In keeping with MARCE-2 goals of developing broadly applicable novel therapeutics, models, and approaches to improving innate and acquired host defenses for important health threats, this project builds upon substantial progress and several publications on developing new models and quantifying both clinical outcomes and intensity and duration of infection with the highly chlorine resistant water borne Cryptosporidium spp. In particular, our neonatal mouse model mimics the effects of cryptosporidial infections in humans causing both growth shortfalls and greatly increased infection severity in the presence of malnutrition. We now have very promising pilot data suggesting that key mucosal repair agents, including alanylglutamine and arginine as well as selected candidate vaccines (from VCU and UMD collaborations), given intranasally elicit immune responses that reduce both intensity and growth impairment from cryptosporidial infections. Thus, our broad, long term objective is to define the optimal mucosal repair agents and their potentially synergistic interactions with documented drivers of innate and acquired immunity to either prevent or ameliorate cryptosporidial infections and their clinical consequences.
Our specific aims will therefore be: 1) to define the effectiveness of alanylglutamine, arginine, and APOE mimetic peptide, given before or after cryptosporidial infection, 2) to determine the interactions and potential synergies of these mucosal repair agents given with CpG, IMO or ClyA-pSEC vaccine vector drivers of innate immunity or with ClyA-CVD908htr-CP15 driving adaptive immune responses;and finally 3) to compare the relative efficacies and potential synergies of the optimal regimen defined above with the marginally effective, but best available anti-protozoal drug nitazoxanide in both our organoid and neonatal mouse models challenged with Cryptosporidium parasites. This approach not only will identify optimal mucosal and immune enhancing approaches to cryptosporidial infection, but will have potential relevance to other enteric infections and vaccines as well.

Public Health Relevance

Cryptosporidium infections constitute a leading global public health threat, not only as the cause of waterborne outbreaks in the US (400,000 persons in Milwaukee in 1992), but also as a leading cause of growth shortfalls and cognitive impairment in children and severe diarrhea in immunocompromised patients. This parasite has been notoriously difficult to treat (over 100 agents tested). Thus, this project has significant public health relevance not only to industrialized countries, but also to developing regions worldwide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057168-10
Application #
8442357
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$231,217
Indirect Cost
$28,072
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Li, Huiguang; Hwang, Young; Perry, Kay et al. (2016) Structure and Metal Binding Properties of a Poxvirus Resolvase. J Biol Chem 291:11094-104
Ramachandran, Girish; Tennant, Sharon M; Boyd, Mary A et al. (2016) Functional Activity of Antibodies Directed towards Flagellin Proteins of Non-Typhoidal Salmonella. PLoS One 11:e0151875
Ray, Greeshma; Schmitt, Phuong Tieu; Schmitt, Anthony P (2016) C-Terminal DxD-Containing Sequences within Paramyxovirus Nucleocapsid Proteins Determine Matrix Protein Compatibility and Can Direct Foreign Proteins into Budding Particles. J Virol 90:3650-60
Chou, Yi-ying; Cuevas, Christian; Carocci, Margot et al. (2016) Identification and Characterization of a Novel Broad-Spectrum Virus Entry Inhibitor. J Virol 90:4494-510
Fraley, Stephanie I; Athamanolap, Pornpat; Masek, Billie J et al. (2016) Nested Machine Learning Facilitates Increased Sequence Content for Large-Scale Automated High Resolution Melt Genotyping. Sci Rep 6:19218
Levy, Revital; Rotfogel, Ziv; Hillman, Dalia et al. (2016) Superantigens hyperinduce inflammatory cytokines by enhancing the B7-2/CD28 costimulatory receptor interaction. Proc Natl Acad Sci U S A 113:E6437-E6446
Molleston, Jerome M; Sabin, Leah R; Moy, Ryan H et al. (2016) A conserved virus-induced cytoplasmic TRAMP-like complex recruits the exosome to target viral RNA for degradation. Genes Dev 30:1658-70
Riblett, Amber M; Blomen, Vincent A; Jae, Lucas T et al. (2016) A Haploid Genetic Screen Identifies Heparan Sulfate Proteoglycans Supporting Rift Valley Fever Virus Infection. J Virol 90:1414-23
Ramachandran, Girish; Boyd, Mary Adetinuke; MacSwords, Jennifer et al. (2016) Opsonophagocytic Assay To Evaluate Immunogenicity of Nontyphoidal Salmonella Vaccines. Clin Vaccine Immunol 23:520-3
Plaut, Roger D; Stibitz, Scott (2015) Improvements to a Markerless Allelic Exchange System for Bacillus anthracis. PLoS One 10:e0142758

Showing the most recent 10 out of 360 publications