The phytotoxin ricin is a class B bioterrorism agent that is lethal to humans after parenteral or mucosal (i.e., respiratory or gastrointestinal) exposure. There is no ricin vaccine or antidote licensed for human use at the present time. A member of the shiga-like family of toxins, ricin is a heterodimeric protein comprised of an enzymatic """"""""A"""""""" subunit and a binding """"""""B"""""""" subunit. The ricin B subunit (RBS) is a lectin that mediates attachment of the toxin to terminal galactose moieties on host cell plasma cell membranes, including the apical surfaces of intestinal epithelial cells. We hypothesize that secretory IgA (SIgA) antibodies -the predominant immunoglobulin class in mucosal secretions-directed against RBS may protect the gastrointestinal epithelium from the cytotoxic effects of ricin.
Aim 1 will test this hypothesis by producing a panel of mouse monoclonal IgA antibodies against the RBS and testing them in vitro for the ability to prevent ricin binding to polarized intestinal epithelial cell monolayers.
Aim 2 will determine the form of RBS and route of mucosal immunization that best induces anti-RBS SIgA antibodies in gastrointestinal secretions of mice, and will test whether these secretions can prevent ricin-induced cytotoxicity in vitro. Finally, Aim 3 will characterize in detail a mouse model of gastrointestinal ricin poisoning we have recently established. The mouse model will then be used to determine whether anti-RBS monoclonal IgA antibodies, or anti-RBS SIgA antibodies induced following mucosal vaccination, can protect the gastrointestinal mucosa in vivo. This information will contribute to the development of a safe and effective mucosal ricin vaccine.
| Neal, Lori M; McCarthy, Elizabeth A; Morris, Carolyn R et al. (2011) Vaccine-induced intestinal immunity to ricin toxin in the absence of secretory IgA. Vaccine 29:681-9 |
| Neal, Lori M; O'Hara, Joanne; Brey 3rd, Robert N et al. (2010) A monoclonal immunoglobulin G antibody directed against an immunodominant linear epitope on the ricin A chain confers systemic and mucosal immunity to ricin. Infect Immun 78:552-61 |
| Mantis, Nicholas J; McGuinness, Carolyn R; Sonuyi, Oluwakemi et al. (2006) Immunoglobulin A antibodies against ricin A and B subunits protect epithelial cells from ricin intoxication. Infect Immun 74:3455-62 |
