COMPLEMENT ACTIVATION BY MANNOSE-BINDING PROTEIN

Project: Research project

Project Details

Description

The long term objectives are to elucidate the role of mannose-binding
protein (MBP) in protecting non-immune hosts from overwhelming infections
or parasitic infestations. The overall objective is to investigate the
newly described capacity of MBP to activate the alternative complement
pathway (ACP) and to enhance serum bactericidal activity. Potential
interactions between MBP, C-reactive protein (CRP), and serum amyloid P
(SAP) in control of complement activation will be studied. Using enteric
gram negative bacteria (primarily Salmonella species) bearing various
amounts of mannose in their LPS, characteristics of susceptible organisms,
of MBP, and of complement which allow participation in this immune
mechanism will be examined. similar studies will be performed using
Leishmania major, a parasite with a distinct, mannose-rich
lipophosphoglycan during its infective stage. The possibility that MBP may
interact with C-reactive protein (CRP) or with serum amyloid P (SAP) to
modulate complement activation will be explored. To achieve these goals,
the following specific aims will be pursued: I. Determine structural
requirements for MBP necessary to enhance C3 deposition on susceptible
bacteria by studying the capacity of MBP proteolytic fragments or hybrids
to enhance C3 binding to bacteria.
II. Investigate the mechanism for enhanced ACP activation by MBP by
examining its interaction with each component of the ACP -C3, Factors B&D,
and properdin - and the regulatory proteins - Factors H&I - using LPS-
bearing liposomes and bacteria
III. Determine LPS components which interact with MBP by comparing its
interaction with rough mutants and smooth wild type strains, by attempting
to block MBP activity with mannose or N-acetylglucosamine or with MAb
directed against each LPS chemotype, and by examining LPS lengths optimum
for interactions with MBP and complement
IV. Determine the mechanism for serum bactericidal activity mediated by
MBP by investigating the effects MBP has on lytic terminal complement
components and on the acceptor sites for C3 amide bond formation
V. Determine if MBP enhances complement deposition on L. major
VI. Determine if complement activation by MBP is affected by CRP or SAP These seem extremely important concepts to understand about MBP, a
circulating protein which prevents invasion of cells by HIV, and also is
involved in immune response to an organism, Salmonella, which is
particularly difficult to eradicate in AIDS patients.
StatusFinished
Effective start/end date1/1/9012/31/94

Funding

  • National Institutes of Health: $96,458.00
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)

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