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Involvement of the fadD33 gene in the growth of Mycobacterium tuberculosis in the liver of BALB/c mice

Dipartimento di Patologia Sperimentale, Biotecnologie Mediche, Infettivologia ed Epidemiologia, Università di Pisa, I-56127 Pisa, Italy¹
Laboratorio di Batteriologia e Micologia Medica, Istituto Superiore di Sanità, I-00161 Roma, Italy²
Dipartimento di Genetica e di Biologia dei Microrganismi, Università di Milano, Italy³

Author for correspondence: C. Garzelli. Tel: +39 050 836 559. Fax: +39 050 836 570. e-mail: garzelli{at}biomed.unipi.it

The potential pathogenic role of Mycobacterium tuberculosis H37Rv fadD33, a gene encoding an acyl-CoA synthase that is underexpressed in the attenuated strain H37Ra, was investigated. In a first approach, fadD33 was cloned and expressed in strain H37Ra to restore gene expression and fadD33-complemented bacteria were used to investigate whether fadD33 might confer any growth advantage to M. tuberculosis H37Ra in an infection model of BALB/c mice. No differences were found in the growth rates of M. tuberculosis H37Rv, H37Ra and fadD33-complemented H37Ra in the lungs and spleen. In contrast, in the liver, where the attenuated strain H37Ra showed impaired growth compared to the virulent strain H37Rv, complementation of the attenuated strain H37Ra with fadD33 restored bacterial replication. In a further approach, the fadD33 gene of strain H37Rv was disrupted by allelic exchange mutagenesis and the virulence of the mutant strain was tested by mouse infection. It was found that disruption of fadD33 decreased M. tuberculosis H37Rv growth in the liver, but not in the lungs or spleen, and complementation of the fadD33-disrupted mutant with fadD33 restored bacterial replication in the liver, but did not affect replication in the lungs and spleen. These findings suggest that fadD33 plays a role in M. tuberculosis virulence by supporting bacterial growth in the liver.

Keywords: virulence genes, experimental infection

Abbreviations: Kan^R, kanamycin-resistance

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