TY - JOUR
T1 - Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells
AU - Jagannath, Chinnaswamy
AU - Lindsey, Devin R.
AU - Dhandayuthapani, Subramanian
AU - Xu, Yi
AU - Hunter, Robert L.
AU - Eissa, N. Tony
N1 - Funding Information:
This study was supported by US National Institutes of Health National Institute of Allergy and Infectious Diseases grant AI49534 (C.J.) and National Heart, Lung, and Blood Institute grant HL080205 (N.T.E.). We are grateful to L.Y. Armitige (University of Texas Health Sciences Center–Houston) for the fbpA and fbpB mutant strains, K. Rock (University of Massachusetts–Worcester) for the BMA.A3 cell line and C. Harding and H. Boom (Case Western Reserve University) for BB7 T cells. Recombinant ESAT-6 was kindly provided by A. Arora (Central Drug Research Institute, India), and TD17 mAb was a gift from K. Huygen (Pasteur Institute). Mycobacterial vector pMV206 was kindly provided by W. Jacobs (Albert Einstein Medical College).
Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2009/3
Y1 - 2009/3
N2 - The variable efficacy of Bacille Calmette Guerin (BCG) vaccination against tuberculosis has prompted efforts to improve the vaccine. In this study, we used autophagy to enhance vaccine efficacy against tuberculosis in a mouse model. We examined the effect of autophagy on the processing of the immunodominant mycobacterial antigen Ag85B by antigen presenting cells (APCs), macrophages and dendritic cells (DCs). We found that rapamycin-induced autophagy enhanced Ag85B presentation by APCs infected with wild-type Mycobacterium tuberculosis H37Rv, H37Rv-derived ΔfbpA attenuated candidate vaccine or BCG. Furthermore, rapamycin enhanced localization of mycobacteria with autophagosomes and lysosomes. Rapamycin-enhanced antigen presentation was attenuated when autophagy was suppressed by 3-methyladenine or by small interfering RNA against beclin-1. Notably, mice immunized with rapamycin-treated DCs infected with either ΔfbpA or BCG showed enhanced T helper type 1-mediated protection when challenged with virulent Mycobacterium tuberculosis. Finally, overexpression of Ag85B in BCG induced autophagy in APCs and enhanced immunogenicity in mice, suggesting that vaccine efficacy can be enhanced by augmenting autophagy-mediated antigen presentation.
AB - The variable efficacy of Bacille Calmette Guerin (BCG) vaccination against tuberculosis has prompted efforts to improve the vaccine. In this study, we used autophagy to enhance vaccine efficacy against tuberculosis in a mouse model. We examined the effect of autophagy on the processing of the immunodominant mycobacterial antigen Ag85B by antigen presenting cells (APCs), macrophages and dendritic cells (DCs). We found that rapamycin-induced autophagy enhanced Ag85B presentation by APCs infected with wild-type Mycobacterium tuberculosis H37Rv, H37Rv-derived ΔfbpA attenuated candidate vaccine or BCG. Furthermore, rapamycin enhanced localization of mycobacteria with autophagosomes and lysosomes. Rapamycin-enhanced antigen presentation was attenuated when autophagy was suppressed by 3-methyladenine or by small interfering RNA against beclin-1. Notably, mice immunized with rapamycin-treated DCs infected with either ΔfbpA or BCG showed enhanced T helper type 1-mediated protection when challenged with virulent Mycobacterium tuberculosis. Finally, overexpression of Ag85B in BCG induced autophagy in APCs and enhanced immunogenicity in mice, suggesting that vaccine efficacy can be enhanced by augmenting autophagy-mediated antigen presentation.
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U2 - 10.1038/nm.1928
DO - 10.1038/nm.1928
M3 - Article
C2 - 19252503
AN - SCOPUS:62049084947
VL - 15
SP - 267
EP - 276
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 3
ER -