Linking longitudinal and cross-sectional biomarker data to understand host-pathogen dynamics: Leptospira in California sea lions (Zalophus californianus) as a case study

PLoS Negl Trop Dis. 2020 Jun 29;14(6):e0008407. doi: 10.1371/journal.pntd.0008407. eCollection 2020 Jun.

Abstract

Confronted with the challenge of understanding population-level processes, disease ecologists and epidemiologists often simplify quantitative data into distinct physiological states (e.g. susceptible, exposed, infected, recovered). However, data defining these states often fall along a spectrum rather than into clear categories. Hence, the host-pathogen relationship is more accurately defined using quantitative data, often integrating multiple diagnostic measures, just as clinicians do to assess their patients. We use quantitative data on a major neglected tropical disease (Leptospira interrogans) in California sea lions (Zalophus californianus) to improve individual-level and population-level understanding of this Leptospira reservoir system. We create a "host-pathogen space" by mapping multiple biomarkers of infection (e.g. serum antibodies, pathogen DNA) and disease state (e.g. serum chemistry values) from 13 longitudinally sampled, severely ill individuals to characterize changes in these values through time. Data from these individuals describe a clear, unidirectional trajectory of disease and recovery within this host-pathogen space. Remarkably, this trajectory also captures the broad patterns in larger cross-sectional datasets of 1456 wild sea lions in all states of health but sampled only once. Our framework enables us to determine an individual's location in their time-course since initial infection, and to visualize the full range of clinical states and antibody responses induced by pathogen exposure. We identify predictive relationships between biomarkers and outcomes such as survival and pathogen shedding, and use these to impute values for missing data, thus increasing the size of the useable dataset. Mapping the host-pathogen space using quantitative biomarker data enables more nuanced understanding of an individual's time course of infection, duration of immunity, and probability of being infectious. Such maps also make efficient use of limited data for rare or poorly understood diseases, by providing a means to rapidly assess the range and extent of potential clinical and immunological profiles. These approaches yield benefits for clinicians needing to triage patients, prevent transmission, and assess immunity, and for disease ecologists or epidemiologists working to develop appropriate risk management strategies to reduce transmission risk on a population scale (e.g. model parameterization using more accurate estimates of duration of immunity and infectiousness) and to assess health impacts on a population scale.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animal Diseases / diagnosis
  • Animal Diseases / immunology
  • Animal Diseases / microbiology
  • Animals
  • Antibodies, Bacterial / blood
  • Bacterial Shedding
  • Biomarkers / blood*
  • California
  • Cross-Sectional Studies
  • Host-Pathogen Interactions / immunology
  • Host-Pathogen Interactions / physiology*
  • Immunity
  • Kinetics
  • Leptospira / pathogenicity*
  • Leptospira interrogans
  • Leptospirosis / diagnosis*
  • Leptospirosis / immunology
  • Leptospirosis / veterinary*
  • Sea Lions / microbiology*
  • Survival Rate

Substances

  • Antibodies, Bacterial
  • Biomarkers

Grants and funding

This work was supported by the National Science Foundation Awards OCE-1335657 (https://www.nsf.gov/funding/pgm_list.jsp?org=OCE; JL-S, KCP) and DEB-1557022 (https://www.nsf.gov/funding/pgm_list.jsp?org=DEB; JL-S and KCP), the John H. Prescott Marine Mammal Rescue Assistance Grant Program (https://www.fisheries.noaa.gov/grant/john-h-prescott-marine-mammal-rescue-assistance-grant-program; JL-S, KCP), the Hellman Family Foundation (https://www.apo.ucla.edu/faculty-career-development/hellman-fellowship/hellman; JL-S), the US Department of Defense Strategic Environmental Research and Development Program Award RC-2635 (https://www.serdp-estcp.org/Funding-Opportunities/SERDP-Solicitations; JL-S, KCP), Cooperative Ecosystem Studies Unit Cooperative Agreement #W9132T1920006 (www.cesu.psu.edu; JL-S, KCP), the De Logi Chair in Biological Sciences (https://www.apo.ucla.edu/academic-listings/endowed-chairs; JL-S), and the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health (https://www.fic.nih.gov/About/Staff/Pages/epidemiology-population.aspx; JL-S, KCP, MGB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.