The efficacy of antibodies (Abs) to toxins and capsules is a complex function of dose, specificity, isotype, complement activation and FcR engagement. However, 120 years after Ab-mediated immunity was first discovered, the relationships between affinity, isotype, and Fc receptor activation have not been rigorously defined for any microbial toxin or capsule. Our group has generated mAbs to five Bacillus anthracis antigens including anthrax toxin components protective antigen, lethal factor, and edema factor, capsule poly((-Dglutamic acid) (PGA), and Anthrolysin. This application proposes to investigate the structure-function relationship for these immunoglobulins with the goal of identifying the optimal combination of affinity, isotype, and specificity that determines protective efficacy. We propose to apply several state of the art technologies available to us in the form of in vitro somatic hypermutation, human FcR technology, V region expression, and Veloclmmune? system to carry out the first comprehensive analysis of this fundamental immunological question while also generating new Ab reagents that are candidates for passive immune therapies.
Three specific aims are proposed:
Aim 1. To investigate the relationship between affinity and efficacy capacity for Abs to anthrax toxins and PGA;
Aim 2. To investigate the efficacy of constant (C) regions in Abneutralization of anthrax toxins and PGA;
Aim 3. To investigate the relationship between human Fc type and Ab-neutralization of anthrax toxins and PGA, We anticipate that the information generated from these studies will result in the design of more effective passive therapeutic strategies.
|Charles, Jermilia; Firth, Andrew E; LoroÃ±o-Pino, Maria A et al. (2016) Merida virus, a putative novel rhabdovirus discovered in Culex and Ochlerotatus spp. mosquitoes in the Yucatan Peninsula of Mexico. J Gen Virol 97:977-87|
|Pham, Alissa M; Santa Maria, Felicia Gilfoy; Lahiri, Tanaya et al. (2016) PKR Transduces MDA5-Dependent Signals for Type I IFN Induction. PLoS Pathog 12:e1005489|
|Song, Jeongmin; Wilhelm, Cara L; Wangdi, Tamding et al. (2016) Absence of TLR11 in Mice Does Not Confer Susceptibility to Salmonella Typhi. Cell 164:827-8|
|Li, Melody M H; Bozzacco, Leonia; Hoffmann, Hans-Heinrich et al. (2016) Interferon regulatory factor 2 protects mice from lethal viral neuroinvasion. J Exp Med 213:2931-2947|
|Moser, Lindsey A; Lim, Pei-Yin; Styer, Linda M et al. (2016) Parameters of Mosquito-Enhanced West Nile Virus Infection. J Virol 90:292-9|
|Basu, Debaleena; Kahn, Jennifer N; Li, Xiao-Ping et al. (2016) Conserved Arginines at the P-Protein Stalk Binding Site and the Active Site Are Critical for Ribosome Interactions of Shiga Toxins but Do Not Contribute to Differences in the Affinity of the A1 Subunits for the Ribosome. Infect Immun 84:3290-3301|
|Steyer, Andrej; JevÅ¡nik, Monika; Petrovec, Miroslav et al. (2016) Narrowing of the Diagnostic Gap of Acute Gastroenteritis in Children 0-6 Years of Age Using a Combination of Classical and Molecular Techniques, Delivers Challenges in Syndromic Approach Diagnostics. Pediatr Infect Dis J 35:e262-70|
|Uhde, Melanie; Ajamian, Mary; Li, Xueting et al. (2016) Expression of C-Reactive Protein and Serum Amyloid A in Early to Late Manifestations of Lyme Disease. Clin Infect Dis 63:1399-1404|
|Jacek, Elzbieta; Tang, Kevin S; Komorowski, Lars et al. (2016) Epitope-Specific Evolution of Human B Cell Responses to Borrelia burgdorferi VlsE Protein from Early to Late Stages of Lyme Disease. J Immunol 196:1036-43|
|Aguilar, Jorge L; Varshney, Avanish K; Pechuan, Ximo et al. (2016) Monoclonal antibodies protect from Staphylococcal Enterotoxin K (SEK) induced toxic shock and sepsis by USA300 Staphylococcus aureus. Virulence :1-10|
Showing the most recent 10 out of 643 publications