The complement system is composed of a number of plasma proteins which, when acting in an ordered and integrated fashion, mediate a variety of important immunological reactions. Activation of the complement system can either be beneficial to the host, such as occurs in resistance to microbial invasion, or it can be detrimental to the host, such as occurs in a variety of immunopathologic reactions. The studies proposed in the current application will focus on two different, but related, aspects of the complement system and its interaction with invading microorganisms. The first series of studies will focus on one of the molecular mechanisms by which the complement system could cause immunopathologic damage to the host during bacterial infections. Gram-positive bacteria possess characteristic polysaccharides in their cell membranes which are called lipoteichoic acids (LTA). Lipoteichoic acids possess two characteristics which may be important in the generation of immunopathologic damage to the host during bacterial infection. First, they are secreted by bacteria and can bind to a variety of host cells. Second, there is some data suggesting that LTA is capable of activating the complement system. Accordingly, we will determine if LTA is able to bind to host cells and endow them with the ability to activate the complement system, thereby causing immunopathologic damage to the host. Although our initial studies will focus on the interaction of pneumococcal LTA and erythrocytes, later experiments will involve LTA from other bacteria, such as streptococci, and other target cells such as type II alveolar cells and vascular endothelial cells. The second series of experiments will focus on the role of the complement system in the host's defense against bacterial infection. Although six capsular serotypes of Haemophilus influenzae exist, only one of them, the type b organism, commonly causes life-threatening systemic disease. The complement system plays an important role in the host's defense against H. influenzae infection. Accordingly, we will study the interaction of the different serotypes (a-f) of encapsulated H. influenzae with the complement system in order to determine if the proclivity of the type b organism to cause systemic disease is due to a relative resistance on its part to the defensive functions of the complement system.
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