Analysis of the immunogenicity of peptide mimotopes of Burkholderia pseudomallei exopolysaccharide
Burkholderia pseudomallei is the causative agent of the disease melioidosis,
which is endemic in the tropics and a concern elsewhere as a biological warfare agent.
Currently no human vaccine exists either in clinical trials or in a licensed form. Recently
passively transferred monoclonal antibodies directed toward the expolysaccharide of B.
pseudomallei have been shown to impart survival when administered prior to lethal
challenge and active immunization using purified exopolysaccharide extends the mean
time to death. Short peptides, termed mimotopes, mimicking native carbohydrate have
been developed and used to induce protective responses against extracellular bacteria.
Here the ability of mimotopes to generate a protective response against a pathogen that
can invade host cells was investigated. Mimotopes immunoreactive to the passive
protective monoclonals were developed and used to generate an antibody response
against B. pseudomallei. Preliminary evaluation of the mimotopes in a murine challenge
model of acute melioidosis identified one mimotope which may have utility by extending
the mean time to death.
Previous work with the Protective Antigen (PA) and first domain of Lethal Factor
(LFn) has focused on delivering cytotoxic T cell antigens to the host cell. Here the
antibody response to a B cell antigen fused to LFn as modeled by Yersinia pestis LcrV
was examined. When LcrV was fused to the N terminal of LFn and codelivered with PA,
the anti-LcrV titer was significantly increased. This increased titer for a B cell antigen
fused to LFn was further examined as a B cell epitope modeled by the mimotopes of B.
pseudomallei exopolysaccharide. Antibody titer against B. pseudomallei raised by LFnmimotope
fusions was not increased over peptide conjugates of the mimotope. Fusion to
LFn did increase the avidity of immune sera for B. pseudomallei to levels matching that
of the parent monoclonal antibodies for B. pseudomallei. Taken together, LFn can be
used to deliver B cell antigens to the immune system and should be considered as a
means to present peptide mimotopes of carbohydrates to the immune system.
School:The Ohio State University
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:microbial exopolysaccharides melioidosis
Date of Publication: