Signal regulatory protein α (SIRPα)+ cells in the adaptive response to ESAT-6/CFP-10 protein of tuberculous mycobacteria

W. Ray Waters, Mitchell V. Palmer, Brian J. Nonnecke, Tyler C. Thacker, D. Mark Estes, Michelle H. Larsen, William R. Jacobs, Peter Andersen, James McNair, F. C. Minion, Konstantin P. Lyaschenko, R. Glyn Hewinson, H. Martin Vordermeier, Randy E. Sacco

Research output: Contribution to journalArticle

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Abstract

Background: Early 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 Findings: In 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 multinucleated giant cells. Conclusions/Significance: These 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.

Original languageEnglish (US)
Article numbere6414
JournalPLoS One
Volume4
Issue number7
DOIs
StatePublished - Jul 29 2009

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regulatory proteins
culture filtrates
Mycobacterium
giant cells
Proteins
proteins
Giant Cells
cells
calves
Macrophages
Mycobacterium bovis
macrophages
Mycobacterium tuberculosis complex
phagosomes
Fusion reactions
bovine tuberculosis
Bovine Tuberculosis
granuloma
hypersensitive response
dendritic cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Signal regulatory protein α (SIRPα)+ cells in the adaptive response to ESAT-6/CFP-10 protein of tuberculous mycobacteria. / Waters, W. Ray; Palmer, Mitchell V.; Nonnecke, Brian J.; Thacker, Tyler C.; Estes, D. Mark; Larsen, Michelle H.; Jacobs, William R.; Andersen, Peter; McNair, James; Minion, F. C.; Lyaschenko, Konstantin P.; Hewinson, R. Glyn; Vordermeier, H. Martin; Sacco, Randy E.

In: PLoS One, Vol. 4, No. 7, e6414, 29.07.2009.

Research output: Contribution to journalArticle

Waters, WR, Palmer, MV, Nonnecke, BJ, Thacker, TC, Estes, DM, Larsen, MH, Jacobs, WR, Andersen, P, McNair, J, Minion, FC, Lyaschenko, KP, Hewinson, RG, Vordermeier, HM & Sacco, RE 2009, 'Signal regulatory protein α (SIRPα)+ cells in the adaptive response to ESAT-6/CFP-10 protein of tuberculous mycobacteria', PLoS One, vol. 4, no. 7, e6414. https://doi.org/10.1371/journal.pone.0006414
Waters, W. Ray ; Palmer, Mitchell V. ; Nonnecke, Brian J. ; Thacker, Tyler C. ; Estes, D. Mark ; Larsen, Michelle H. ; Jacobs, William R. ; Andersen, Peter ; McNair, James ; Minion, F. C. ; Lyaschenko, Konstantin P. ; Hewinson, R. Glyn ; Vordermeier, H. Martin ; Sacco, Randy E. / Signal regulatory protein α (SIRPα)+ cells in the adaptive response to ESAT-6/CFP-10 protein of tuberculous mycobacteria. In: PLoS One. 2009 ; Vol. 4, No. 7.
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abstract = "Background: Early 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 Findings: In 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 multinucleated giant cells. Conclusions/Significance: These 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.",
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AU - Waters, W. Ray

AU - Palmer, Mitchell V.

AU - Nonnecke, Brian J.

AU - Thacker, Tyler C.

AU - Estes, D. Mark

AU - Larsen, Michelle H.

AU - Jacobs, William R.

AU - Andersen, Peter

AU - McNair, James

AU - Minion, F. C.

AU - Lyaschenko, Konstantin P.

AU - Hewinson, R. Glyn

AU - Vordermeier, H. Martin

AU - Sacco, Randy E.

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N2 - Background: Early 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 Findings: In 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 multinucleated giant cells. Conclusions/Significance: These 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.

AB - Background: Early 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 Findings: In 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 multinucleated giant cells. Conclusions/Significance: These 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.

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