How Escherichia coli Circumvent Complement-Mediated Killing

Abstract

Complement is a crucial arm of the innate immune response against invading bacterial pathogens, and one of its main functions is to recognize and destroy target cells. Similar to other pathogens, Escherichia coli has evolved mechanisms to overcome complement activation. It is well known that capsular polysaccharide may confer resistance to complement-mediated killing and phagocytosis, being one of the strategies adopted by this bacterium to survive in serum. In addition, proteases produced by E. coli have been shown to downregulate the complement system. Pic, an autotransporter secreted by different pathogens in the Enterobacteriaceae family, is able to cleave C2, C3/C3b, and C4/C4b and works synergistically with human Factor I and Factor H (FH), thereby promoting inactivation of C3b. Extracellular serine protease P, a serine protease of enterohemorrhagic E. coli (EHEC), downregulates complement activation by cleaving C3/C3b and C5. StcE, a metalloprotease secreted by EHEC, inhibits the classical complement-mediated cell lysis by potentiating the action of C1 inhibitor, and the periplasmic protease Prc contributes to E. coli complement evasion by interfering with the classical pathway activation and by preventing membrane attack complex deposition. Finally, it has been described that E. coli proteins interact with negative complement regulators to modulate complement activation. The functional consequences resulting from the interaction of outer membrane protein A, new lipoprotein I, outer membrane protein W, and Stx2 with proteins of the FH family and C4b-binding protein (C4BP) are discussed in detail. In brief, in this review, we focused on the different mechanisms used by pathogenic E. coli to circumvent complement attack, allowing these bacteria to promote a successful infection.

Antibody opsonization enhances MAIT cell responsiveness to bacteria via a TNF‐dependent mechanism

“…Both IgM and IgG antibodies deposited on the pathogen surface further trigger the complement system by initiating the activation of the classical complement pathway. Certain pathogens like E. coli , however, have evolved mechanisms to avoid complement attack and therefore are rescued from complement‐mediated lysis . As a result, pathogens become opsonized with both complement‐fragments and IgG‐molecules under in vivo conditions.…”

“…Certain pathogens like E. coli, however, have evolved mechanisms to avoid complement attack and therefore are rescued from complement-mediated lysis. 34 As a result, pathogens become opsonized with both complement-fragments and IgG-molecules under in vivo conditions.…”

Ecotin, a microbial inhibitor of serine proteases, blocks multiple complement dependent and independent microbicidal activities of human serum

“…Microbial pathogens evolved a variety of complement evasion strategies. These mainly rely on the acquisition or expression of complement regulators and inhibitors, or on the degradation of complement components [36][37][38], demonstrating that complement inhibition is a crucial defense mechanism of pathogenic microbes. In this paper, we unequivocally prove that ecotin inhibits both antibody-independent CS pathways, the LP and the AP, and it also blocks an apparently complement unrelated antibacterial serum activity.…”

Bacterial killing by complement requires direct anchoring of Membrane Attack Complex precursor C5b-7

“…We identified complement-resistant E. coli strains that blocked MAC-mediated killing by preventing efficient anchoring of C5b-7 to the bacterial cell envelope and subsequent insertion of MAC pores. Although several mechanisms of bacterial complement evasion have been described (33–36), these are mostly not MAC-specific because they block initial complement activation steps such as recognition or the deposition of functional convertases (35,37,38). Preventing efficient anchoring of C5b-7 to thus affect insertion of MAC pores into the bacterial cell envelope has not, to our knowledge, been reported before on E. coli .…”