Vaccination with Recombinant Mycobacterium tuberculosis PknD Attenuates Bacterial Dissemination to the Brain in Guinea Pigs

Journal Article · Tue Jun 11 00:00:00 EDT 2013 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0066310· OSTI ID:1627613

Skerry, Ciaran ^[1]; Pokkali, Supriya ^[2]; Pinn, Michael ^[2]; Be, Nicholas A. ^[3]; Harper, Jamie ^[2]; Karakousis, Petros C. ^[2]; Jain, Sanjay K. ^[2]

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1. Johns Hopkins University, Baltimore, MD (United States); DOE/OSTI
2. Johns Hopkins University, Baltimore, MD (United States)
3. Johns Hopkins University, Baltimore, MD (United States); Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

We have previously identified Mycobacterium tuberculosis PknD to be an important virulence factor required for the pathogenesis of central nervous system (CNS) tuberculosis (TB). Specifically, PknD mediates bacillary invasion of the blood-brain barrier, which can be neutralized by specific antisera, suggesting its potential role as a therapeutic target against TB meningitis. We utilized an aerosol challenge guinea pig model of CNS TB and compared the protective efficacy of recombinant M. tuberculosis PknD subunit protein with that of M. bovis BCG against bacillary dissemination to the brain. BCG vaccination limited the pulmonary bacillary burden after aerosol challenge with virulent M. tuberculosis in guinea pigs and also reduced bacillary dissemination to the brain (P = 0.01). PknD vaccination also offered significant protection against bacterial dissemination to the brain, which was no different from BCG (P>0.24), even though PknD vaccinated animals had almost 100-fold higher pulmonary bacterial burdens. Higher levels of PknD-specific IgG were noted in animals immunized with PknD, but not in BCG-vaccinated or control animals. Furthermore, pre-incubation of M. tuberculosis with sera from PknD-vaccinated animals, but not with sera from BCG-vaccinated or control animals, significantly reduced bacterial invasion in a human blood-brain barrier model (P<0.01). Current recommendations for administering BCG at birth are based on protection gained against severe disease, such as TB meningitis, during infancy. We demonstrate that vaccination with recombinant M. tuberculosis PknD subunit offers a novel strategy to protect against TB meningitis, which is equivalent to BCG in a guinea pig model. Moreover, since BCG lacks the PknD sensor, BCG could also be boosted to develop a more effective vaccine against TB meningitis, a devastating disease that disproportionately affects young children.

• Research Organization: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
• Sponsoring Organization: National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER)
• Grant/Contract Number: AC52-07NA27344
• OSTI ID: 1627613
• Journal Information: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 6 Vol. 8; ISSN 1932-6203
• Publisher: Public Library of Science
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
HIV vaccines
aerosols
central nervous system
guinea pigs
mycobacterium tuberculosis
recombinant vaccines
tuberculosis
vaccination and immunization