Antibody-independent killing of gram-negative bacteria via the classical pathway

It has been recognised since 1895 that some gram-negative bacteria are sensitive towards the lytic action of serum. Many aspects of this phenomenon in regard to antibody-dependent activation of the complement system and the activation of the alternative pathway in the presence and absence of antibodies had been investigated. However, a lot of serum-sensitive bacteria are killed in nonimmune sera and bind directly C1 in the absence of antibodies. Therefore, we were interested in the killing capacity of an antibody-independent activated classical pathway. For the immediate killing of these serum-sensitive bacteria within even one hour, all complement components are essential. The effective bactericidal effect is dependent on the classical pathway components like C1, C4, C2 and Ca2+. C1 is directly bound to the bacteria, becomes activated and is able to cleave C4. For C2-conversion and the further activation of the cascade, an additional serum factor different from an antibody is required. This factor seems to mediate the attachment of C4b to the bacterial surface, which is a prerequisite for the formation of the classical C3-convertase, C4b2a, on the cell surface. The antibody-independent interaction with C1 occurs via C1q, which binds to LPS and possibly also via another C1-subcomponent, C1r and/or C1s. The latter is supposed to interact with outer membrane proteins providing the tight interaction of C1 with the bacteria. This mechanism might be of importance for the killing of R-forms of gram-negative bacteria.