Section: Research

Peter Rice, M.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Infectious Diseases and Immunology
   Medicine

Other Affiliation(s):
   Interdisciplinary Graduate Program
   Program in Immunology and Virology

Host Interactions with Neisseria gonorrhoeae

1. Complement

Research in the Rice laboratory involves the identification of unique determinants present on bacterial surfaces that may serve as suitable vaccine candidates to protect against infection in humans.  In some cases these determinants may also activate or regulate a series of inflammatory mediators called complement (C), which are made up of a group of proteins that are activated sequentially as part of the innate immune response: (1) to combat invading bacteria that infect humans by killing the bacteria and to also enhance their clearance by phagocytes; (2) to facilitate the development of the adaptive immune response to invading bacteria to protect against future infection caused by these organisms and (3) to amplify this immune response once it has developed.  Under certain conditions C works to the disadvantage of the host because it is hijacked by microorganisms to down-regulate the activation and binding of C and to also enhance entry into non-professional phagocytes (epithelial cells) where organisms gain sanctuary; these areas of study are important to consider when vaccines sometimes don’t work. The laboratory examines C interactions with bacteria, particularly the Neisseria species, having been first to report interactions of Neiseria gonorrhoeae with complement down-regulator molecules (factor H; an alternative pathway of C inhibitor) and C4 binding protein (C4BP; a classical pathway of C inhibitor). These are major factors that enable this bacterial species to escape immune surveillance. In particular, the laboratory is also characterizing molecular differences in C down-regulator molecules derived from different mammalian species to understand better the evolutionary aspects of the specificity of Neisseria infections for humans and to also guide the design of experimental models that will be suitable for study of these infections (see below).

2. Vaccine development

As a prelude to identifying suitable vaccine candidates to protect against gonococcal infection, the laboratory first identified and characterized blocking (or subverting) antibody targets on Neisseria species that interfere with productive killing (in vitro ) by C dependent bactericidal antibodies.  These antibody responses were elicited in a human vaccination trial that used a complex outer membrane structure as an immunogen that had been derived from N. gonorrhoeae.  A potentially protective response (C dependent bactericidal antibodies) that was elicited in men by the vaccine was subverted by the accompanying blocking antibody response directed against small amounts of  a reduction modifiable protein (Rmp) present in the vaccine, which caused the vaccine to fail when the men who received it were not protected upon subsequent urethral (experimental) challenge with virulentN. gonorrhoeae (experimental urethral gonorrhea in men is safe and an IRB approved method to study this disease).  Blocking antibodies are present in normal human serum and are also elicited by gonococcal infection itself. These antibodies may interfere with a protective immune response that is often seen with other bacterial infections and may explain the lack of protective  immunity that occurs after gonococcal infection. In efforts to identify suitable subunit vaccine candidates against gonorrhea devoid of blocking activity, the laboratory is recognized for its work in bacterial lipopolysaccharide (or lipooligosaccharide [LOS]) chemistry, having reported the first known conserved gonococcal LOS derived oligosaccharide epitope (called 2C7) that is present on almost all wild-type strains of N. gonorrhoeae.  This epitope, located in the core of LOS as lactose substitutions on each of the two core heptose molecules of LOS, elicits complement dependent antibody activity in humans both in natural infection and as a consequence of immunization. 

The Rice laboratory and its collaborators have performed extensive biochemical, structural and genetic analysis of this carbohydrate epitope and the surrounding structure(s) to define their role in C binding. To circumvent inherent disadvantages of carbohydrate antigens as immunogens when they are used as vaccines, the laboratory also  “converted” the 2C7 epitope first into an anti-idiotope (protein), and then into a peptide, vaccine candidates; both have been shown to be the immunologic counterparts (surrogates) of the oligosaccharide epitope.  These surrogates, when used as immunogens in experimental animals (mice), elicit C dependent bactericidal antibodies directed against the nominal LOS epitopes after immunization. These inventions have been issued U.S. and foreign patents and are being configured with appropriate adjuvants for use in: (1) experimental models in mice adapted to stimulate the human complement down-regulator system by creating human transgenics (human C4BP initially, then human factor H and other human complement regulators if they prove important)—see above and (2) for experimental trials in human subjects. 

Office: LRB-321
Phone: 508-856-4492
E-mail: Peter.Rice@umassmed.edu
Keywords: Immunology, Infectious Disease, Vaccine

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