Inferring biomarkers for Mycobacterium avium subsp. paratuberculosis infection and disease progression in cattle using experimental data.
Available diagnostic assays for Mycobacterium avium subsp. paratuberculosis (MAP) have poor sensitivities and cannot detect early stages of infection, therefore, there is need to find new diagnostic markers for early infection detection and disease stages. We analyzed longitudinal IFN-γ, ELISA-antibody and fecal shedding experimental sensitivity scores for MAP infection detection and disease progression. We used both statistical methods and dynamic mathematical models to (i) evaluate the empirical assays (ii) infer and explain biological mechanisms that affect the time evolution of the biomarkers, and (iii) predict disease stages of 57 animals that were naturally infected with MAP. This analysis confirms that the fecal test is the best marker for disease progression and illustrates that Th1/Th2 (IFN-γ/ELISA antibodies) assays are important for infection detection, but cannot reliably predict persistent infections. Our results show that the theoretical simulated macrophage-based assay is a potential good diagnostic marker for MAP persistent infections and predictor of disease specific stages. We therefore recommend specifically designed experiments to test the use of a based assay in the diagnosis of MAP infections.
Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.|Department of Infectious Disease Epidemiology. Imperial College London, UK.|National Institute for Mathematical and Biological Synthesis, University of Tennessee, Volunteer Blvd, Suite 106, Knoxville, TN, 37996, USA.
Gesham
G
Magombedze
Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UK.
Tinevimbo
T
Shiri
National Institute for Mathematical and Biological Synthesis, University of Tennessee, Volunteer Blvd, Suite 106, Knoxville, TN, 37996, USA.|Department of Forestry, Wildlife, and Fisheries, University of Tennessee, Knoxville, TN 37996-1527, USA.
Shigetoshi
S
Eda
USDA-ARS, National Animal Disease, Ames, IA 50010, USA.
Judy R
JR
Stabel
D000818:Animals; D001681:Biological Assay; D015415:Biomarkers / Q000032:analysis*; D002417:Cattle; D002418:Cattle Diseases / Q000175:diagnosis / Q000276:immunology / Q000382:microbiology* / Q000473:pathology*; D018450:Disease Progression; D005243:Feces / Q000382:microbiology; D007371:Interferon-gamma / Q000378:metabolism; D007700:Kinetics; D008264:Macrophages / Q000382:microbiology / Q000473:pathology; D008954:Models, Biological; D016927:Mycobacterium avium subsp. paratuberculosis / Q000472:pathogenicity*; D010283:Paratuberculosis / Q000175:diagnosis / Q000276:immunology / Q000382:microbiology* / Q000473:pathology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D015415:Biomarkers; D007371:Interferon-gamma