ADHERENCE FACTORS OF NON PATHOGENIC MICROORGANISMS AND...

Details ADHERENCE FACTORS OF NON PATHOGENIC MICROORGANISMS AND... ADHERENCE FACTORS OF NON PATHOGENIC MICROORGANISMS AND...

1998-09-30

2003-01-14

Smith, Lynette R. F. (Department: 1645)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Bacterium or component thereof or substance produced by said...

C424S184100, C424S185100, C424S193100, C536S023100, C536S023500, C435S069100, C435S069700, C435S252100, C435S252300, C435S007100, C435S007200, C530S300000, C530S350000

Reexamination Certificate

active

06506389

ABSTRACT:

SUMMARY OF THE INVENTION
This invention relates to the screening of bacteria, in particular non pathogenic bacteria for those bacteria that can adhere to specific sites of the mucosa called receptors. More specifically the invention is directed at screening of non pathogenic Gram positive bacteria in particular lactic acid bacterial (LAB) species, more in particular bacteria of the genera
Lactobacillus
and
Bifidobacterium
. A preference is expressed for screening bacteria indigenous to farm animals, pets and humans.
The invention comprises a method of screening for a particular group of adherence factors of the non pathogenic bacteria not previously recognised. In particular the adherence factors e.g. of Lactobacilli are of interest. This novel group of adherence factors of non pathogenic bacteria comprises proteins that are structurally related to virulence factors of certain classes of pathogenic microorganisms.
The invention also relates to the application of bacteria obtainable via the screening method of the invention, in particular to Lactobacilli producing said adherence factors, application of the adherence factors as such, application of parts of the bacteria and application of parts of an adherence factor from the novel group for various pharmaceutical applications. Such application may comprise the treatment or prophylaxis of infections of the gastro-intestinal tract, the respiratory tract, urogenital tract, the oral cavity or any other part of the body in particular any internal part of the body that can be colonised by pathogenic microorganisms.
Another suitable example of application comprises the targeting of specific compounds to cells of the mucosa, for example with the aim to evoke a specific mucosal immune response against said compound, or to modulate the immune response.
Novel microorganisms obtainable e.g. through recombinant DNA technology expressing or overexpressing any of the novel adherence factors or effective parts thereof are also included within the invention.
The nucleic acid sequences encoding the adherence factors and fragments of said sequences encoding mucosa binding expression products are also part of the invention as are the recombinant products resulting from expression of said nucleic acid sequences.
Novel pharmaceutical compositions comprising the nucleic acid or expression products thereof or microorganisms expressing or overexpressing an adherence factor of the novel type also fall within the scope of the invention.
BACKGROUND TO THE INVENTION
Pathogenic viruses and bacteria can adhere to specific sites of the mucosa, called receptors and invade the underlying cells via these receptors, resulting in illness or even the death of the host organism. For public and animal health care it is essential that effective and cheap means are available to prevent and/or cure infections diseases in humans and animals.
The mucosa form the porte d'entrée of numerous pathogenic bacteria, for example of Gram negative bacteria of the genera Escherichia, Campylobacter, Haemophilus, Shigella, Vibrio, Pasteurella, Yersinia, Salmonella, Gram positive bacteria like Mycobacterium, Listeria, Clostridium, Staphylococcus and viruses like rotavirus, poliovirus, measles and many other microorganisms well known to a person skilled in the art of microbial infections.
Bacteria of the genus Campylobacter for example can cause severe enteritis in humans and animals after oral ingestion.
C.jejuni
is a major cause of diarrhoea in humans and occasionally in animals. Beside diarrhoea,
C.jejuni
can occasionally also cause appendicitis, meningitis, abortion and urinary tract infection in humans. In developed countries, persons of all ages are affected and Campylobacter infections are as common as infections caused by Salmonella, Shigella or
Vibrio cholerae.
Mycobacteria such as
Mycobacterium tuberculosis
and
Mycobacterium leprae
also cause serious diseases such as tuberculosis and lepra respectively. These bacteria cause the death of many individuals in particular in the less well developed countries. These microorganisms invade the body via the mucosa of the respiratory tract.
Pathogenic microorganisms can adhere to parts of the body e.g. the gastro-intestinal tract, thereby initiating a disease. The studies of the adhesion of pathogenic microorganisms to parts of the body of a host organism have resulted in a wealth of data. From these studies it has become clear that adhesion of pathogenic bacteria can be mediated by proteins. Detailed information is available about proteins from pathogenic bacteria that bind to components of the extra cellular matrix, e.g. collagens, fibronectin or proteoglycans. Particular examples are the mycobacterial fibronectin-binding proteins, the fibronectin- and collagen-binding proteins of Streptococci and Staphylococci. specific enterobacterial fimbrial types, and surface proteins of Yersinias and the A-protein of Aeromonas (for a review, see Westerlund and Korhonen, Mol. Microbiol. 9:687-694 1993).
Information about the adhesion of Gram-positive, non pathogenic bacteria to surfaces of a host organism is more limited, in particular information regarding specific binding of mucosal receptors by non pathogenic microorganisms is scarce.
It is common knowledge that the normal human gastro-intestinal tract is colonized by a variety of non pathogenic microorganisms including bacteria of the genera Lactobacillus, Streptococcus, Enterococcus, Bifidobacterium, Clostridium, Bacteroides, and others. These microorganisms form part of the indigenous microflora of the human being. As such considerable interest has been directed to elucidating the mechanisms of adherence and the role of adhesion in gastro-intestinal colonisation. However the mechanisms of adhesion of LAB, a well examined group of non pathogenic bacteria present in gut microflora of humans and animals are in general more complex than those of the gastro-intestinal pathogens (Hasty et al. Infect. Immun. 60:2147-2152 1992).
Adhesion of non-pathogenic bacteria may be specific or aspecific. Hydrophobic and electrostatic adhesion mechanisms are involved in non-specific adhesion. Specific adhesion is characterized by a so-called “lock-and key mechanism”, in which the adherence factor binds to a specific receptor. Specific adhesion is usually associated with the adhesion of microorganisms to receptors on living tissues. Adherence factors or adhesins are, in general, surface bound molecules. The adhesin can be firmly attached to the surface of the bacterium or loosely bound. The receptor is a component or structure on the surface of the cell where the bacterium will bind by an active site of the adhesin (Rutter et al, 1984 Mechanisms of adhesion in “Microbial adhesion and aggregation” Marshall. K. C. ed, pp 5-19, Springer-Verlag, Berlin).
Lactic acid bacteria, particularly Lactobacillus and Enterococcus, are examples of non pathogenic Gram-positive bacteria that play a key role in the establishment and maintenance of the microflora of the gastro-intestinal tract of man and animals. Lactobacillus species have been isolated from various regions of the human gastro-intestinal tract (Molin et al, J. Appl. Bacteriol. 74, 314-323 1993).
The determinants supposedly responsible for the adhesion of some strains have been studied, and certain structures are reported to be involved in the mechanism of adhesion. However, because of the complexity of the intestinal ecosystem, little is known about why and how certain bacterial strains adhere to and colonize specific regions of the gastro-intestinal tract.
There is indeed great confusion in the literature about the mechanisms of adhesion of Lactobacilli to the gastro-intestinal mucosa. Fuller described the adhesion of Lactobacillus to chicken crop epithelium and concluded that the adhesion was mediated by polysaccharides (Fuller, J. Gen Microbiol. 87:245-250 1975). However, Conway and Adams (J. Gen. Microbiol. 135:1167-1173 1989), who found no evidence for a role of polysaccharides in the adhesion of lactobacilli, suggested that other component

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