Host cells for expression of clostridial toxins and proteins

Details Host cells for expression of clostridial toxins and proteins Host cells for expression of clostridial toxins and proteins

1998-08-28

2001-04-10

Pak, Michael (Department: 1647)

Chemistry: molecular biology and microbiology

Micro-organism, per se ; compositions thereof; proces of...

Bacteria or actinomycetales; media therefor

C435S325000

Reexamination Certificate

active

06214602

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the overproduction of Clostridium toxins and proteins by hosts such as
E. coli
. These proteins and toxins find use in various medical and veterinary applications, including vaccine production, as well as treatment of neurological and other diseases and conditions.
BACKGROUND OF THE INVENTION
The genus Clostridium is comprised of gram-positive, anaerobic, spore-forming bacilli. The natural habitat of these organisms is the environment and the intestinal tracts of humans and other animals. Indeed, clostridia are ubiquitous; they are commonly found in soil, dust, sewage, marine sediments, decaying vegetation, and mud. (See e.g., Sneath et al., “Clostridium,” Bergey's
Manual® of Systematic Bacteriology
, Vol. 2, pp. 1141-1200, Williams & Wilkins [1986]). Despite the identification of approximately 100 species of Clostridium, only a small number have been recognized as etiologic agents of medical and veterinary importance. Nonetheless, these species are associated with very serious diseases, including botulism, tetanus, anaerobic cellulitis, gas gangrene, bacteremia, pseudomembranous colitis, and clostridial gastroenteritis. Table 1 lists some of the species of medical and veterinary importance and the diseases with which they are associated. As virtually all of these species have been isolated from fecal samples of apparently healthy persons, some of these isolates may be transient, rather than permanent residents of the colonic flora.
TABLE 1
Clostridium
Species Of Medical And Veterinary Importance*
Species
Disease
C. aminovalericum
Bacteriuria (pregnant women)
C. argentinese
Infected wounds; Bacteremia; Botulism;
Infections of amniotic fluid
C. baratii
Infected war wounds; Peritonitis;
Infectious processes of the eye, ear and
prostate
C. beijerinckikii
Infected wounds
C. bifermentans
Infected wounds; Abscesses;
Gas Gangrene; Bacteremia
C. botulinum
Food poisoning; Botulism (wound, food,
infant)
C. butyricum
Urinary tract, lower respiratory tract,
pleural cavity, and abdominal infections;
Infected wounds; Abscesses; Bacteremia
C. cadaveris
Abscesses; Infected wounds
C. carnis
Soft tissue infections; Bacteremia
C. chauvoei
Blackleg
C. clostridioforme
Abdominal, cervical, scrotal, pleural,
and other infections;
Septicemia; Peritonitis; Appendicitis
C. cochlearium
Isolated from human disease processes,
but role in disease unknown.
C. difficile
Antimicrobial-associated diarrhea;
Pseudomembranous enterocolitis;
Bacteremia; Pyogenic infections
C. fallax
Soft tissue infections
C. ghnoii
Soft tissue infections
C. glycolicum
Wound infections; Abscesses; Peritonitis
C. hastiforme
Infected war wounds; Bacteremia; Abscesses
C. histolyticum
Infected war wounds; Gas gangrene;
Gingival plaque isolate
C. indolis
Gastrointestinal tract infections
C. innocuum
Gastrointestinal tract infections; Empyema
C. irregulare
Penile lesions
C. leptum
Isolated from human disease processes,
but role in disease unknown.
C. limosum
Bacteremia; Peritonitis; Pulmonary infections
C. malenominatum
Various infectious processes
C. novyi
Infected wounds; Gas gangrene; Blackleg,
Big head (ovine);
Redwater disease (bovine)
C. oroticum
Urinary tract infections; Rectal abscesses.
C. paraputrificum
Bacteremia; Peritonitis; Infected wounds;
Appendicitis
C. perfringens
Gas gangrene; Anaerobic cellulitis;
Intra-abdominal abscesses;
Soft tissue infections; Food poisoning;
Necrotizing pneumonia; Empyema;
Meningitis; Bacteremia; Uterine Infections;
Enteritis necrotans; Lamb dysentery; Struck;
Ovine Enterotoxemia;
C. putrefaciens
Bacteriuria (Pregnant women with
bacteremia)
C. putrificum
Abscesses; Infected wounds; Bacteremia
C. ramosum
Infections of the abdominal cavity, genital
tract, lung, and biliary tract; Bacteremia
C. sartagoforme
Isolated from human disease processes,
but role in disease unknown.
C. septicum
Gas gangrene; Bacteremia; Suppurative
infections; Necrotizing enterocolitis; Braxy
C. sordellii
Gas gangrene; Wound infections; Penile
lesions; Bacteremia; Abscesses;
Abdominal and vaginal infections
C. sphenoides
Appendicitis; Bacteremia; Bone and soft
tissue infections; Intraperitoneal infections;
Infected war wounds; Visceral gas gangrene;
Renal abscesses
C. sporogenes
Gas gangrene; Bacteremia; Endocarditis;
central nervous system and pleuropulmonary
infections; Penile lesions; Infected war
wounds; Other pyogenic infections
C. subterminale
Bacteremia; Empyema; Biliary tract, soft
tissue and bone infections
C. symbiosum
Liver abscesses; Bacteremia; Infections
resulting due to bowel flora
C. tertium
Gas gangrene; Appendicitis; Brain abscesses;
Intestinal tract and soft tissue infections;
Infected war wounds; Periodontitis;
Bacteremia
C. tetani
Tetanus; Infected gums and teeth; Corneal
ulcerations; Mastoid and middle ear
infections; Intraperitoneal infections; Tetanus
neonatorum; Postpartum uterine infections;
Soft tissue infections, especially related
to trauma (including abrasions and
lacerations); Infections related to use of
contaminated needles
C. thermosaccharolyticum
Isolated from human disease processes,
but role in disease unknown.
*Compiled from Engelkirk et al. “Classification”, Principles and Practice of Clinical Anaerobic Bacteriology, pp. 22-23, Star Publishing Co., Belmont, CA (1992);
Stephen and Petrowski, “Toxins Which Traverse Membranes and Deregulate Cells,” in Bacterial Toxins, 2d ed., pp. 66-67, American Society for Microbiology (1986);
Berkow and Fletcher (eds.), “Bacterial Diseases,” Merck Manual of Diagnosis and Therapy, 16th ed., pp. 116-126, Merck Research Laboratories, Rahway, N.J. (1992);
and Siegmond and Fraser (eds.), “Clostridial Infections,” Merck Veterinary Manual, 5th ed., pp. 396-409, Merck & Co., Rahway, N.J. (1979).
In most cases, the pathogenicity of these organisms is related to the release of powerful exotoxins or highly destructive enzymes. Indeed, several species of the genus Clostridium produce toxins and other enzymes of great medical and veterinary significance (Hatheway, Clin. Microbiol. Rev., 3:66-98 [1990]).
Perhaps because of their significance for human and veterinary medicine, much research has been conducted on these toxins, in particular those of
C. botulinum, C. tetani
, and
C. peringens
, although much recent work has also been conducted on
C. difficile.
C. botulinum
Several strains of
Clostridium botulinum
produce toxins of significance to human and animal health (Hatheway, Clin. Microbiol. Rev., 3:66-98 (1990]). The effects of these toxins range from diarrheal diseases that can cause destruction of the colon, to paralytic effects that can cause death. Neonates and humans and animals in poor health (e.g, those suffering from diseases associated with old age or immunodeficiency diseases) are particularly at risk for developing severe clostridial diseases such as botulism.
Clostridium botulinum
produces the most poisonous biological toxin known, with a lethal human dose in the nanogram range. Botulinal toxin blocks nerve transmission to the muscles, resulting in flaccid paralysis. When the toxin reaches airway and respiratory muscles, it results in respiratory failure that can cause death (Arnon, J. Infect. Dis., 154:201-206 [1986]).
C. botulinum
spores are carried by dust and are found on vegetables taken from the soil, on fresh fruits, and on agricultural products such as honey. Under conditions favorable to the organism, the spores germinate to vegetative cells, resulting in the production of the toxin (Arnon, Ann. Rev. Med., 31:541 [1980]).
Botulism disease may be grouped into four types, based on the method of introduction of toxin into the bloodstream. Food-borne botulism results from ingesting improperly preserved and inadequately heated food that contains botulinal toxin (i.e., the toxin is pre-formed prior to ingestion). There were 355 cases of food-borne botulism in the United States between 1976 and 1984 (MacDonald et al., Am. J. Epidemiol., 124:794 [1986]). The death rate due to botulinal toxin has been reported as 12% and

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