title: Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model.
abstract: Cryptosporidium is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of C. parvum oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to C. parvum challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to Cryptosporidium, priming with C. parvum (106 oocysts) provides robust protective immunity against re-challenge despite ongoing PM. C. parvum priming restores mucosal Th1-type effectors (CD3+CD8+CD103+ T-cells) and cytokines (IFNγ, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with Cryptosporidium antigens expressed in the S. Typhi vector 908htr, however, do not enhance Th1-type responses to C. parvum challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated S. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate C. parvum severity during PM, but neither as effectively as viable C. parvum priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to C. parvum, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically C. parvum priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of Cryptosporidium immunity and future vaccine strategies in malnourished children.
authors.affiliation: Division of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Luther A
authors.initials: LA
authors.lastname: Bartelt
authors.affiliation: Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: David T
authors.initials: DT
authors.lastname: Bolick
authors.affiliation: Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Glynis L
authors.initials: GL
authors.lastname: Kolling
authors.affiliation: Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: James K
authors.initials: JK
authors.lastname: Roche
authors.affiliation: Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Edna I
authors.initials: EI
authors.lastname: Zaenker
authors.affiliation: Molecular Biology and Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Lara
authors.affiliation: Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Francisco Jose
authors.initials: FJ
authors.lastname: Noronha
authors.affiliation: Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Cowardin
authors.affiliation: Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: John H
authors.initials: JH
authors.lastname: Moore
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois, United States of America.|Departments of Pathology and Medicine-Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Jerrold R
authors.initials: JR
authors.lastname: Turner
authors.affiliation: Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Cirle A
authors.initials: CA
authors.lastname: Warren
authors.affiliation: Molecular Biology and Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Buck
authors.affiliation: Division of Infectious Diseases and Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Guerrant
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D003457:Cryptosporidiosis / Q000517:prevention & control*; D003458:Cryptosporidium / Q000276:immunology*; D004044:Dietary Proteins / Q000008:administration & dosage*; D005260:Female; D044342:Malnutrition / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016052:Protozoan Vaccines / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D004044:Dietary Proteins; D016052:Protozoan Vaccines