Drug-resistant micro-organisms continue to emerge and the number of patients susceptible to these infections is increasing dramatically. Consequently, any technologies and insights that utilize the innate powers of the immune system as a therapeutic agent will have the greatest benefit to sick patients. New scientific findings demonstrate that it is possible to employ molecular strategies that can strengthen the immune response to a given antigen or to direct it to combat an overlooked, hidden, or treatment-resistant foe. The complexity of the immune system with its abundance of compounds and molecular strategies can forge medical innovation and help practitioners to develop therapies that might combat maladies ranging from pneumonia that repeatedly afflicts people with cystic fibrosis to deep and silent infections that promote pain and inflammation in arthritic disorders. Improvement in pharmaceutical and nutraceutical delivery systems is of key importance now and in the future.
While the power and flexibility of the immune system against infection is remarkable, intracellular bacterial parasites, Chlamydia (Chlamydia trachomatis, Chlamydia psittaci and Chlamydia pneumonia) that proliferate within host cells and in the bone, gall bladder and sinus cavities are difficult for the immune system to conquer. In many cases, it seems to expend all its energy engaging in endless microbial warfare without ever completely winning the battle. The tremendous diversity and mutability of many infections and their ability to intelligently exploit the cells and interactions of the immune system to propagate themselves, is the main focus of this column. Why? Because infections of this nature are the most prevalent infections facing humans and are of serious concern in immunodeficient patients as they relentlessly produce endotoxins that activate prolonged inflammation and tissue damage in the organism. Unraveling the signals that cause these infections to proliferate will require that clinicians learn natural and safe ways to strengthen innate responses to invading microbes, mitigate the damage that immune cells do to the body, and correct or eliminate nutritional deficiencies that cause immunological unresponsiveness.
This column will focus primarily on biofilms, Chlamydia pasittaci and Chlamydia pneumonia as primary pathogens in the genesis of many high profile diseases. Chlamydia enters into cells via abnormalities of key cell membrane receptors, and settles down into anaerobic tissue sites as a mucous-like and sticky matrix where it aggregates, communicates, and constructs slimy edifices called biofilms. (1-7) Because biofilms resonate harmoniously and consist of a dense symbiotic aggregation of microbes embedded in a highly hydrated polymer, polysaccharide matrix of its own secretion, they often end up in the cornea, tonsils, wounds, nasopharynx, middle ear, prostate and urinary tract, teeth (under root canals, fillings, implants, or as chronic bacterial ostitis in extraction sites), dental plaque, oral soft tissues, gall bladder, GI epithelium, heart (endocarditis) and lungs, making them notoriously difficult to treat. Their anti-microbial resistance coupled with the inaccuracy of current lab tests to diagnose hidden biofilms and intracellular infections makes biofilms the greatest clinical challenge facing doctors today. (8-13)
Bacterial biofims are ubiquitous--dental plaque (which confront us daily) and the slime that grows inside a flower vase after two or three days are common examples. The biofilm concept of chronic infections explains a phenomenon that has troubled clinicians for some time: blood cultures from patients who show many signs of overt bacterial infection are often negative. According to Dr. J.W. Costerton, of the Center for Biofilm Engineering at Montana State University "biofilms are in all of the chronic infections examined in the 12 years during which this morphological series was pursued." He further states "When the model used to analyze a natural process is incorrect, our attempts to understand and manipulate the process will fail, many honest and conscientious people will be frustrated, and the reputations of whole research groups will be damaged. In the case of chronic bacterial diseases, diagnostic microbiology labs reported that cultures of Pseudomonas aeruginosa from Cystic Fibrosis (CF) patients were sensitive to antibiotics (e.g., cloxacillin), but pulmonary clinicians saw little improvement when these antibiotics were used. The sera of CF patients contained very large amounts of specific antibodies against Pseudomonas, but the disease persisted, and the use of anti-Pseudomonas vaccines resulted in the deaths of some patients. Middle ear specimens from children with chronic otitis media with effusion (COME) yielded negative bacterial cultures, so that a host-sustained inflammatory etiology was suspected, but the factors driving the inflammation could not be identified and serology did not confirm the persistent involvement of viruses. Patients with raging febrile prostate infections yielded expressed prostatic secretion (EPS) samples that produced cultures negative for bacteria, and material recovered from osteomyelitis debridations with frank pus yielded only a few colonies of skin and environmental organisms. All was shadows and fog, and the reputations of the microbiology units of many hospitals plummeted from the high levels they had attained earlier." (14)
Biofilms have material properties similar to those of a viscous fluid and micro-colonies are deformable as they oscillate in high-shear systems, breaking off and detaching as biofilm fragments that spread into different areas of the body. (15,16) Biofilm-related infections are involved in the deterioration of gums and jawbone that eventually leads to loss of teeth (periodontal disease); ear infections in the outer ear canal, middle and inner ear, stubborn sinus infections, and chronic gall bladder and cardiac infections. In addition, root canal teeth and dental implants often become colonized by Chlamydia creating a slow developing but persistent infection that often lingers for years. In most cases, we have found that the infection is extremely difficult to diagnose and eradicate.
Even in the healthy immune system, the unleashing of its magnificent and diverse arsenal of antimicrobial agents fails to conquer biofilms and intracellular Chlamydia. Likewise, even long-term treatment with one antibiotic after another, infections persist. Our research has begun to shed light on the mechanisms of biofilm resistance to antimicrobial agents. The primary problem is the inability of the antimicrobial agent to fully penetrate the biofilm leaving bacteria to exist in a protected state as they mutate and adopt a distinct and intrinsically resistant phenotype. Mutational aberrations may contribute to altered infectivity and changes in the amino acid signature patterns of Chlamydia, although additional studies will be required to address these issues.
Understanding Biofilm Resistance
A biofilm's exceptional resistance stems from several characteristics:
1. As they activate specialized resistance genes, bacteria in biofilms benefit from pooling their efforts. Colonies of bacteria can produce enzymes to inactivate the antiseptic hydrogen peroxide and allow other immune-fighting compounds (molecules and cells that the immune system unleashes) to be evaded. Microorganisms that attach to a surface turn on new genes, turn off others, and embark on a developmental path that is completely different from that taken by microbes growing in traditional suspended cultures. Moreover, the wide range of conditions present in a biofilm permit several bacterial species to live side by side and thrive as one species feeds off the metabolic wastes of another, aiding them both.
2. Dormant cells don't participate in the activity; they aren't usually vulnerable to drugs (although these bacteria don't actively contribute to the growing colony, they can weather the catastrophe of antibiotic treatment and quickly renew the biofilm afterward as competition from other microbes are decreased).
3. The interior of the biofilm offers a shelter from antibiotics (it harbors little oxygen, which some antibiotics need to work) and anti-microbial herbs (molecular structure is too large to penetrate or dissolve a biofilm). The diversity of bacteria in a biofilm can occupy a spectrum of physiological states, from rapidly growing to dormant.
4. Overburdening of the liver's detoxification mechanism with stressors (chemicals, dysbiotic bowels, mycotoxins, heavy metals, parasites, mycoplasma and herpetic infections, etc) causes biofilms to enter the gall bladder and damage the sphincter of oddi causing chronic duodenitis, the primary cause of maldigestion, malnourishment and inefficient liver detoxification, weakening the immune system even more. (17,18) To make matters worse, electron micrographs with laser scanning confocal microscopy document that biofims manufacture stones--"calculi" in the gall bladder and kidneys. (19,20)
5. Undiagnosed dental foci from old root canals, extraction sites, implants, cracked fillings, periodontal pockets allow bioflims to proliferate and spread into the sinus cavities, heart and gall bladder. Moreover, cells that detach from biofilms end up growing on native heart valves (resulting in endocarditis) and they usually circulate until they block or jam a capillary bed causing profound damage if they detach and find their way to critical loci in the lungs or in the brain. (17,18,42,43)
Understanding Effective Treatment Strategies
While the immune system can mop up free-floating bacteria in the blood, it has difficulty reaching bacteria in biofilms. In most cases, doctors resort to the overuse of antibiotics, but bacteria in biofilms clearly react differently than lone bacterial cells do to these assaults and all this treatment accomplishes is to allow the biofilm bacteria to flourish and gain resistance as the antibiotic eliminates susceptible cells and bacteria. Effective treatment should consist of strategies that:
1. Penetrate the biofilm. New biomolecular technologies developed by the author allow for the micronization (less than one hundredth of a millimeter) and concentration (100:1 to 600:1) of phytochemicals and anti-microbial herbs hold great promise for the eradication of biofilms. Understanding the diffusion methods of nutrients into biofilms and the mix of metabolic states at different layers of a biofilm, provide a methodology for the effective biomolecular penetration of anti-biofilm, antibacterial, antibiotic, antimycotic, antimicrobial, and antiviral phytochemical compounds deep into biofilms, thereby allowing them to dissolve and be eliminated. (21-26)
2. Remove all stressors. Stressors that overload and weaken the immune system must be eliminated. Most importantly, clinicians must remove interferences (dental foci, implants, etc) and define and weed out stressors (chemicals, overburdened detoxification functions, dysbiotic bowels, mycotoxins, heavy metals, mycoplasma and herpetic infections, etc). (27,28)
3. Disrupt the bacterial exchange of intercellular signals (analogous to hormones) that are important in mediating the formation of the complex architecture of natural biofilms. The recognition that biofilm formation is a biologically regulated process is an insight that carries profound medical significance because it envisions the use of phytomedicines as new therapeutic targets. Phytomedicines--concentrated from 100:1 to 600:1--break up biofilm infections. When micronized, phytomedicines can interfere with the biofilm developmental process so that the immune system can quickly conquer the infection. (4-7)
4. Optimize the immunological synapse to prevent Chlamydia entry into cells or attachment to biofilm sites. Without delving into the complexities of receptor dynamics and intracellular trafficking, cells communicate with their environment through membrane receptors, which recognize molecules and particles in the extracellular matrix, and gate them in or out of the cell. Our research has focused on the entry and intracellular traffic of Chlamydia due to specific biochemical imbalances. Receptors on lymphocytes (T lymphocyte antigen receptor and the receptors of a cytokine, the interleukin 2) are essential for the immune response. As an intracellular parasite, the entry of Chlamydia into the host cell, in particular by epithelial cells, determines its impact and resultant threat to human health. For an optimal immunological synapse, the cell membrane protein ezrin and the T cell antigen receptor should be polarized towards the antigen presenting cell contact site upon antigen recognition. In turn, polarized endocytic vesicles are transported to the cell-cell contact site and this transport facilitates the accumulation at the immunological synapse of membrane receptors that undergo cycles of endocytosis and recycling. However, when erzin has a negative charge due to an aspartic acid deficiency or is mutated, Protein Kinase C, a key signaling molecule for T cell activation that also translocates to the immunological synapse, is diminished, reducing T cell activation. Our preliminary findings indicate that correcting an aspartic acid deficiency while maintaining an adequate daily dose of the histamine-GLA-zinc complex to counter unwanted inflammation, (29,30) may help normalize the polarity of ezrin and thus provide a link between membrane and actin cytoskeleton components that helps proper molecular clustering at the immunological synapse and T cell activation. (6,32-42)
In summary, sophisticated tools of microbiology reveal that chronic diseases involve pathogenic mechanisms demonstrating unequivocally that bacterial biofilms are both present and metabolically active, even when bacteria cultures are negative. Biofilms force victims to submit to the abuse and overuse of antibiotics for the remainder of their lives. (45) The fact that chronic infections commonly grow in biofilms goes some distance toward explaining the perceived anomalies of many diseases, and offers a measure of hope that they can eventually be controlled.
Successful clinical treatment and reduction of tenacious biofilm stressors requires the development of new agents to control biofilm infections by interfering with the biofilm developmental process thereby allowing the immune response to naturally conquer the microbial threat of Chlamydia and other symbiotic infections. In some cases, an implant must be removed, a procedure that is often costly, dangerous, and traumatic for the patient.
A hallmark of all biofilm diseases is the chronic nature of the infections as infections linger for months, years, or even a lifetime as it compromises the quality of life and exhausts the immune system. With new exciting insights about biofilms and how Chlamydia enters cells, it becomes plausible that solutions to prolonged inflammation (commonly due to bacterial endotoxins) will be found. Since swollen and inflamed tissue allows biofilms to proliferate and block the immune system from fighting infection, it makes sense to find natural ways to diminish unwanted inflammation. (29-31)
In retrospect, it is astonishing that medicine has overlooked biofilms and has not used the elegant weapons of the plant kingdom in appropriate biomolecular concentrates to disrupt the microcolonies of bacteria that underlie biofilms.
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Proof of Mycoplasma infection via vaccines?
Verkooyen RP; Sijmons M; Fries E; Van Belkum A; Verbrugh HA Widely used, commercially available Chlamydia pneumoniae antigen contaminated with mycoplasma. J Med Microbiol 46: 419-24 (1997)
by Paul Yanick, Jr., PhD [c]2004
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