Abstract
BackgroundEarly secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) are co-secreted proteins of Mycobacterium tuberculosis complex mycobacteria (includes M. bovis, the zoonotic agent of bovine tuberculosis) involved in phagolysosome escape of the bacillus and, potentially, in the efficient induction of granulomas. Upon tuberculosis infection, multi-nucleate giant cells are elicited, likely as a response aimed at containing mycobacteria. In tissue culture models, signal regulatory protein (SIRP)α (also referred to as macrophage fusion receptor or CD172a) is essential for multi-nucleate giant cell formation.Methodology/Principal FindingsIn the present study, ESAT-6/CFP-10 complex and SIRPα interactions were evaluated with samples obtained from calves experimentally infected with M. bovis. Peripheral blood CD172a+ (SIRPα-expressing) cells from M. bovis-infected calves proliferated upon in vitro stimulation with ESAT-6/CFP-10 (either as a fusion protein or a peptide cocktail), but not with cells from animals receiving M. bovis strains lacking ESAT-6/CFP-10 (i.e, M. bovis BCG or M. bovis ΔRD1). Sorted CD172a+ cells from these cultures had a dendritic cell/macrophage morphology, bound fluorescently-tagged rESAT-6:CFP-10, bound and phagocytosed live M. bovis BCG, and co-expressed CD11c, DEC-205, CD44, MHC II, CD80/86 (a subset also co-expressed CD11b or CD8α). Intradermal administration of rESAT-6:CFP-10 into tuberculous calves elicited a delayed type hypersensitive response consisting of CD11c+, CD172a+, and CD3+ cells, including CD172a-expressing multi-nucleated giant cells.Conclusions/SignificanceThese findings demonstrate the ability of ESAT-6/CFP-10 to specifically expand CD172a+ cells, bind to CD172a+ cells, and induce multi-nucleated giant cells expressing CD172a.
Highlights
Tuberculosis (TB) in humans and animals may result from exposure to bacilli within the Mycobacterium tuberculosis complex (i.e., M. tuberculosis, M. bovis, M. africanum, M. pinnipedi, M. microti, M. caprae, or M. canetti [1])
Both bacillus Calmette Guerin (BCG) and DRD-1 attenuated M. bovis vaccine strains lack Early secretory antigenic target-6 (ESAT-6), culture filtrate protein-10 (CFP-10), and select ESX-1 secretion apparatus genes; these strains do not produce ESAT-6 or CFP-10. Stimulation with another immunodominant antigen of M. bovis (i.e., MPB83) did not result in expansion of CD172a+ cells (Table 1, Fig. 1), despite significant proliferation of other cell types (CD172a2/PKH67lo in Fig. 1A and data not shown) to MPB83 stimulation. These findings demonstrate that ESAT-6/CFP-10 stimulation of peripheral blood mononuclear cells (PBMC) from TB-infected cattle results in an environment conducive to the proliferation and/or maturation of CD172a+ cells
Multiple functions are proposed for ESAT-6 and CFP-10 proteins produced by M. tb-complex mycobacteria [reviewed in 16]
Summary
Tuberculosis (TB) in humans and animals may result from exposure to bacilli within the Mycobacterium tuberculosis complex (i.e., M. tuberculosis, M. bovis, M. africanum, M. pinnipedi, M. microti, M. caprae, or M. canetti [1]). Secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) are co-secreted proteins of. EsxA and esxB genes encode ESAT-6 and CFP-10, respectively, and are located in the region of difference 1 (RD-1), an area of the virulent M. tb complex genome not present in the vaccine strain, M. bovis bacillus Calmette Guerin (BCG) and most other non-tuberculous mycobacteria [3,4,5,6]. During M. marinum infection of zebrafish, macrophage aggregation is dependent upon RD-1 determinants [16,17], further supporting a receptor-mediated interaction of ESAT-6/CFP-10 with host cells. Secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) are co-secreted proteins of Mycobacterium tuberculosis complex mycobacteria (includes M. bovis, the zoonotic agent of bovine tuberculosis) involved in phagolysosome escape of the bacillus and, potentially, in the efficient induction of granulomas. Signal regulatory protein (SIRP)a ( referred to as macrophage fusion receptor or CD172a) is essential for multi-nucleate giant cell formation
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