James Samuel, PhD

Education and Training

• Miami University, BA, 1976
• Washington State University, MS, 1983
• Washington State University, PhD, 1986

Research Interests

• Molecular Pathogenesis of Coxiella burnetii, the agent of Q fever
• Our laboratory works with the obligate intracellular bacterial pathogen, Coxiella burnetii, the etiologic agent of Q fever and a category B biothreat agent. Because of their obligate intracellular growth restriction, they have become exquisitely adapted to their specific niche, which is similar to a typical terminal phagolysosome that evolves into a large, replicative vacuole. C. burnetii depends on various strategies to down-regulate the normal innate host response to bacterial infection. The organism is extremely sensitive to oxidative stress, lacking several repair genes essential to mitigate oxidative DNA damage, has a reduce requirement for and uptake systems for acquisition of iron, and actively inhibits activation of an oxidative burst by phagocytic cells through the secretion of an acid phosphatase. Isolates that originate from acute Q fever patients are able to induce acute, atypical pneumonia in rodent challenge models while isolates from chronic Q fevers patients (most commonly endocarditis and hepatitis) do not cause acute disease in animal models, confirming distinct pathotype virulence potentials between isolate groups.
• The long-term goal of this research is to understand the molecular pathogenic mechanisms involved in the host-pathogen interaction. To accomplish this broad goal, projects in the lab are designed to test the molecular mechanisms employed by both the host and pathogen. Current pathogen studies include 1) broad survey of proteins secreted via a type 4 secretion system (T4SS) followed by determination of essentiality of each substrate for virulence and detailed analysis of mechanism of host modulation 2) survey of essential virulence loci identified by specific mutant screens, and 3) definition of the relative virulence of phylogenetically distinct isolate groups.
• Our studies and those of other key research groups in this field have allowed the development of a more refined model of host-pathogen interactions and mechanisms used for survival and pathogenesis (Figure 1). These studies have been enabled by recent paradigm-shifting advances in experimental approach allowing for growth in extracellular media and generation of defined mutants and resulting in a renaissance of discovery this important, but seldom-studied pathogen.
• One overriding emphasis by the pathogen is to dampen typical innate response during infection. At least four T4SS effectors localize to the nucleus (CBU1314, CBU 794, CBU1217, and CBU1524/CaeA) during ectopic expression and may be involved in the transcriptional modulation that occurs during C. burnetii infection. We are currently screening through transposon mutants and site-specific mutants for those effectors that mediate this dampening of innate response to infection.
• Vaccine and Diagnostic Development against Q fever
• These current studies are focused on 1) the response to infection by the host, especially by cells of the immune system, 2) understanding the components of protective immunity elicited by a killed whole cellular antigen (WCV-1) and, 3) identify appropriate vaccine strategies composed of recombinant and native antigens to elicit protective immunity. Protection against Q fever can be induced by vaccination with (WCV-1), yet due to the adverse reaction to vaccination of previously sensitized individuals, wide use of the vaccine has not been employed and no Q fever vaccine is available in the US. Our recent studies demonstrated that antibody against the O side chain polysaccharide of C. burnetii LPS is an important component of vaccine-induced immunity. Additionally, control of infection by vaccinates involves the ability to stimulate recall responses to antigen by memory T cells that activate interferon gamma-mediated killing by host macrophages. These vaccine strategies are being evaluated in rodent and non-human primate models of human Q fever.