Binding of Vitronectin by the Moraxella catarrhalis UspA2 Protein Interferes with Late Stages of the Complement Cascade

Fusobacterium necrophorum subspecies funduliforme is an obligate anaerobic Gram-negative rod causing invasive infections such as the life-threatening Lemierre’s syndrome (sore throat, septicemia, jugular vein thrombosis, and disseminated infection). The aim of our study was to understand if and how F. necrophorum avoids C activation. We studied 12 F. necrophorum subsp. funduliforme strains isolated from patients with sepsis. All strains were resistant to serum killing after a 1-h incubation in 20% serum. The bacteria bound, at different levels, the C inhibitor factor H (fH). Binding was ionic and specific in nature and occurred via sites on both the N terminus and the C terminus of fH. Bound fH remained functionally active as a cofactor for factor I in the cleavage of C3b. Interestingly, patients with the most severe symptoms carried strains with the strongest ability to bind fH. An increased C3b deposition and membrane attack complex formation on the surface of a weakly fH-binding strain was observed and its survival in serum at 3.5 h was impaired. This strain had not caused a typical Lemierre’s syndrome. These data, and the fact that fH-binding correlated with the severity of disease, suggest that the binding of fH contributes to virulence and survival of F. necrophorum subsp. funduliforme in the human host. Our data show, for the first time, that an anaerobic bacterium is able to bind the C inhibitor fH to evade C attack.

Section: Discussionmentioning

confidence: 99%

Factor H Binding as a Complement Evasion Mechanism for an Anaerobic Pathogen, Fusobacterium necrophorum

Friberg

Carlson

Kentala

et al. 2008

“…This interaction contributed to serum resistance of Hib strains and was linked to Hsf protein expression. Moraxella catarrhalis ubiquitous surface protein A2 is another surface molecule that has been found to bind vitronectin and significantly contributes to serum resistance (43).…”

Section: Discussionmentioning

confidence: 99%

NontypeableHaemophilus influenzaeProtein E Binds Vitronectin and Is Important for Serum Resistance

Hallström

Blom

Zipfel

et al. 2009

138

Nontypeable Haemophilus influenzae (NTHi) commonly causes local disease in the upper and lower respiratory tract and has recently been shown to interfere with both the classical and alternative pathways of complement activation. The terminal pathway of the complement system is regulated by vitronectin that is a component of both plasma and the extracellular matrix. In this study, we identify protein E (PE; 16 kDa), which is a recently characterized ubiquitous outer membrane protein, as a vitronectin-binding protein of NTHi. A PE-deficient NTHi mutant had a markedly reduced survival in serum compared with the PE-expressing isogenic NTHi wild type. Moreover, the PE-deficient mutant showed a significantly decreased binding to both soluble and immobilized vitronectin. In parallel, PE-expressing Escherichia coli bound soluble vitronectin and adhered to immobilized vitronectin compared with controls. Surface plasmon resonance technology revealed a KD of 0.4 μΜ for the interaction between recombinant PE and immobilized vitronectin. Moreover, the PE-dependent vitronectin-binding site was located at the heparin-binding domains of vitronectin and the major vitronectin-binding domain was found in the central core of PE (aa 84–108). Importantly, vitronectin bound to the surface of NTHi 3655 reduced membrane attack complex-induced hemolysis. In contrast to incubation with normal human serum, NTHi 3655 showed a reduced survival in vitronectin-depleted human serum, thus demonstrating that vitronectin mediates a protective role at the bacterial surface. Our findings show that PE, by binding vitronectin, may play an important role in NTHi pathogenesis.

“…Accordingly, the complement system contains numerous cell surfacebound and fluid-phase regulatory proteins that restrict complement at both the levels of activation and membrane attack (15). Not surprisingly, pathogenic microbes have evolved the ability to recruit and exploit fluid-phase complement regulatory proteins such as factor H (fH), C4b-binding protein (C4bp), and vitronectin (2,(16)(17)(18). The Rck homolog in Yersinia enterocolitica, Ail, has been shown to bind the key fluid-phase regulator of the AP, fH.…”

mentioning

confidence: 99%

Human Complement Factor H Binds to Outer Membrane Protein Rck of Salmonella

Jarva

Meri

2010

Serum resistance, or resistance to complement-mediated killing, is a key virulence property of microbial pathogens. Rck is a 17-kDa outer membrane protein encoded on the virulence plasmid of Salmonella enterica serovars Typhimurium and Enteritidis. When expressed in either Escherichia coli or S. enterica Typhimurium, Rck confers serum resistance independent of LPS length. Recently, the Rck homolog from Yersinia enterocolitica, Ail, has been shown to bind the complement regulatory protein factor H (fH). Based on these observations, we hypothesized that Rck may also possess this ability. Using both flow cytometery and direct binding analysis, we demonstrate that Rck expressed in E. coli binds fH. We observed fH binding to Rck from human serum and also using the purified protein. Expression of Rck protected bacteria from alternative pathway-mediated killing and was associated with a reduction in C3b, Bb, and membrane attack complex deposition. fH bound to Rck promoted C3b cleavage in the presence of factor I. Binding was specific and mediated by two regions in fH, the short consensus repeats 5–7 and 19 to 20. These results suggest that fH recruitment by Rck is functional and can protect a normally serum-sensitive heterologous host against complement attack. Binding and exploitation of fH may thus contribute to Rck-mediated serum resistance.