Microbiological Aspects of S. aureus Infections
Staphylococci are gram-positive bacteria represented by more than a dozen species ranging from those indigenous to normal flora of the skin, and mucosal surfaces, to highly virulent pathogens. Among the many staphylococci species, S. aureus is among the most common and most virulent forms of staphylococci encountered throughout history, from the pre-antibiotic era to the present time.
Staphylococcal infections are characterized by intense suppuration, necrosis of local tissues, and a tendency for the infected area to form "walled off" abscesses. S. aureus can cause skin infections (furuncles, carbuncles, and impetigo) as well as deep lesions from bacteria spread from skin lesions (bones, joints, soft tissues, and deep organs). S. aureus is also a major cause of wound infections. Surgical wound infections may be very severe and even fatal at times. S. aureus can produce various toxins causing scalded skin syndrome, toxic shock syndrome, and staphylococcal food poisoning.
Treatments of staphylococcal infections with antibiotics were originally very successful. However, after many years use of beta-lactam antibiotics, S. aureus became resistant to many classes of antibiotics. MRSA strains manifest increasing prevalence in hospital-acquired infections as well as in nosocomial and community-onset infections. Vancomycin, as the "last resort" antibiotic, is still effective but reports on emergence of VISA indicate that this situation is changing rather rapidly. Antibiotic resistance in a bacterium is usually conferred by plasmid-encoded genes, and as such, resistance genes can be transferred to antibiotic-susceptible strains from reservoir strains containing these resistance genes.
According to a July 13, 2005 Wall Street Journal article, a Pennsylvania state agency conducted a study regarding hospital-acquired infections. The article indicated that the “…agency has found that 11,668 hospital-acquired infections were associated with 1,793 deaths, 205,000 extra hospital days and $2 billion in additional hospital charges last year”. The article goes on to say, “Extrapolating from the Pennsylvania data to the rest of the country suggests that more than 125 people a day are dying from hospital-acquired infections with an associated $50 billion of related hospital charges every year…”
Most community-acquired infections of S. aureus are autoinfections, with strains being carried in the anterior nares or on the skin. Hospital epidemics, on the other hand, are caused by highly virulent and antibiotic-resistant strains of S. aureus associated with patients undergoing invasive treatments. These epidemics are a continuing and recurrent problem. S. aureus strains produce a variety of substances that may contribute to their virulence. The most important factors include alpha-hemolysin, pyrogenic exfoliatins, coagulase, protein A, and other extracellular enzymatically active substances.
Although a variety of phenotypes and products appear to contribute to S. aureus virulence, no one factor can be singled out as the primary contributor to its ability to multiply and cause lesions in the tissues. Therefore, a single candidate for an effective immunization appears unlikely. Natural immunity to staphylococcal infections is of short duration and incomplete, although involving both humoral and cellular mechanisms. Obviously, a different approach to vaccination is in order.
Based on years of research and development in Europe, a novel preventative and therapeutical approach has been developed by ImmLab. This approach is based on use of a broad-range of antigens derived from staphylococcal cells.
Immunity to Staphylococcal Infections
Resistance of human organism against bacterial pathogens involves both innate and adaptive immunity. Innate immunity provides mechanisms for immediate protection against a wide variety of pathogens.
a pattern recognition system for the pathogens
activation of effector mechanisms quickly destroying the pathogens
pathways that can activate adaptive immunity
Adaptive immunity provides responses to persistent pathogens, and has both humoral and cellular components. Innate response to pathogens initiates, controls and instructs the adaptive immune response. In order to establish a persistent infection, bacterial pathogens posses a plethora of mechanisms (so called virulence factors) to overcome the multi-layered host defenses.
S. aureus is a human and animal pathogen with many virulence factors described. It targets native or adaptive immune responses. S. aureus has several mechanisms that allow the pathogen to prevent, or even hijack, this response to its advantage. Not only can the bacteria develop a resistance against antimicrobial proteins, they can also survive inside neutrophils. This is likely an important factor in persistent infections. In addition, various strains of S. aureus may posses some of the battery of toxins and enzymes and other products that enhance infectivity and bacterial survival and proliferation. Here, a combination of host’s cellular and humoral mechanisms comes into place. Antibodies specific against toxins and enzymes and other soluble products neutralize their activities while antibodies specific against cells and cellular components opsonize the targeted cells and enhance their phagocytosis. It thus seems very plausible to speculate that, in patients with chronic S. aureus infections, one or more defense pathways may not be activated or functional.
In summary, ImmLab’s scientists found that long-term application of SL activates the host’s immune responses and leads, in a high percentage of patients with chronic S. aureus infection, to the clearance of the pathogen or at least to a significant improvement. The SL are prepared from selected S. aureus strains that are lyzed by selected bacteriophages. The resultant lyzate is thus a solution of S. aureus antigens in relatively native conformations. Our hypothesis is that SL induces several innate and adaptive immune responses through multiple mechanisms.
Ultimately, the combined action of antibodies, cytokines, activated cells, and increased capacity for respiratory burst produces a milieu for the clearance of chronic infections. Furthermore, in some specific applications, such as local treatment of wound infections, the direct bacteriolytic activity of bacteriophages may also play an important role. The above general information has been respectfully submitted by ImmLab for the consideration of interested parties. Further, more specific, discussion of ImmLab’s inventions and plans may continue upon receipt of a properly executed confidentiality agreement.
ImmLab’s Progress to Date
ImmLab’s technological accomplishments are based on approximately forty years of research and testing. The research and testing has continued for all these years, primarily as a result of the unwavering determination and persistence of the scientist who originated the mission and unconditionally transferred the technology to ImmLab.
The following summarizes briefly our progress to date:
The tremendous need is undeniable.
The viability of the mission has been established.
The huge, worldwide market is recognized.
Our initial patents have has been granted.
The application process for additional patents continues.
The current testing and patent process includes:
o Mode of action
The team of scientists (including the original inventor), physicians and various associates continue to work tirelessly.
The products are ready for manufacture.
The manufacturing process is relatively simple and economical. In April, 2001 ImmLab’s patent attorney, along with her associates and her entire firm, committed to help ImmLab accomplish its mission. The firm has, and will continue to insure that the investment in the mission is protected by a sound intellectual property strategy.
Staphylococcal Lysate (SL) is prepared by lysis of S. aureus culture with a polyvalent bacteriophage. Staphylococcal phages belong mostly to the Siphoviridae family, e.g., phages with double-stranded linear DNA and with long noncontractile tails. SL is a complex of antigenic components of ribosomal, cytoplasmic, nuclear, cell wall, and membranous origin of the staphylococcal cell.
SL has been clinically effective in the treatment of all staphylococcal infections of adults, as well as chronic conditions in pediatrics (chronic upper respiratory diseases, bronchial asthma, chronic sinusitis, cystic fibrosis) and in dermatology (acne vulgaris).
ImmLab staphylococcal vaccines are created by introducing the genome of the staphylococcal bacteriophage into the staphylococcal cell, resulting in the production of highly immunogenic vaccine comprised of all staphylococcal proteins and cell-wall components.
In the animal experiments, SL is protective in the murine septic model against lethal and sublethal challenges using laboratory and field strains of S. aureus. The animal models show vigorous immune responses in all tested species (rabbits, rats, mice, and calves). SL is administered subcutaneously (s.c.), intramasculary (i.m.) in veterinary medicine, or in nasal drops (pediatrics). It can be applied directly into wounds in osteomyelitis as an addition to s.c. therapy. Laboratory data suggested that the clinical improvement of patients (observed in 70-90% of cases) may be related to stimulation of peripheral blood mononuclear cells and induction of metabolic burst in phagocytes.
Stable, tested and effective staphylococcal vaccines
Immunology Laboratories, Inc.
Stimulation of the Human and Animal Immune System with the Staphylococcal Lysate
Based on the accumulated literature data, as well as our experimental evidence, we (ImmLab) propose a hypothesis that explains immunostimulatory mechanisms of SL. The lysate is prepared, as mentioned above, by the activity of lytic phages producing two key proteins:
holins, forming pores in the cell wall allowing access of the second component
enzyme(s), catalyzing degradation of cell wall yielding smaller peptidoglycans
As a result, the whole staphylococcal cell finally bursts open and extrudes bacteriophage particles. This is a very gentle procedure of cell lysis yielding a complex mixture of proteins, lipids, lipoproteins, lipoteichoic acids, peptidoglycans, DNA fragments, etc. We propose that these compounds in their native or modified configuration are recognized by the pattern recognition system and, by complex pathways, induce innate response and stimulate adaptive immune response.
In the end, the host’s immune system (originally not responding or hyporesponding to a chronic staphylococcal infection) is re-activated and capable of detecting and destroying the pathogens. This model is supported by our findings on stimulation of circulatory cells in healthy human volunteers. The whole blood stimulated with SL responds by increased production of TNF alpha. SL activates CD4+ lymphocytes and increases their production of interpheron gamma. In phagocytes, the respiratory burst is increased. Together with induction of antigen-specific antibodies, all these factors promote clearance of S. aureus infections.
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