The proposed U19 ICIDR Program is focused on human infection and disease by Leptospira. Our overall approach is to use fundamental biological scientific methods combined with clinical/field studies in contrasting epidemiological contexts in Peru and Sri Lanka, to develop new, clinically actionable diagnostic tests. Taking into account the local, regional, and international diversity of Leptospira, the proposed research addresses a hitherto insurmountable gap in the field, that of obtaining diagnostic tests for leptospirosis that are inexpensive, sensitive and efficient, yet easily deployable and effective regardless of the underlying transmission dynamics. The improved accuracy and efficiency of these tests will enable timely administration of appropriate therapy, which is vital for improving clinical outcomes. The overall goal of this Program is to develop robust tools and approaches that will effectively quantify the Global Burden of Leptospirosis, addressing several key goals shared by the international leptospirosis research community as articulated by the World Health Organization's Leptospirosis Epidemiology Reference Group (LERG).1, 2 These approaches, which are applicable to all leptospirosis-endemic and epidemic-prone sites, are summarized as follows: 1. Carry out prospective, field-based clinical studies of suspected acute leptospirosis cases in known or suspected highly endemic settings in Peru (Project 1) and Sri Lanka (Project 2) where the diversity of Leptospira is high and includes the most highly pathogenic as well as less pathogenic (but still infectious) Leptospira. These sites will include contrasting urban vs. rural and seasonal vs. perennial leptospirosis risk areas in Peru and Sri Lanka. The projects will focus on both hospitalized cases (more severe disease) and outpatients (generally mild spectrum of disease) with dedicated attention to comprehensively follow up clinical and microbiological/molecular outcomes; 2. Characterize serum and urine samples from field studies with regard to leptospirosis diagnosis using conventional serology (MAT, ELISA),3, 4, 5 routine culture, our published culture-independent molecular techniques (conventional PCR,6, 7 qPCR,8 Multi Locus Sequence Typing (MLST)9, 10); 3. Test newly developed antigen-detection tests (LPS; alternatively, Leptospira proteins) and antibody- based serological tests using protein microarray technology based on our newly developed Leptospira Genome Project database (PATRIC,; deposited in GenBank, (both accessed March 7, 2014)) against conventional diagnostics (gold standard re-defined as MAT (on paired samples) plus PCR of blood/urine, given the insensitivity of current culture techniques (problems with past gold-standard diagnostics discussed in Refs.11, 12). The expected outcomes of this program are 1) New tools to diagnose leptospirosis and to identify leptospiral infection of humans; 2) Define and optimize the generalizability of these new tools in diverse and representative settings in Peru and Sri Lanka, and beyond (for example, through the U.S. Centers for Disease Control and Prevention that receives samples from all over the world; see Renee Galloway, Letter of Support); and 3) Enhancing research capacity of foreign collaborators by facilitating development of independent creative scientific thinking, hypothesis generation and testing, and new approaches to addressing clinical and translational research problems of highest priority to the endemic country. Additional benefits from this project include clear application to OneHealth medicine because human leptospirosis reflects interactions of humans with zoonotic domestic and agricultural sources such as dogs, cattle, pigs, and water buffalo, wild and peridomestic rodents and marsupials. The tools developed here will have direct application and translation to veterinary and agricultural settings but such work will be beyond the scope of the present project.

Public Health Relevance

The proposed U19 ICIDR Program is focused on human infection and disease by Leptospira. Our overall approach is to use fundamental biological scientific methods combined with clinical/field studies in contrasting epidemiological contexts in Peru and Sri Lanka to develop new, clinically relevant diagnostic tests. This work will guide new efforts to determine the Global Burden of Disease due to Leptospirosis, of both national domestic and military importance, and internationally. Project 1: Developing Diagnostics for Assessing Leptospirosis Burden of Disease in Peru Project Leader: Jessica Ricaldi, MD, PhD, DTM&H DESCRIPTION (as provided by applicant): Leptospirosis is among the world's most important zoonotic infectious diseases, annually affecting an estimated 868,000 people globally, with an estimated case fatality rate of 5-10%. Important gaps remain in translating recent fundamental molecular advances in studies of Leptospira and leptospirosis to public health approaches to preventing and ameliorating this infectious disease. The long-term goal of this project is to develop and validate new tools for the diagnosis of leptospirosis, in order to be able to address the true global burden of disease. In this study we propose to develop new field study sites in contrasting places to determine nationally as well as regionally important serovars (Aim 1). These studies will allow us to obtain well-characterized isolates to determine national and regional repertoire of Leptospira in a country of known diversity (Aim 2). The collaboration with Dr. Agampodi and the group in Sri Lanka will allow us to evaluate even more geographically distinct environments. Therefore this South-South collaboration build upon well-established scientific relationships is a key aspect of this project, in addition to the research capacity building and cross-disciplinary research outcomes. Lastly we propose to develop ultra-sensitive, broad-spectrum, rapid, inexpensive tests based on 1) high affinity monoclonal antibodies to lipopolysaccharide; 2) antigen detection by using targets identified using protein arrays. PUBLIC RELEVANCE: Leptospirosis is a globally important infectious disease-affecting people globally. The goal of this project is to develop and validate diagnostic tests that can be used worldwide, independent of the predominant regional leptospiral serovars. The impact of this project is broad, and has the ultimate goal of determining the true global burden of disease for leptospirosis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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Mukhopadhyay, Suman
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Agampodi, Suneth B; Dahanayaka, Niroshan J; Nöckler, Karsten et al. (2016) Redefining Gold Standard Testing for Diagnosing Leptospirosis: Further Evidence from a Well-Characterized, Flood-Related Outbreak in Sri Lanka. Am J Trop Med Hyg 95:531-6
Fouts, Derrick E; Matthias, Michael A; Adhikarla, Haritha et al. (2016) What Makes a Bacterial Species Pathogenic?:Comparative Genomic Analysis of the Genus Leptospira. PLoS Negl Trop Dis 10:e0004403