Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model

Authors

Luther A. Bartelt, University of North Carolina
David T. Bolick, University of Virginia
Glynis L. Kolling, University of Virginia
James K. Roche, University of Virginia
Edna I. Zaenker, University of Virginia
Ana M. Lara, Virginia Commonwealth University
Francisco Jose Noronha, University of Virginia
Carrie A. Cowardin, University of Virginia
John H. Moore, University of Virginia
Jerrold R. Turner, University of Chicago, and Brigham and Women’s Hospital
Cirle A. Warren, University of Virginia
Gregory A. Buck, Virginia Commonwealth UniversityFollow
Richard L. Guerrant, University of Virginia

Document Type

Article

Original Publication Date

2016

Journal/Book/Conference Title

PLOS ONE: Neglected Tropical Diseases

Volume

10

Issue

7

DOI of Original Publication

10.1371/journal.pntd.0004820

Comments

Originally published at http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0004820.

Date of Submission

November 2016

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.

Rights

Copyright: © 2016 Bartelt et al.

Is Part Of

VCU Biochemistry and Molecular Biology Publications