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Selective delipidation of Mycobacterium bovis BCG enables direct pulmonary vaccination and enhances protection against Mycobacterium tuberculosis

Mucosal Immunology (2019) | Download Citation

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Abstract

Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), is the leading killer due to an infectious organism. Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only vaccine approved against TB, however, its efficacy against pulmonary TB is poor. While BCG is currently inoculated intradermally, the natural route of M.tb infection is through the lung. Excessive lung pathology caused by pulmonary inoculation of BCG has prevented the use of this immunization route. Here, we show that selective chemical treatment of BCG with petroleum ether removes inflammatory lipids from the bacterial surface while keeping BCG viable. Pulmonary vaccination using this modified BCG attenuated inflammatory responses, prevented immunopathology of the lung, and significantly increased protection against M.tb infection in mice. We further directly linked IL-17A as the responsible contributor of improved immunity against M.tb infection. These results provide evidence that selective removal of cytotoxic lipids from the BCG surface attenuates inflammation and offers a safer and superior vaccine against TB causing less damage post-infectious challenge with M.tb.

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Acknowledgements

This work was supported by the National Institute of Allergy and Infectious Diseases grant numbers [AI073856 and AI093570] to J.B.T.; by a National Institute on Aging grant number [AG051428] supporting J.T. and J.B.T.; and by The Ohio State University (OSU) College of Medicine Systems in Integrative Biology Training Grant [T32-GM068412], and NIH/NIAID [AI039570-S1] and NIH/NIA [AG051428-S1] supplements supporting J.I.M. This study was also partially supported by a CTSA award UL1TR001070 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. We thank the University Laboratory Animal Resources facility and personnel, the Biosafety Level 3 program facility and personnel, and the Comparative Pathology and Mouse Phenotyping Shared Resource (P30 CA016058) at OSU for their technical support.

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Affiliations

  1. Texas Biomedical Research Institute, San Antonio, TX, 78227, USA

    • Juan I. Moliva
    • , Varun Dwivedi
    • , Joanne Turner
    •  & Jordi B. Torrelles
  2. Department of Microbial Infection and Immunity, Wexner College of Medicine, The Ohio State University, Columbus, OH, 43210, USA

    • Juan I. Moliva
    • , Austin P. Hossfeld
    • , Sabeen Sidiki
    • , Cynthia H. Canan
    • , Joanne Turner
    •  & Jordi B. Torrelles
  3. Department of Infectious Diseases and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, 01536, USA

    • Gillian Beamer

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Contributions

Conceptualization, J.I.M., J.T., and J.B.T.; Methodology, J.I.M., J.T., and J.B.T.; Investigation, J.I.M., A.P.H., S.S., C.H.C., V.D., and G.B.; Writing – Original Draft, J.I.M.; Writing – Review & Editing, J.I.M., J.T., and J.B.T.; Funding Acquisition, J.T and J.B.T.; Supervision, J.T. and J.B.T.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Joanne Turner or Jordi B. Torrelles.

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DOI

https://doi.org/10.1038/s41385-019-0148-2