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Characterization of Auxotrophic Mutants of Mycobacterium tuberculosis and Their Potential as Vaccine Candidates
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| Zeitschriftentitel: | Infection and Immunity |
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| Personen und Körperschaften: | , , , |
| In: | Infection and Immunity, 69, 2001, 2, S. 1142-1150 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society for Microbiology
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| Schlagwörter: |
| Zusammenfassung: | <jats:title>ABSTRACT</jats:title> <jats:p> Auxotrophic mutants of <jats:italic>Mycobacterium tuberculosis</jats:italic> have been proposed as new vaccine candidates. We have analyzed the virulence and vaccine potential of <jats:italic>M. tuberculosis</jats:italic> strains containing defined mutations in genes involved in methionine ( <jats:italic>metB</jats:italic> ), proline ( <jats:italic>proC</jats:italic> ), or tryptophan ( <jats:italic>trpD</jats:italic> ) amino acid biosynthesis. The <jats:italic>metB</jats:italic> mutant was a prototrophic strain, whereas the <jats:italic>proC</jats:italic> and <jats:italic>trpD</jats:italic> mutants were auxotrophic for proline and tryptophan, respectively. Following infection of murine bone marrow-derived macrophages, H37Rv and the <jats:italic>metB</jats:italic> mutant strain survived intracellularly for over 10 days, whereas over 90% of <jats:italic>proC</jats:italic> and <jats:italic>trpD</jats:italic> mutants were killed during this time. In SCID mice, both H37Rv and the <jats:italic>metB</jats:italic> mutant were highly virulent, with mouse median survival times (MST) of 28.5 and 42 days, respectively. The <jats:italic>proC</jats:italic> mutant was significantly attenuated (MST, 130 days), whereas the <jats:italic>trpD</jats:italic> mutant was essentially avirulent in an immunocompromised host. Following infection of immunocompetent DBA mice with H37Rv, mice survived for a median of 83.5 days and the <jats:italic>metB</jats:italic> mutant now showed a clear reduction in virulence, with two of five infected mice surviving for 360 days. Both <jats:italic>proC</jats:italic> and <jats:italic>trpD</jats:italic> mutants were avirulent (MST of >360 days). In vaccination studies, prior infection with either the <jats:italic>proC</jats:italic> or <jats:italic>trpD</jats:italic> mutant gave protection equivalent ( <jats:italic>proC</jats:italic> mutant) to or better ( <jats:italic>trpD</jats:italic> mutant) than BCG against challenge with <jats:italic>M. tuberculosis</jats:italic> H37Rv. In summary, <jats:italic>proC</jats:italic> and <jats:italic>trpD</jats:italic> genes are essential for the virulence of <jats:italic>M. tuberculosis</jats:italic> , and mutants with disruptions in either of these genes show strong potential as vaccine candidates. </jats:p> |
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| Umfang: | 1142-1150 |
| ISSN: |
0019-9567
1098-5522 |
| DOI: | 10.1128/iai.69.2.1442-1150.2001 |