title: Mycobacterium bovis BCG vaccines exhibit defects in alanine and serine catabolism.
abstract: Mycobacterium bovis BCG is the only accepted vaccine for the prevention of tuberculosis (TB) in humans. BCG is a live vaccine, and induction of immunity to TB requires productive infection of the host by BCG. However, BCG is not a satisfactory vaccine, because it fails to protect against pulmonary TB in adults. In this study, we found that BCG strains cannot utilize many naturally occurring amino acids as the sole nitrogen source for growth. This defect is caused, at least partially, by the lack of functional metabolic enzymes. All BCG strains are unable to catabolize L-alanine or D-alanine due to a frameshift mutation in the L-alanine dehydrogenase gene (ald). Some BCG strains, such as BCG-Pasteur and BCG-Frappier, cannot catabolize L-serine, apparently due to inadequate expression of L-serine deaminase (sdaA). We also found that undegraded alanine and serine inhibit the growth of BCG through blockage of glutamine synthetase. These results suggest that BCG strains are limited in nitrogen metabolic capacity and predict defects that may restrict multiplication and persistence of the live vaccine within the host.
authors.affiliation: Department of Medical Genetics and Microbiology, University of Toronto, Ontario M5S 1A8, Canada.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Chen
authors.forename: David C
authors.initials: DC
authors.lastname: Alexander
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Behr
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
mesh_terms: D000409:Alanine / Q000378:metabolism*; D050788:Alanine Dehydrogenase; D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001500:BCG Vaccine / Q000235:genetics; D002417:Cattle; D003470:Culture Media; D016368:Frameshift Mutation; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors; D012695:L-Serine Dehydratase / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009163:Mycobacterium bovis / Q000201:enzymology* / Q000235:genetics* / Q000254:growth & development; D012694:Serine / Q000378:metabolism*
chemical_list: D001500:BCG Vaccine; D003470:Culture Media; D012694:Serine; D000594:Amino Acid Oxidoreductases; D050788:Alanine Dehydrogenase; D012695:L-Serine Dehydratase; D005974:Glutamate-Ammonia Ligase; D000409:Alanine