title: Rationalized design of a mucosal vaccine protects againstMycobacterium tuberculosischallenge in mice.
abstract: Pulmonary tuberculosis (TB) caused byMycobacterium tuberculosis(Mtb) is a leading cause of global morbidity and mortality. The only licensed TB vaccine,Mycobacterium bovisbacillus Calmette-Guerin (BCG), has variable efficacy in protecting against pulmonary TB. Thus, the development of more effective TB vaccines is critical to control the TB epidemic. Specifically, vaccines delivered through the mucosal route are known to induce Th17 responses and provide superior protection againstMtbinfection. However, already tested Th17-inducing mucosal adjuvants, such as heat-labile enterotoxins and cholera toxins, are not considered safe for use in humans. In the current study, we rationally screened adjuvants for their ability to induce Th17-polarizing cytokines in dendritic cells (DCs) and determined whether they could be used in a protective mucosal TB vaccine. Our new studies show that monophosphoryl lipid A (MPL), when used in combination with chitosan, potently induces Th17-polarizing cytokines in DCs and downstream Th17/Th1 mucosal responses and confers significant protection in mice challenged with a clinicalMtbstrain. Additionally, we show that both TLRs and the inflammasome pathways are activated in DCs by MPL-chitosan to mediate induction of Th17-polarizing cytokines. Together, our studies put forward the potential of a new, protective mucosal TB vaccine candidate, which incorporates safe adjuvants already approved for use in humans.
authors.affiliation: Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Mushtaq
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, Missouri, USA.|School of Medicine, Yangzhou University, Yangzhou, People's Republic of China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Jiao
authors.affiliation: Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Racquel
authors.initials: R
authors.lastname: Domingo-Gonzalez
authors.affiliation: Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Shibali
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Griffiths
authors.affiliation: Department of Medicine, Division of Allergy, Immunology, and Rheumatology, University of Rochester Medical Center, Rochester, New York, USA; and.
authors.forename: Javier
authors.initials: J
authors.lastname: Rangel-Moreno
authors.affiliation: Department of Pediatrics and Microbiology/Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Uma M
authors.initials: UM
authors.lastname: Nagarajan
authors.affiliation: Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, Missouri, USA; khader@wustl.edu.
authors.forename: Shabaana A
authors.initials: SA
authors.lastname: Khader
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001500:BCG Vaccine / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*
chemical_list: D001500:BCG Vaccine; D016207:Cytokines
keywords: Th17/Th1 responses; adjuvants; mucosal immunity; tuberculosis