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Immunity to enterotoxin-producing bacteria

A.-M. SVENNERHOLM and J. HOLMGREN

BACKGROUND

Enteric infection associated with diarrhoeal disease is a major health problem,

particularly in developing countries where these infections cause at least 1
billion episodes of diarrhoea and 5-10 million deaths each year l - 3 . Although
a wide variety of bacteria, viruses and parasites may cause diarrhoea through
many different pathogenic mechanisms, the most common cause is bacteria
that give rise to disease through production of enterotoxins. It has been
estimated that such bacteria account for almost 50% of all diarrhoeal episodes.
Vibrio cholerae 01 is the prototype for the group of enterotoxin-producing
bacteria. Other members include enterotoxigenic Escherichia coli (ETEC),
some but not all non-01 V. cholerae, V. parahaemolyticus, Aeromonas
hydrophila and a number of Gram-negative genera which occasionally may
produce enterotoxins, e.g. Salmonella, Citrobacter, Klebsiella and Campylobacter.
The disease caused by enterotoxin-producing bacteria is characterized by
watery stools without blood and mucus. In the most severe cases the diarrhoea
may result in moderate to severe dehydration that is sometimes fatal; the
mortality rate in non-treated severe cholera may be as high as 50-60%. In
some instances the diarrhoea is accompanied by nausea, vomiting, abdominal
cramps, anorexia and fever 3 . Most cases of entertoxin-induced disease can
be successfully treated by oral rehydration therapy although parenteral
administration of water and electrolytes may be necessary in severely
dehydrated patients4 .
V. cholerae 01 is most often associated with severe and sometimes
life-threatening disease with purging of up to 25litres of water and electrolytes
per day; more than 150000 people die from cholera each year. ETEC is the
most common cause of diarrhoea in developing countries ('" 25% of all cases)
and in travellers to these areas ( '" 30- 50% of all cases). The clinical spectrum
ofETEC diarrhoea is variable, ranging from mild to cholera-like life-threatening
disease l - 3 .
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T. T. MacDonald (ed.), Immunology of Gastrointestinal Disease
© Springer Science+Business Media Dordrecht 1992
 IMMUNOLOGY OF GASTROINTESTINAL DISEASE

The only vaccine that has been available for immunoprophylaxis against
enterotoxin-induced diarrhoeas is the parenteral killed whole-cell cholera
vaccine which has only afforded up to 50% protection for 3-6 months 4 .
Recently, however, a new oral cholera vaccine based on a combination of
cholera B subunit and killed whole cells has been developed and shown to
afford 60-70% protection for at least 3 years 5 ; efforts are now underway to
introduce the use of this vaccine in several countries. For immunoprophylaxis
against other enterotoxin-induced infections no vaccine is yet available,
although the oral B subunit-whole cell cholera vaccine was shown to afford
substantial, though rather short-lasting, protection also against diarrhoea
caused by ETEC producing cholera-like, heat-labile enterotoxin 6 .
There are several approaches to develop new vaccines for immunoprophylaxis
against entertoxin-induced diarrhoeal diseases. Such vaccines should be
designed to induce immune responses interfering with the major pathogenic
events of the various infections. This review will outline present knowledge
on the immune mechanisms operating against enterotoxigenic bacteria based
on studies in experimental animals infected with such organisms or immunized
with toxin antigens, as well as in humans convalescing from natural disease
or given toxoid-containing vaccines.

PATHOGENIC MECHANISMS IN ENTEROTOXIN-INDUCED

DIARRHOEAL DISEASE

Bacterial colonization
The major pathogenic mechanisms of enterotoxigenic bacteria include
colonization of the small intestine and elaboration of one or more enterotoxins
that through various mechanisms may induce water and electrolyte secretion
resulting in diarrhoea. The colonization is dependent on receptor-ligand
interactions between bacteria and host cells which usually are specific for
the species, phenotype and epithelial cell type of the host. All enterotoxin-
producing bacteria seem to possess distinct attachment factors, so-called
adhesins or colonization factors, that are either fimbrial or outer-membrane
proteins in nature 7.8. The host receptors, on the other hand, usually consist
of oligo saccharides or glycoconjugates on the epithelial cell surface or in the
mucus layer 9. Analogous carbohydrates have been found in human secretions,
e.g. in milk, and have been proposed to have a protective function against
cholera and maybe also against entertoxin-induced E. coli diarrhoea 1o • ll .
In V. cholerae the toxin-co regulated pilus (TCP) has been shown to be of
importance for colonization of the intestine 12. Other adhesins such as the
mannose-binding pilus antigen associated with the EI Tor biotypelO.13.13a
may also playa role. In ETEC, various species-associated colonization factor
fimbriae have been identified. A majority of human ETEC isolates express
either of three distinct colonization factors antigens (CFAs), i.e. CFA/I,
CF A/II or CF A/IV 8 . Whereas CF A/I is a homogeneous protein consisting
of '" 100 identical subunits of 15 kD each, CF A/II consists of three
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