Aerosolization is the most dangerous route of infection by select agents. Because of difficulty in diagnosis, it would be valuable to have therapies active against a broad range of aerosolized pathogens. Remarkably, ittle is known about the pathophysiology, microbiology, and immunology associated with aerosol delivery. This is due mostly to infrastructure requirements for aerosolization experiments, the specialized equipment that is necessary, and the limited number of individuals trained in the field of aerobiology. The work proposed in this application addresses this lack of understanding by combining expertise in aerobiology, microbial pathogenesis, immunology, and gene therapy. The ultimate goal of this program is to identify commonalities or deficiencies in host responses that can be targeted by immunotherapies, treatments that would benefit an individual exposed to any number of bioterrorism agents. To address this, three different select agent bacterial pathogens have been chosen for detailed study: Francisella tularensis, Yersinia pestis, and Burkholderia pseudomallei. Each of these pathogens alters host responses, thereby enhancing their success against the host. Bolstering host responses, therefore, is an attractive strategy to mitigate morbidity and mortality by agents like these three pathogens, regardless of the actual bacterium infecting the host. To identify immunotherapies providing cross-pathogen protection against aerosol infection, we propose these specific aims:
Aim 1 : To characterize the natural history of bacterial select agents delivered by aerosol. The objective of this aim is to characterize the pathophysiology of the three bacterial pathogens aerosolized into mice.
Aim 2 : To determine shared and distinct innate and bridging immune responses to bacterial select agents. These studies will characterize the innate and bridging immune response to F. tularensis, B. pseudomallei, and Y. pestis.
Aim 3 : To manipulate early host responses as therapeutic interventions. These studies will investigate whether augmenting innate and/or bridging immune responses with Th1 or Th17 effector cytokines can bolster host resistance to F. tularensis, B. pseudomallei, and Y. pestis delivered as an aerosol.

Public Health Relevance

Biological attacks are most likely to be delivered by aerosolization because this route of infection causes severe disease. The goal of these studies is to develop therapies that are active against a broad range of pulmonary infections by biodefense agents, regardless of the etiology.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZAI1-DDS-M)
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University of Maryland Baltimore
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Kaempfer, Raymond; Popugailo, Andrey; Levy, Revital et al. (2017) Bacterial superantigen toxins induce a lethal cytokine storm by enhancing B7-2/CD28 costimulatory receptor engagement, a critical immune checkpoint. Receptors Clin Investig 4:
Bridge, Dacie R; Blum, Faith C; Jang, Sungil et al. (2017) Creation and Initial Characterization of Isogenic Helicobacter pylori CagA EPIYA Variants Reveals Differential Activation of Host Cell Signaling Pathways. Sci Rep 7:11057
Molleston, Jerome M; Cherry, Sara (2017) Attacked from All Sides: RNA Decay in Antiviral Defense. Viruses 9:
Cifuentes-Muñoz, Nicolás; Sun, Weina; Ray, Greeshma et al. (2017) Mutations in the Transmembrane Domain and Cytoplasmic Tail of Hendra Virus Fusion Protein Disrupt Virus-Like-Particle Assembly. J Virol 91:
Wahid, Rezwanul; Fresnay, Stephanie; Levine, Myron M et al. (2016) Cross-reactive multifunctional CD4+ T cell responses against Salmonella enterica serovars Typhi, Paratyphi A and Paratyphi B in humans following immunization with live oral typhoid vaccine Ty21a. Clin Immunol 173:87-95
Li, Huiguang; Hwang, Young; Perry, Kay et al. (2016) Structure and Metal Binding Properties of a Poxvirus Resolvase. J Biol Chem 291:11094-104
Ramachandran, Girish; Tennant, Sharon M; Boyd, Mary A et al. (2016) Functional Activity of Antibodies Directed towards Flagellin Proteins of Non-Typhoidal Salmonella. PLoS One 11:e0151875
Molleston, Jerome M; Sabin, Leah R; Moy, Ryan H et al. (2016) A conserved virus-induced cytoplasmic TRAMP-like complex recruits the exosome to target viral RNA for degradation. Genes Dev 30:1658-70
Riblett, Amber M; Blomen, Vincent A; Jae, Lucas T et al. (2016) A Haploid Genetic Screen Identifies Heparan Sulfate Proteoglycans Supporting Rift Valley Fever Virus Infection. J Virol 90:1414-23
Chou, Yi-ying; Cuevas, Christian; Carocci, Margot et al. (2016) Identification and Characterization of a Novel Broad-Spectrum Virus Entry Inhibitor. J Virol 90:4494-510

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