Defense against the Host Immune Responses
2002 Kenneth Todar University of Wisconsin-Madison Department of Bacteriology
Bacterial Mechanisms to Overcome Host Immune Defenses
Antibody-mediated immunity (AMI) is the principal specific immune response effective against extracellular bacteria. The major protective immune response against intracellular bacteria is cell-mediated immunity (CMI).
On epithelial surfaces, the main antibacterial immune defense of the host is the protection afforded by secretory IgA. Once the epithelial surfaces have been penetrated, however, the major immune defenses of AMI and CMI are encountered.
If there is a way for an organism to successfully bypass or overcome the immune 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 immune defenses of the host, which contribute to the virulence of the microbe and the pathology of the disease.
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 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 to the Ag which may persist even after birth.
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.
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 "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
As already mentioned, 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 Ig 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 immune 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 ability.
The fibronectin coat of Treponema pallidumprovide an immunological disguise for the spirochetes.
In E. coli K1, that causes meningitis in newborns, a capsule composed predominantly of sialic acid provides an antigenic disguise, as does the hyaluronic acid capsule of Streptococcus pyogenes.
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.
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. The most likely explanations for this are due to (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 pathogens inhibit immune responses. It seems probable that it is due to interference with the immune 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 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. 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) are residents of cells that are neither phagocytes nor APC's and their antigens are not displayed on the infected cell's surface.
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.
Examples of some bacterial pathogens that grow at tissue sites generally inaccessible to the forces of AMI and CMI are given below.
-Streptococcus mutans. The bacterium 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 choleraemultiplies 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.
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.
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 avoid forces of the immune response is to periodically changing antigens, i.e., to undergo antigenic variation. Some bacteria avoid the host antibody response by changing from one type of fimbriae 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. Pathogenic bacteria can vary (change) other surface proteins, especially outer membrane proteins, that are the targets of antibodies.
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.
Borrelia recurrentis is a spirochete that causes the human disease relapsing fever. 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 immune 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 immune 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 bacterium appears and a new set of antibodies is formed in the host. Thus, this bacterium can change its antigens during the course of an infection in a single host, and this variation in bacterial antigens contributes significantly to the course of the infection.
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, increases resistance to cervical proteases, increases resistance to phagocytosis and immune lysis, and is presumably necessary for successful infection.
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. Antigenic variation is prevalent among pathogenic viruses as well.
If the immune response is the main 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. Perhaps this explains why many bacteria exist in a great variety of antigenic types.
Evading Complement
Antibodies that are bound to bacterial surfaces will activate complement by the classical pathway and bacterial polysaccharides activate complement by the alternative pathway. Bacteria in serum and other tissues, especially Gram-negative bacteria, need protection from the antimicrobial effects of complement.
One role of capsules in bacterial virulence is to protect the bacteria from complement activation and the ensuing inflammatory response. Polysaccharide capsules can hide bacterial components such as LPS or peptidoglycan which can induce the alternate complement pathway. Some bacterial capsules are able to inhibit formation of the C3b complex on their surfaces, thus avoiding C3b opsonization and subsequent formation of C5b and the membrane attack complex (MAC) on the bacterial cell surface. Capsules that contain sialic acid (a common component of host cell glycoproteins), such as found in Neisseria meningitidis, have this effect.
One of the principal targets of complement on Gram-negative bacteria is LPS. It serves as the attachment site for C3b and triggers the alternative pathway of activation. It also binds C5b.
LPS can be modified by pathogens in two ways that affects its interaction with complement.
First, by attachment of sialic acid residues to the LPS O antigen, a bacterium can prevent the formation of C3 convertase just as capsules that contain sialic acid can do so. Both Neisseria meningitidis and Haemophilus influenzae, which cause bacterial meningitis, are able to covalently attach sialic acid residues to their O antigens resulting in resistance to MAC. Second, LPS with long, intact O antigen side-chains can prevent effective MAC killing. Apparently the MAC complex is held too far from the vulnerable outer membrane to be effective.
Bacteria that are not killed and lysed in serum by the complement MAC are said to be serum resistant. As might be expected many of the Gram-negative bacteria that cause systemic infections, (bacteremia or septicemia) are serum resistant. Gram-positive bacteria are naturally serum-resistant since their cells are not enclosed in an outer membrane.
Other ways that pathogens are able to inhibit the activity of complement is to destroy one or more of the components of complement. Pseudomonas aeruginosa produces an extracellular elastase enzyme that inactivates components of complement.
The following research is the property of StealthDeath. This information has been obtained utilizing standard search engines on documents available to public view on the Internet. However, you may not use this research beyond my postings here as I am claiming copyright to my library of information, which has taken 8 years to assemble. These abstracts, document sections and narration are provided here on FreeConservatives.com for criticism, news reporting, and education as a documentary presentation. Your participation is greatly appreciated and needed to help direct which information will be used to create a DVD presentation exposing fraudulent medical care in America.
Want to see something really scary?
For all those that believe that bacteria cannot routinely stealth, live and travel through the bloodstream to create organ infections, I present the following as a representative summary of hundreds of papers on the topic. This is how a human can be sick and not know it. No elevated white blood counts or fevers are present in many cases. Chlamydia is just one example of a stealth infection that medical dogma refuses to acknowledge as a multi-organ invading organism. They have also failed to recognize the numerous transmission pathways.
If there is a way for an organism to successfully bypass or overcome the immune 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 immune defenses of the host, which contribute to the virulence of the microbe and the pathology of the disease.
Bacteria that are not killed and lysed in serum by the complement MAC are said to be serum resistant. As might be expected many of the Gram-negative bacteria that cause systemic infections, (bacteremia or septicemia) are serum resistant. Gram-positive bacteria are naturally serum-resistant since their cells are not enclosed in an outer membrane.
(MECHANISMS OF BACTERIAL PATHOGENICITY: Bacterial Defense against the Host Immune Responses, 2002 Kenneth Todar University of Wisconsin-Madison Department of Bacteriology)
Serum resistance is a crucial virulence factor for the development<SUP> </SUP>of systemic infections, including bacteraemia, by many pathogenic<SUP> </SUP>bacteria. (Identification of the outer-membrane protein PagC required for the serum resistance phenotype in Salmonella enterica serovar Choleraesuis, Miki Nishio, Nobuhiko Okada, Tsuyoshi Miki, Takeshi Haneda and Hirofumi Danbara, Department of Microbiology, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan )
This textbook has evolved from lectures presented in my bacteriology courses at the University of Wisconsin-Madison. Its contents are suitable for reading or presentation in courses or course modules concerning general microbiology and medical bacteriology at the college and advanced high school levels of education.
Todar's Online Textbook of Bacteriology http://www.textbookofbacteriology.net/ (http://www.textbookofbacteriology.net/)
SEE THIS DOCUMENT BETTER AT: http://textbookofbacteriology.net/antiimmuno.html
Kenneth Todar
University of Wisconsin
Department of Bacteriology
Madison, Wisconsin 53706
MECHANISMS OF BACTERIAL PATHOGENICITY: Bacterial Defense against the Host Immune Responses
2002 Kenneth Todar University of Wisconsin-Madison Department of Bacteriology
Bacterial Mechanisms to Overcome Host Immune Defenses
Antibody-mediated immunity (AMI) is the principal specific immune response effective against extracellular bacteria. The major protective immune response against intracellular bacteria is cell-mediated immunity (CMI).
On epithelial surfaces, the main antibacterial immune defense of the host is the protection afforded by secretory IgA. Once the epithelial surfaces have been penetrated, however, the major immune defenses of AMI and CMI are encountered.
If there is a way for an organism to successfully bypass or overcome the immune 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 immune defenses of the host, which contribute to the virulence of the microbe and the pathology of the disease.
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 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 to the Ag which may persist even after birth.
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.
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 "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
As already mentioned, 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 Ig 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 immune 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 ability.
The fibronectin coat of Treponema pallidumprovide an immunological disguise for the spirochetes.
In E. coli K1, that causes meningitis in newborns, a capsule composed predominantly of sialic acid provides an antigenic disguise, as does the hyaluronic acid capsule of Streptococcus pyogenes.
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.
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. The most likely explanations for this are due to (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 pathogens inhibit immune responses. It seems probable that it is due to interference with the immune 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 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. 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) are residents of cells that are neither phagocytes nor APC's and their antigens are not displayed on the infected cell's surface.
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.
Examples of some bacterial pathogens that grow at tissue sites generally inaccessible to the forces of AMI and CMI are given below.
-Streptococcus mutans. The bacterium 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 choleraemultiplies 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.
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.
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 avoid forces of the immune response is to periodically changing antigens, i.e., to undergo antigenic variation. Some bacteria avoid the host antibody response by changing from one type of fimbriae 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. Pathogenic bacteria can vary (change) other surface proteins, especially outer membrane proteins, that are the targets of antibodies.
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.
Borrelia recurrentis is a spirochete that causes the human disease relapsing fever. 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 immune 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 immune 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 bacterium appears and a new set of antibodies is formed in the host. Thus, this bacterium can change its antigens during the course of an infection in a single host, and this variation in bacterial antigens contributes significantly to the course of the infection.
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, increases resistance to cervical proteases, increases resistance to phagocytosis and immune lysis, and is presumably necessary for successful infection.
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. Antigenic variation is prevalent among pathogenic viruses as well.
If the immune response is the main 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. Perhaps this explains why many bacteria exist in a great variety of antigenic types.
Evading Complement
Antibodies that are bound to bacterial surfaces will activate complement by the classical pathway and bacterial polysaccharides activate complement by the alternative pathway. Bacteria in serum and other tissues, especially Gram-negative bacteria, need protection from the antimicrobial effects of complement.
One role of capsules in bacterial virulence is to protect the bacteria from complement activation and the ensuing inflammatory response. Polysaccharide capsules can hide bacterial components such as LPS or peptidoglycan which can induce the alternate complement pathway. Some bacterial capsules are able to inhibit formation of the C3b complex on their surfaces, thus avoiding C3b opsonization and subsequent formation of C5b and the membrane attack complex (MAC) on the bacterial cell surface. Capsules that contain sialic acid (a common component of host cell glycoproteins), such as found in Neisseria meningitidis, have this effect.
One of the principal targets of complement on Gram-negative bacteria is LPS. It serves as the attachment site for C3b and triggers the alternative pathway of activation. It also binds C5b.
LPS can be modified by pathogens in two ways that affects its interaction with complement.
First, by attachment of sialic acid residues to the LPS O antigen, a bacterium can prevent the formation of C3 convertase just as capsules that contain sialic acid can do so. Both Neisseria meningitidis and Haemophilus influenzae, which cause bacterial meningitis, are able to covalently attach sialic acid residues to their O antigens resulting in resistance to MAC. Second, LPS with long, intact O antigen side-chains can prevent effective MAC killing. Apparently the MAC complex is held too far from the vulnerable outer membrane to be effective.
Bacteria that are not killed and lysed in serum by the complement MAC are said to be serum resistant. As might be expected many of the Gram-negative bacteria that cause systemic infections, (bacteremia or septicemia) are serum resistant. Gram-positive bacteria are naturally serum-resistant since their cells are not enclosed in an outer membrane.
Other ways that pathogens are able to inhibit the activity of complement is to destroy one or more of the components of complement. Pseudomonas aeruginosa produces an extracellular elastase enzyme that inactivates components of complement.