Figure 4. Gene complementation of eccCa1 (Rv3870) restores EsxA secretion, EsxA specific T cell responses and increases virulence.
(a) Western blot comparing secretion of EsxA and Ag85B in culture filtrate and bacterial pellet from in vitro grown cultures of M.tb DK9897 and M.tb DK9897 complemented with the Rv3870-72 gene cassette (DK9897::pKG18). For clarity the blots are cropped, full-length blots can be seen in Supplementary Figure S2. Lung cells isolated from mice infected for six weeks with H37Rv or the complemented DK9897 strain (DK9897::pKG18) were stimulated with either Ag85B, EsxH (TB10.4) or EsxA protein. The following day the percentage of CD4+ CD3+ double-positive cells producing at least one of the cytokines TNF-α, IFN-γ, IL-2 or IL-17 in response to antigen stimulation was determined for individual mice (n = 4) by flow cytometry. (c) Individual lungs from mice infected with H37Rv, DK9897 or DK9897::pKG18 for six weeks were homogenized and plated in serial dilutions. After two weeks incubation, the number of mycobacteria was determined. Mean and SEMs are indicated, p = 0.03, two-tailed t-test.