Francisella tularensis (Ft), a Gram negative intracellular bacterium, the etiologic agent of tularemia, and is classified as a Category A agent because it can contracted with low inocula by the respiratory route and causes rapid morbidity and mortality if untreated. While attenuated for humans, mice infected i.n. or i.p. with Ft Live Vaccine Strain (LVS), a type B strain, contract a tularemia-like disease. In this grant cycle, we reported that Ft LVS induces in mice a potent inflammatory response in vivo and in vitro. Using Ft LVS mutants that fail to escape from the phagosome or fail to replicate intracellularly in murine macrophages, we identified the signaling pathways by the host innate immune system is activated. Ft LVS induces TLR2- mediated signaling;however, once Ft escapes from the phagosome into the cytosol, IFN-J3 is produced and reutilized, and the inflammasome activated. Despite this robust inflammatory response, the host succumbs to infection. Our data indicate that Ft LVS initiates a strong inflammatory response leading to development of """"""""classically activated"""""""" macrophages (CA-M0);however, once IL-4 and IL-13 are induced by infected macrophages, they differentiate into """"""""alternatively activated"""""""" (AA-M0), thereby facilitating intracellular replication. Ft LVS-infected IL-4Ra~'~ and STAT6""""""""'"""""""" macrophages fail to differentiate into AA-M0 and control intracellular replication, while Ft LVS-infected macrophages treated with rIFN-p restrict bacterial growth. Ft LVS lipopolysaccharide (LPS), a poor TLR4 agonist, fails to induce an inflammatory response. However, when mice are vaccinated with Ft LVS LPS 2 days prior to lethal i.p. challenge, a protective anti-LPS antibody response is induced by splenic B-1a cells. We will now seek novel ways to control respiratory infection with Ft LVS and Schu S4, a virulent type A strain, by testing the hypotheses that (1) Schu S4, like Ft LVS, drives AA-M0 to evade host responses;(2) agents that interfere with development ofAA-M0 will increase the anti-microbial response in vivo;and, (3) increasing the immunogenicity of a Ft LVS LPS vaccine will protect mice against respiratory and systemic challenge with Ft LVS and Schu S4. The main objective of this proposal is to develop novel therapies for tularemia based on interfering with development of AA-M0, as well as improve development of a safe vaccine(s) that protects against both type A and B strains.
F. tularensis (Ft) is a bacterial pathogen that replicates intracellularly in macrophages. It is classified as a Category A agent based on its ease of aerosolization, low infectious dose, and rapid onset of debilitating disease. By understanding the interplay between the innate and adaptive immune response to Ft, we may be able to identify mechanisms whereby the host response to this agent can be manipulated, allowing more time for intervention with antibiotics and the host's own adaptive immune response to control the pathogen.
|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|
Showing the most recent 10 out of 373 publications