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The overarching research objective of the Sellati laboratory is to understand how host responses are tailored to the specific pathogens they encounter, particularly pathogens that represent emerging and re-emerging infectious agents whose arthropod vector are ticks. Studies in the laboratory focus on two distinct, yet interrelated, aspects of bacterial pathogenesis (i.e., disease development and resolution). In both instances, innate immunity, a pre-programmed first-line defense against invading pathogens, plays a defining role in the disease process. A fundamental question we hope to answer is why some individuals present with more severe and/or persistent inflammation during infection than others. Current efforts span three research programs focused on combating Lyme disease, tularemia, and antibiotic resistant bacterial infections. Lyme disease, a multisystem chronic inflammatory disorder that affects the skin, joints, heart, and nervous system, is caused by infection with the tick-borne spirochetal bacterium, Borrelia burgdorferi. We have identified key players in the signal transduction pathway responsible for immune cell activation that contributes to clinical manifestations. Cell surface receptors including CD14, a 55-kDa polypeptide expressed on neutrophils and monocytes/macrophages, and Toll-like Receptor 2, whose engagement of bacterial lipoproteins communicates a “danger signal” to the cell’s interior, regulate the secretion of several pro- and anti-inflammatory immune modulators. Such regulation is thought to play a critical role in Lyme pathogenesis and thus these signaling pathways provide rich targets for therapeutic intervention. With an infectious dose requiring as few as 10 individual bacteria Francisella tularensis, a Gram-negative facultative intracellular pathogen, can cause a lethal vector-borne pulmonary disease in humans known as tularemia. These features, coupled with its ability to contaminate food and water and the ease of intentional dissemination via aerosol, have resulted in the pathogen being listed as a category “A” biothreat agent by the U.S. Centers for Disease Control and Prevention. Current efforts are focused on revealing the mechanism(s) whereby F. tularensis modulates host lipid mediator production as a means to alter innate cell death programs and establish a principally anti-inflammatory or immunosuppressed environment in which to replicate. Other studies focus on antigen presentation in the context of vaccination and the role of TLR2 signaling in the development of protective immunity. Specifically, ongoing efforts aim to develop a pan-bacterial, rapid vaccine-development platform that radically alters the current approach to vaccination against highly infectious agents. Coupled with the existence of biological threat agents engineered to be impervious to treatment, the full range of antibiotic-resistant microbes found in hospitals and the broader environment represent a “clear and present danger” to military personnel, first responders, and the general public. Current efforts to combat the public health challenges associated with antibiotic resistance center around our ability to engineer self-assembling antimicrobial nanofibers (SAANs) to be non-toxic and noninflammatory to human cells, resistant to degradation, and pan-bactericidal in effect. These properties make SAANs the ideal substitute for traditional antibiotics and adding them to the clinical “arsenal” will have a transformative impact on the field of anti-infective therapy. SAANs are being tested against select biological threat agents (i.e., F. tularensis and Yersinia pestis) as well as highly antibiotic-resistant Acinetobacter baumannii, which is responsible for nosocomial, community-acquired infections as well as those acquired following war or natural disasters. The therapeutic potential of SAANs is being evaluated using well-characterized and validated mouse models of respiratory tularemia and plague as well as deep tissue wound and respiratory infections with A. baumannii.