Enhanced antimycobacterial response to recombinant Mycobacterium bovis BCG expressing latency-associated peptide.
With a view to exploring the role of transforming growth factor beta (TGF-beta) during mycobacterial infection, recombinant clones of bacillus Calmette-Guérin (BCG) were engineered to express the natural antagonist of TGF-beta, latency-activated peptide (LAP). Induction of TGF-beta activity was reduced when macrophages were infected with BCG expressing the LAP construct (LAP-BCG). There was a significant reduction in the growth of LAP-BCG in comparison to that of control BCG following intravenous infection in a mouse model. The enhanced control of mycobacterial replication was associated with an increase in the production of gamma interferon by splenocytes challenged during the acute stage of infection but with a diminished recall response assessed after 13 weeks. Organ weight and hydroxyproline content, representing tissue pathology, were also lower in mice infected with LAP-BCG. The results are consistent with the hypothesis that TGF-beta has a detrimental effect on mycobacterial immunity. While a reduction in TGF-beta activity augments the initial response to BCG vaccination, early bacterial clearance may adversely affect the induction of a long-term memory response by LAP-BCG.
Marshall
B G
BG
Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London, United Kingdom. ben.marshall@suht.swest.nhs.uk
Wangoo
A
A
O'Gaora
P
P
Cook
H T
HT
Shaw
R J
RJ
Young
D B
DB
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology*; D011498:Protein Precursors / Q000235:genetics / Q000276:immunology*; D011995:Recombination, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D053773:Transforming Growth Factor beta1; D014376:Tuberculosis / Q000276:immunology*
D010446:Peptide Fragments; D011498:Protein Precursors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1