NYMC Student Theses and Dissertations

Date of Award

5-19-2020

Document Type

Master's Thesis - Restricted (NYMC/Touro only) Access

Degree Name

Master of Science

Department

Microbiology and Immunology

First Advisor

Chandra Shekhar Bakshi, DVM, Ph.D.

Second Advisor

Raj Tiwari, Ph.D.

Third Advisor

Dana Mordue, Ph.D.

Abstract

Francisella tularensis (F. tularensis) is an intracellular, Gram-negative bacterium that causes the disease tularemia. Strains of F. tularensis subspecies tularensis (Type A) are extremely virulent in animals and humans, with an infectious dose (ID50 ) of less than 10 colony-forming units (CFU). Combined with its ease of aerosolization, limited antibiotic treatment options, and high morbidity and mortality, the United States Centers for Disease Control and Prevention (CDC) has classified F. tularensis as a Category A/Tier 1 select agent, indicating its potential use as a bioweapon. Francisella infection can occur in various forms, the six most common being: ulceroglandular , gastrointestinal, oculoglandular, oropharyngeal, typhoidal, and pneumonic, with pneumonic tularemia being the main cause of concern. The pneumonic form of the disease can manifest from only 10 organisms from the Type A strain and can cause up to 30-60% mortality without treatment. Though there are antibiotic regimens in place for tularemia, relapses are common. This knowledge, combined with the fact that there is no licensed vaccine and streptomycin (the primary drug of choice for treatment of Francisella)-resistant strains exist, warrants the search for natural therapies to either serve as a sole treatment option directly or to synergistically act in combination with current antibiotics regimens. In this study, we explored the therapeutic potential of Traditional Chinese Medicine (TCM) compounds and a Nuphar lutea plant extract (Nupharidine) in the treatment of pneumonic tularemia. TCM compounds and Nupharidine were tested for their Francisella-cidal activity under acellular growth conditions and their ability to kill intracellular Francisella. Furthermore, Nupharidine was also tested for its therapeutic potential for the treatment of pneumonic tularemia in mice. xi Using bacterial killing and cell culture assays, we demonstrated that Nupharidine has bactericidal effects against F. tularensis Live Vaccine Strain (LVS). Intraperitoneal injection of Nupharidine in mice infected intranasally with F. tularensis extended median time to death in C57BL/6 mice and resulted in 25% protection in BALB/c mice as compared to the untreated controls. Collectively, the results from this study demonstrate that Nupharidine may be developed as a potential therapeutic option for the treatment of fatal pneumonic tularemia.

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