Clinical Relevance. Leptospirosis is a potentially fatal bacterial infection that is considered by the Centers for Disease Control to be the most widespread infectious disease that can be acquired from infected animals. Flu-like symptoms, often the only symptoms of early disease in leptospirosis, are characteristic of many infectious diseases, delaying diagnosis and treatment. Diagnosis is further hindered by the lack of a reliable blood test for acute leptospirosis. A safe and effective human leptospiral vaccine currently does not exist. Recent studies have demonstrated that the Lig proteins of Leptospira can serve as serologic antigens for detection of leptospiral infection in its early stages. Moreover, studies with hamsters, the standard animal model used in leptospirosis research, demonstrated that vaccination with the LigA protein prevented disease when the animals were later injected with Leptospira, although the bacteria were still able to colonize the kidneys. Our proposed studies of the binding properties of Lig proteins to human and rodent cells will allow us to rationally improve the effectiveness of the LigA vaccine, which may target the attachment activity of the Lig proteins. Novel treatments for leptospirosis can also be developed by identifying protease inhibitors of the leptospiral enzyme that causes LigA to be released from the bacteria thereby possibly facilitating spread of the bacteria throughout the body. Inhibitors of the same class are currently administered to patients infected with HIV to stall progression to AIDS. PUBLIC HEALTH RELEVANCE: Potential Impact on Veteran Health Care. Leptospirosis is a neglected disease of poverty in the United States. Urban residents are at particular risk for leptospirosis if homelessness results in exposure to urine of rats shedding Leptospira. One study found that 16% of Baltimore's inner city black males, an important component of the patient population served by VA medical centers. The Department of Veterans Affairs has identified leptospirosis as an important potential cause of illness for military personnel serving in many areas of the world, including Afghanistan and the Middle East. Ocular and neurologic manifestations of leptospirosis may not appear for several months to years following the initial exposure. For these reasons, there is an urgent need for new serodiagnostic tools to rapidly identify military personnel and veterans exposed to Leptospira. Additionally, a safe and effective low-cost vaccine may be beneficial for VA populations at risk for leptospirosis.