Chemistry: molecular biology and microbiology – Vector – per se
Reexamination Certificate
1999-08-31
2003-10-21
McGarry, Sean (Department: 1635)
Chemistry: molecular biology and microbiology
Vector, per se
C536S023100, C536S023400, C536S023200, C536S024300, C536S024320, C435S325000, C435S252300
Reexamination Certificate
active
06635473
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the fields of microbiology and molecular biology and more particularly is in the field of biological products for the prevention, treatment or diagnosis of coagulase negative staphylococcal infections in man and animals.
BACKGROUND OF THE INVENTION
Staphylococci are Gram-positive spherical cells, usually arranged in grape-like irregular clusters. Some are members of the normal flora of the skin and mucous membranes of humans, others cause suppuration, abscess formation, a variety of pyogenic infections, and even fatal septicemia. Pathogenic staphylococci often hemolyze blood, coagulate plasma, and produce a variety of extracellular enzymes and toxins. The most common type of food poisoning is caused by a heat-stable staphylococcal enterotoxin. The genus Staphylococcus has at least 30 species. The three main species of clinical importance are
Staphylococcus aureus, Staphylococcus epidermidis
, and
Staphylococcus saprophyticus. Staphylococcus aureus
is coagulase-positive, which differentiates it from the other species.
S. aureus
is a major pathogen for humans. Almost every person has some type of
S. aureus
infection during a lifetime, ranging in severity from food poisoning or minor skin infections to severe life-threatening infections.
The coagulase-negative staphylococci are normal human flora which sometimes cause infection, often associated with implanted devices especially in very young, old and immunocompromised patients. Approximately 75% of the infections caused by coagulase-negative staphylococci are due to
S. epidermidis
. Infections due to
Staphylococcus warneri, Staphylococcus hominis
, and other species are less common.
S. saprophyticus
is a relatively common cause of urinary tract infections in young women. The staphylococci produce catalase, which differentiates them from the streptococci.
Both
Staphylococcus aureus
and
Staphylococcus epidermidis
have a characteristic propensity for invading skin and adjacent tissues at the site of prosthetic medical devices, including intravascular catheters, cerebrospinal fluid shunts, hemodialysis shunts, vascular grafts, and extended wear contact lenses. Within 48 to 72 hours, relatively large numbers of staphylococci are demonstrable at the site of insertion of these foreign bodies. (Archer, G. L., in Remington, J. S., et al., Current Clinical Topics in Infectious Diseases, McGraw-Hill, New York, 25-46, 1986.)
Staphylococcus epidermidis
is a generally avirulent commensal organism of the human skin, and is the principal etiologic agent of infections of peripheral and central venous catheters, prosthetic heart valves, artificial joints, and other prosthetic devices. It has been demonstrated that
S. epidermidis
cells attach and proliferate on the inner or outer surfaces of catheters, irrespective of their composition—whether polyethylene, polyvinylchloride, polyvinylfluoride or polyester based.
Initial localized infections of indwelling medical devices can lead to more serious invasive infections such as septicemia, osteomyelitis, and endocarditis. Vascular catheters are thought to become infected when microorganisms gain access to the device, and hence the bloodstream, by migration from the skin surface down the transcutaneous portion of the catheter. In infections associated with medical devices, plastic and metal surfaces become coated with host plasma and matrix proteins such as fibrinogen, vitronectin and fibronectin shortly after implantation.
S. epidermidis
bacteremia can result in an excess hospital stay of 8 days, which is quite expensive.
Although the virulence of coagulase-negative staphylococci is enhanced in the presence of a foreign body, the microbial factors that permit these normal skin commensals to become nosocomial pathogens have not been well characterized. The ability of coagulase-negative
S. epidermidis
to adhere to these proteins is of crucial importance for initiating infection. As adherence is believed to be the critical first step in the pathogenesis of coagulase-negative staphylococcal foreign-body infections, attention has focused on surface properties of these organisms that might mediate adherence to, and then colonization of, polymeric prosthetic materials.
A number of factors influence an organism's ability to adhere to prosthetic material. These include characteristics of the microorganism and the biomaterial, and the nature of the surrounding environment. The initial attraction between the organism and the host is influenced by nonspecific forces such as surface charge, polarity, Van der Waal forces and hydrophobic interactions. The critical stage of adherence involves specific interactions between cell surface adhesins and immobilized host proteins. To date, investigation concerning the adherence of
S. epidermidis
to biomaterials has concerned itself primarily with the role of the extracellular polysaccharide or glycocalyx, also known as slime. Despite intensive study, however, the proposed role of slime in the pathogenesis of disease or even its composition remain debated. (Drewry et al.,
Clin. Microbiol
28:1292-1296, 1990) Currently, extracellular slime is thought to play a role in the later stages of adherence and persistence of infection. It may serve as an ion exchange resin to optimize a local nutritional environment, prevent penetration of antibiotics into the macro-colony or protect bacteria from phagocytic host defense cells. Peters et al. have shown by electron microscopy studies that extracellular polysaccharide appears in the later stages of attachment and is not present during the initial phase of adherence. (
J. Infect. Dis
., 65146:479-482, 1982) Hogt et al. demonstrated that removal of the extracellular slime layer by repeated washing does not diminish the ability of
S. epidermidis
to adhere to biomaterials. (
J. Gen. Microbiol
. 129:2959-2968, 1983)
Thus far, study of exopolysaccharide has lent little to prevention of initial adherence by the bacteria. Several other studies have identified other potential adhesins of
S. epidermidis
including the polysaccharide adhesin (PS/A) observed by Tojo et al. (
J. Infect. Dis
. 157:713-722, 1988) and the slime associated antigen (SAA) of Christensen et al. (
Infect Immun
, 58:2906-2911, 1990).
It has been demonstrated that PS/A is a complex mixture of monosaccharide adhesins which blocks adherence of PS/A producing strains of
S. epidermidis
. In an animal model of endocarditis antibodies directed against PS/A were protective. However, it is not clear whether this protective effect was specific, related to anti-adhesive effects of the antibody or due to a more generalized increase in the efficiency of opsonophagocytosis of blood borne bacteria. It has been hypothesized that each adhesin functions in different stages of the adherence process with one or more of these adhesins responsible for initial attraction while others are needed for aggregation in the macro-colonies.
Despite many studies, factors involved in the initial adherence of
S. epidermidis
to biomaterials remain largely unknown. Further unknown is a practical method for preventing the first stage of infection, adherence or adhesion. Therefore, a great need remains for the discovery and characterization of bacterial adhesin proteins and the genes that encode them.
Accordingly, it is an object of the present invention to provide cell-wall associated extracellular matrix binding proteins of coagulase-negative staphylococci.
It is a further object of the present invention to provide coagulase-negative staphylococcal surface proteins that are able to inhibit staphylococcal adhesion to the immobilized extracellular matrix or host cells present on the surface of implanted biomaterials.
It is a further object of the present invention to provide a coagulase-negative staphylococci vaccine, to generate antisera and antibodies to coagulase-negative staphylococcal proteins, and to isolate antibodies to coagulase-negative staphylococci.
It is a further object of the present invention to provide improve
Davis Stacy
Foster Timothy J.
Hartford Orla
Hook Magnus A. O.
McCrea Kirk
Larson & Taylor PLC
McGarry Sean
The Provost Fellows and Scholars of the College of the Holy and
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