Chemistry: molecular biology and microbiology – Micro-organism – per se ; compositions thereof; proces of... – Bacteria or actinomycetales; media therefor
Patent
1997-04-21
1999-08-10
Minnifield, Nita
Chemistry: molecular biology and microbiology
Micro-organism, per se ; compositions thereof; proces of...
Bacteria or actinomycetales; media therefor
435 711, 435 91, 435170, 435 691, 4351723, 4352523, 435232, 4353201, 435 693, C12N 112, C12N 120, C12N 1500, C12P 2104
Patent
active
059358386
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a method of cultivating bacteria. More precisely, the method is concerned with cultivating bacteria having genes in plasmids which code for surface or membrane bound antigens or other proteins and which are expressed in a temperature regulated manner for the production of desired bacterial products.
BACKGROUND
Bacteria and viruses often express on or within their membrane, proteins which in a certain environment function as a support for the organism to associate in a specific way or adhere to a surface. Such a surface may be the inner wall of the gastro-intestinal tract, the oesophagus or any other biological surface or membrane in a human or animal body, where an organism may find an optimal environment for growth. Membrane proteins of this kind are often named colonization-factor-antigens (CFA) or fimbriae. In the literature, other words such as pili, hemagglutinins, filamentous or fibrillar proteins are used for the same kind of substances. For convenience, "CFA" will be used herein to cover all these kinds of membrane proteins which also may have an antigenic character.
A number of bacteria which are of medical interest have been shown to produce CFAs associated with their membrane. Among these, the ones which are most important for humans, are organisms which colonize the human gastro-intestinal tract and the respiratory airways. Examples of organisms which colonize the gastro-intestinal tract are enterotoxigenic Escherichia coli, Vibrio cholerae, Helicobacter pylor, Campylobacter, Shigellae, Salmonellae and Yersinia.
Of particular medical interest is the enterotoxigenic Escherichia coli (ETEC), since it is one of the major causes of diarrhea among children in the developing countries and accounts for more than 1 billion diarrhea episodes and at least one million deaths per year, primarily among children. In the same way, Vibrio cholerae and Campylobacter cause diarrhea among people in the developing countries. ETEC and Campylobacter are also the major cause of diarrhea among travellers to these regions. Helicobacter pylori has recently become important due to its connection with stomach ulcers.
For most of these organisms the production of their CFAs is controlled by various factors in the environment, which in turn may activate regulatory genes in the plasmid DNA.
Thus, for a bacterium which has its natural growth environment in the human intestine it is advantageous to optimize its growth and possibility of survival to conditions in the intestine. In other words, there is an optimal strategy of survival which implies the production of adhesive proteins in the environment where there are suitable conditions for survival.
As is known from the literature, one such parameter that activates regulatory plasmid genes is the temperature, implying that the production of CFAs in a number of bacteria is temperature regulated. Several human pathogenic organisms have been shown to produce CFAs at temperatures above room temperature only, and not at room temperature. Some of these organisms are of specific commercial interest, since it has been shown that it is possible to produce oral vaccines against these organisms or bacteria.
In WO 92/14487 a method for production and use of an oral ETEC vaccine is disclosed. The ETEC bacteria are grown at 37.degree. C. from agar plates to liquid medium in order to obtain commercial quantities of the ETEC bacteria with CFAs and their sub-components (CS-antigens). These subsequently formalin killed bacteria may then be used as an oral vaccine against the ETEC bacteria. The CFA and CS antigens will thus function as antigens in the immunological processing that will take place in the intestine.
In the scaling up of the production of ETEC bacteria having CFAs it was surprisingly found that the bacteria lost their ability to produce CFAs more and more for each new generation. In the studying of the reason for this, it was noticed that the loss of the ability of the bacteria to produce CFAs at temperatures above room temperature was accompanie
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Askelof Per
Carlin Nils
Nilsson Bo
Paulsson Agneta
Minnifield Nita
SBL Vaccin AB
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