The Lectin Complement Pathway Is Involved in Protection Against Enteroaggregative Escherichia coli Infection

Abstract

Enteroaggregative Escherichia coli (EAEC) causes acute and persistent diarrhea worldwide. Still, the involvement of host factors in EAEC infections is unresolved. Binding of recognition molecules from the lectin pathway of complement to EAEC strains have been observed, but the importance is not known. Our aim was to uncover the involvement of these molecules in innate complement dependent immune protection toward EAEC. Binding of mannose-binding lectin, ficolin-1, -2, and -3 to four prototypic EAEC strains, and ficolin-2 binding to 56 clinical EAEC isolates were screened by a consumption-based ELISA method. Flow cytometry was used to determine deposition of C4b, C3b, and the bactericidal C5b-9 membrane attack complex (MAC) on the bacteria in combination with different complement inhibitors. In addition, the direct serum bactericidal effect was assessed. Screening of the prototypic EAEC strains revealed that ficolin-2 was the major binder among the lectin pathway recognition molecules. However, among the clinical EAEC isolates only a restricted number (n = 5) of the isolates bound ficolin-2. Using the ficolin-2 binding isolate C322-17 as a model, we found that incubation with normal human serum led to deposition of C4b, C3b, and to MAC formation. No inhibition of complement deposition was observed when a C1q inhibitor was added, while partial inhibition was observed when ficolin-2 or factor D inhibitors were used separately. Combining the inhibitors against ficolin-2 and factor D led to virtually complete inhibition of complement deposition and protection against direct bacterial killing. These results demonstrate that ficolin-2 may play an important role in innate immune protection against EAEC when an appropriate ligand is exposed, but many EAEC strains evade lectin pathway recognition and may, therefore, circumvent this strategy of innate host immune protection.

Biochemical and structural characterization of a recombinant fibrinogen-related lectin from Penaeus monodon

“…There are reports that other shrimp fibrinogen-related lectins require Ca 2+ ion for ligand binding [29][30][31][32][33] . However, several ficolins are also capable of Ca 2+ -independent ligand binding 19,[34][35][36] . The role of Ca 2+ ion in PmFREP ligand binding modulated by protein stability need to be further investigated.…”

Decreased Ficolin-3-mediated Complement Lectin Pathway Activation and Alternative Pathway Amplification During Bacterial Infections in Patients With Type 2 Diabetes Mellitus

“…Based on previous studies some human pathogens, such as Hafnia alvei ( 32 ) can activate the ficolin-3 mediated lectin pathway and ficolin-3 is linked with growth inhibition of Aerococcus viridans ( 54 ). Additionally, ficolin-3 recognized pathogenic Pasteurella pneumotropica and two pathogenic E. coli (enteroaggregative E. coli O71 and enteropathogenic E. coli O111 ab:H2) in an interaction study ( 31 ), but Sorensen et al did not find any binding capacity of four prototypic enteroaggregative E. coli strains to recombinant ficolin-3 ( 55 ). Complement evasion strategies of E. coli , and altered factor H could also contribute to the diminished F3-LP activation and AP amplification in T2DM patients having E. coli related UTIs.…”

Antibodies Specific to Membrane Proteins Are Effective in Complement-Mediated Killing of Mycoplasma bovis

“…Although the MAC can effectively kill a wide range of Gram-negative bacteria, including E. coli (17) and N. meningitidis (32), the exact mechanism of this process remains poorly understood.…”

“…Bacteria can trigger all known routes of complement activation (i.e., the classical, lectin, and alternative pathways) through the recognition of conserved bacterial structures, resulting in the formation of the membrane attack complex (MAC), which has a split-washer shape comprising different complement components (C5b, C6, C7, C8, and multiple copies of C9) (11–13). Generally, the MAC is thought to kill Gram-negative bacteria by direct lysis or by destroying the metabolic system (14–17). However, the ability of the MAC to directly kill bacteria remains under debate.…”