Mycobacterial Membrane Vesicles Administered Systemically in Mice Induce a Protective Immune Response to Surface Compartments of Mycobacterium tuberculosis

ABSTRACT Pathogenic and nonpathogenic species of bacteria and fungi release membrane vesicles (MV), containing proteins, polysaccharides, and lipids, into the extracellular milieu. Previously, we demonstrated that several mycobacterial species, including bacillus Calmette-Guerin (BCG) and Mycobacterium tuberculosis, release MV containing lipids and proteins that subvert host immune response in a Toll-like receptor 2 (TLR2)-dependent manner (R. Prados-Rosales et al., J. Clin. Invest. 121:1471–1483, 2011, doi:10.1172/JCI44261). In this work, we analyzed the vaccine potential of MV in a mouse model and compared the effects of immunization with MV to those of standard BCG vaccination. Immunization with MV from BCG or M. tuberculosis elicited a mixed humoral and cellular response directed to both membrane and cell wall components, such as lipoproteins. However, only vaccination with M. tuberculosis MV was able to protect as well as live BCG immunization. M. tuberculosis MV boosted BCG vaccine efficacy. In summary, MV are highly immunogenic without adjuvants and elicit immune responses comparable to those achieved with BCG in protection against M. tuberculosis. IMPORTANCE This work offers a new vaccine approach against tuberculosis using mycobacterial MV. Mycobacterium MV are a naturally released product combining immunogenic antigens in the context of a lipid structure. The fact that MV do not need adjuvants and elicit protection comparable to that elicited by the BCG vaccine encourages vaccine approaches that combine protein antigens and lipids. Consequently, mycobacterium MV establish a new type of vaccine formulation. This work offers a new vaccine approach against tuberculosis using mycobacterial MV. Mycobacterium MV are a naturally released product combining immunogenic antigens in the context of a lipid structure. The fact that MV do not need adjuvants and elicit protection comparable to that elicited by the BCG vaccine encourages vaccine approaches that combine protein antigens and lipids. Consequently, mycobacterium MV establish a new type of vaccine formulation.

[1]  A. Casadevall,et al.  Extracellular vesicles produced by the Gram‐positive bacterium Bacillus subtilis are disrupted by the lipopeptide surfactin , 2014, Molecular microbiology.

[2]  A. Casadevall,et al.  Characterization of protective extracellular membrane-derived vesicles produced by Streptococcus pneumoniae. , 2014, Journal of proteomics.

[3]  Andrea De Maria,et al.  Immunology of Tuberculosis , 2014, Mediterranean journal of hematology and infectious diseases.

[4]  Daniel G. Piqué,et al.  Role for Mycobacterium tuberculosis Membrane Vesicles in Iron Acquisition , 2014, Journal of bacteriology.

[5]  Ryung S. Kim,et al.  Immunogenicity of mycobacterial vesicles in humans: identification of a new tuberculosis antibody biomarker. , 2013, Tuberculosis.

[6]  Tae-Young Roh,et al.  Immunization with Escherichia coli Outer Membrane Vesicles Protects Bacteria-Induced Lethality via Th1 and Th17 Cell Responses , 2013, The Journal of Immunology.

[7]  A. Casadevall,et al.  Antibody-mediated immunity against tuberculosis: implications for vaccine development. , 2013, Cell host & microbe.

[8]  A. Heiser,et al.  Phosphatidylinositol di-mannoside and derivates modulate the immune response to and efficacy of a tuberculosis protein vaccine against Mycobacterium bovis infection. , 2012, Vaccine.

[9]  Bing Chen,et al.  A recombinant Mycobacterium smegmatis induces potent bactericidal immunity against Mycobacterium tuberculosis , 2011, Nature Medicine.

[10]  María A García,et al.  Proteoliposomes from Mycobacterium smegmatis induce immune cross-reactivity against Mycobacterium tuberculosis antigens in mice. , 2011, Vaccine.

[11]  M. McConnell,et al.  Outer membrane vesicles as an acellular vaccine against Acinetobacter baumannii. , 2011, Vaccine.

[12]  A. Casadevall,et al.  Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice. , 2011, The Journal of clinical investigation.

[13]  G. Schoolnik,et al.  A multistage tuberculosis vaccine that confers efficient protection before and after exposure , 2011, Nature Medicine.

[14]  Joshua Labaer,et al.  Protein microarray signature of autoantibody biomarkers for the early detection of breast cancer. , 2011, Journal of proteome research.

[15]  C. Boog,et al.  Differential Effect of TLR2 and TLR4 on the Immune Response after Immunization with a Vaccine against Neisseria meningitidis or Bordetella pertussis , 2010, PloS one.

[16]  Xuedong Ding,et al.  Mycobacterium tuberculosis Lipoproteins Directly Regulate Human Memory CD4+ T Cell Activation via Toll-Like Receptors 1 and 2 , 2010, Infection and Immunity.

[17]  A. Casadevall,et al.  Biogenesis of extracellular vesicles in yeast , 2010, Communicative & integrative biology.

[18]  Stefan H E Kaufmann,et al.  Future vaccination strategies against tuberculosis: thinking outside the box. , 2010, Immunity.

[19]  A. Casadevall,et al.  Bacillus anthracis produces membrane-derived vesicles containing biologically active toxins , 2010, Proceedings of the National Academy of Sciences.

[20]  Nicole A. Kruh,et al.  Proteomic analysis identifies highly antigenic proteins in exosomes from M. tuberculosis‐infected and culture filtrate protein‐treated macrophages , 2010, Proteomics.

[21]  A. Casadevall,et al.  Characterization of Yeast Extracellular Vesicles: Evidence for the Participation of Different Pathways of Cellular Traffic in Vesicle Biogenesis , 2010, PloS one.

[22]  C. Boog,et al.  The Structure of Neisseria meningitidis Lipid A Determines Outcome in Experimental Meningococcal Disease , 2010, Infection and Immunity.

[23]  C. Harding,et al.  Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Toll-like receptors , 2010, Nature Reviews Microbiology.

[24]  D. Putnam,et al.  Delivery of foreign antigens by engineered outer membrane vesicle vaccines , 2010, Proceedings of the National Academy of Sciences.

[25]  J. Stéphenne,et al.  The need for new vaccines. , 2009, Vaccine.

[26]  S. Porcelli,et al.  Evasion and subversion of antigen presentation by Mycobacterium tuberculosis. , 2009, Tissue antigens.

[27]  E. Rosenqvist,et al.  Properties and clinical performance of vaccines containing outer membrane vesicles from Neisseria meningitidis. , 2009, Vaccine.

[28]  S. Kaufmann,et al.  Immunogenicity and Protective Efficacy of Prime-Boost Regimens with Recombinant ΔureC hly+Mycobacterium bovis BCG and Modified Vaccinia Virus Ankara Expressing M. tuberculosis Antigen 85A against Murine Tuberculosis , 2008, Infection and Immunity.

[29]  Eric J. Nelson,et al.  Characterization of Vibrio cholerae Outer Membrane Vesicles as a Candidate Vaccine for Cholera , 2008, Infection and Immunity.

[30]  A. Hill,et al.  Multifunctional, High-Level Cytokine-Producing Th1 Cells in the Lung, but Not Spleen, Correlate with Protection against Mycobacterium tuberculosis Aerosol Challenge in Mice , 2008, The Journal of Immunology.

[31]  Eric J. Nelson,et al.  Immunization with Vibrio cholerae Outer Membrane Vesicles Induces Protective Immunity in Mice , 2008, Infection and Immunity.

[32]  Yanhui Hu,et al.  Next generation high density self assembling functional protein arrays , 2008, Nature Methods.

[33]  R. Alaniz,et al.  Membrane vesicles are immunogenic facsimiles of Salmonella typhimurium that potently activate dendritic cells, prime B and T cell responses, and stimulate protective immunity in vivo , 2008, The Journal of Immunology.

[34]  A. Casadevall,et al.  Extracellular Vesicles Produced by Cryptococcus neoformans Contain Protein Components Associated with Virulence , 2007, Eukaryotic Cell.

[35]  F. Sotolongo,et al.  Cuban Meningococcal BC Vaccine: Experiences & Contributions from 20 Years of Application. , 2007, MEDICC review.

[36]  Mario Roederer,et al.  Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major , 2007, Nature Medicine.

[37]  J. Slack.  Metaplasia and transdifferentiation: from pure biology to the clinic , 2007, Nature Reviews Molecular Cell Biology.

[38]  R. Locksley,et al.  IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge , 2007, Nature Immunology.

[39]  Julian Parkhill,et al.  Genome plasticity of BCG and impact on vaccine efficacy , 2007, Proceedings of the National Academy of Sciences.

[40]  J. Heeney,et al.  Immunological correlates of protection from HIV infection and disease , 2006, Nature Immunology.

[41]  Mario Roederer,et al.  Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates , 2006, The Journal of experimental medicine.

[42]  M. Kuehn,et al.  Bacterial outer membrane vesicles and the host-pathogen interaction. , 2005, Genes & development.

[43]  John T. Belisle,et al.  Mycobacterium tuberculosis LprG (Rv1411c): A Novel TLR-2 Ligand That Inhibits Human Macrophage Class II MHC Antigen Processing1 , 2004, The Journal of Immunology.

[44]  Bhupinder Bhullar,et al.  Self-Assembling Protein Microarrays , 2004, Science.

[45]  Jeannette Adu-Bobie,et al.  Vaccination against Neisseria meningitidis Using Three Variants of the Lipoprotein GNA1870 , 2003, The Journal of experimental medicine.

[46]  T. Lyberg,et al.  Outer membrane vesicles from Neisseria meningitidis , 2002, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[47]  M. Thakur,et al.  Global tuberculosis control report. , 2001, The National medical journal of India.

[48]  F. Oftung,et al.  Intranasal Administration of a Meningococcal Outer Membrane Vesicle Vaccine Induces Persistent Local Mucosal Antibodies and Serum Antibodies with Strong Bactericidal Activity in Humans , 1998, Infection and Immunity.

[49]  H. Vordermeier,et al.  Vaccination with recombinant vaccinia viruses protects mice against Mycobacterium tuberculosis infection , 1997, Immunology.

[50]  L. Kesavalu,et al.  Porphyromonas gingivalis virulence in mice: induction of immunity to bacterial components , 1992, Infection and immunity.

[51]  M. Daffé,et al.  Breaking down the wall: fractionation of mycobacteria. , 2007, Journal of microbiological methods.

[52]  S. Kaufmann,et al.  Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis. , 2006, Immunity.

[53]  J. Keenan,et al.  A role for the bacterial outer membrane in the pathogenesis of Helicobacter pylori infection. , 2000, FEMS microbiology letters.

[54]  Global Tuberculosis Programme.  Global tuberculosis control : WHO report , 1997 .