Clostridium perfringens epsilon toxin (ETX) is a class B CDC/USDA overlap toxin and a major virulence factor in natural veterinary infections caused by ETX-producing C. perfingens isolates. Currently there are no ETX therapeutics (NIH prefers ETX therapeutics over vaccines because natural ETX-related disease in humans is uncommon). Early steps in ETX action on host cells are poorly understood, which has negatively impacted the development of ETX therapeutics. To remedy the limited understanding of early steps in ETX action and begin exploring the development of ETX therapeutics, the following specific aims will be pursued in this MARGE project (part of Program V, interactions between toxins and host cells): i) Aim 1 will identify the ETX receptor in kidney, brain and lung by expression cloning approaches;ii) Aim 2 will immunolocalize the distribution of the identified receptor in animal and human tissues;iii) Aim 3 will evaluate the pathogenic importance of the identified ETX receptor using antibody blocking approaches, siRNA-mediated reduction of receptor expression, and (if available) receptor knock-out mice;iv) Aim 4 will analyze, by mass spectrometry, the protein composition of ETX complexes formed in the plasma membrane of sensitive host cells to gain further insights into ETX action;v) since previous studies have shown that sialidases can increase ETX binding/activity in MDCK cells, Aim 5 will use isogenic sialidase mutants to evaluate the hypothesis that sialidases similarly potentiate the virulence of ETX-producing isolates and vi) Aim 6 will evaluate the therapeutic potential of ETX receptor decoys. These studies are expected to produce new approaches for therapeutic inhibition of ETX activity, which is a current priority for NIH biodefense activities.
Because of its potency, Clostridium perfringens epsilon toxin (ETX) is listed as a CDC/USDA overlap class B select toxin. Development of ETX therapeutics has been hindered by limited understanding of the early steps in ETX action. This project seeks to understand the early steps in ETX action, particularly the interactions between ETX and its receptor, and exploit this knowledge to develop ETX therapeutics.
|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