Immune Evasion of<i>Moraxella catarrhalis</i>Involves Ubiquitous Surface Protein A-Dependent C3d Binding

Hallström, Teresia; Nordström, Therése; Tan, Thuan Tong; Manolov, Taras; Lambris, John D.; Isenman, David E.; Zipfel, Peter F.; Blom, Anna M.; Riesbeck, Kristian

doi:10.4049/jimmunol.1002621

Cited by 25 publications

(33 citation statements)

References 85 publications

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“…3A, fulllength UspA2 30 -539 (amino acids 30 to 539 of UspA2) of M. catarrhalis Bc5 bound plasminogen in a dose-dependent manner, as determined by an ELISA. To pinpoint the plasminogen-binding region of UspA2, a series of truncated recombinant proteins were used (8,9,14). Our results revealed that all UspA2 fragments, except for UspA2 165-318 and UspA2 , significantly bound plasminogen in comparison with the negative-control protein YfeA.…”

Section: Uspa2 and Uspa2h Are The Major Plasminogen-binding Proteins mentioning

confidence: 84%

“…catarrhalis clinical isolates exhibit a high degree of serum resistance (7)(8)(9). This serum resistance is dependent on the acquisition of host serum complement regulators such as vitronectin, factor H, and C4BP and the complement components C3 and C3d (9,(11)(12)(13)(14). Clinical isolates of M. catarrhalis have variable serum resistance that cannot be correlated with the recruitment of a single complement inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…UspA2 and UspA2H are trimeric autotransporters composed of head, neck, stalk, and hydrophobic membrane-anchoring domains (14). We mapped the plasminogen-binding region of UspA2 and UspA2H by using truncated proteins that were recombinantly expressed in E. coli.…”

Section: Uspa2 and Uspa2h Are The Major Plasminogen-binding Proteins mentioning

confidence: 99%

“…In addition, C4b-binding protein (C4BP) is utilized by M. catarrhalis for inhibition of the classical pathway of complement activation (11). M. catarrhalis also binds factor H, one of the regulators of the alternative pathway (12), and directly interacts with complement (13,14), strategies that help increase bacterial survival.…”

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confidence: 99%

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Moraxella catarrhalis Binds Plasminogen To Evade Host Innate Immunity

et al. 2015

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bSeveral bacterial species recruit the complement regulators C4b-binding protein, factor H, and vitronectin, resulting in resistance against the bactericidal activity of human serum. It was recently demonstrated that bacteria also bind plasminogen, which is converted to plasmin that degrades C3b and C5. In this study, we found that a series of clinical isolates (n ‫؍‬ 58) of the respiratory pathogen Moraxella catarrhalis, which is commonly isolated from preschool children and adults with chronic obstructive pulmonary disease (COPD), significantly binds human plasminogen. Ubiquitous surface protein A2 (UspA2) and hybrid UspA2 (UspA2H) were identified as the plasminogen-binding factors in the outer membrane proteome of Moraxella. Furthermore, expression of a series of truncated recombinant UspA2 and UspA2H proteins followed by a detailed analysis of protein-protein interactions suggested that the N-terminal head domains bound to the kringle domains of plasminogen. The binding affinity constant (K D ) values of full-length UspA2 30 -539 (amino acids 30 to 539 of UspA2) and full-length UspA2H 50 -720 for immobilized plasminogen were 4.8 ؋ 10 ؊8 M and 3.13 ؋ 10 ؊8 M, respectively, as measured by biolayer interferometry. Plasminogen bound to intact M. catarrhalis or to recombinant UspA2/UspA2H was readily accessible for a urokinase plasminogen activator that converted the zymogen into active plasmin, as verified by the specific substrate S-2251 and a degradation assay with fibrinogen. Importantly, plasmin bound at the bacterial surface also degraded C3b and C5, which consequently may contribute to reduced bacterial killing. Our findings suggest that binding of plasminogen to M. catarrhalis may lead to increased virulence and, hence, more efficient colonization of the host.

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Section: Uspa2 and Uspa2h Are The Major Plasminogen-binding Proteins mentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Uspa2 and Uspa2h Are The Major Plasminogen-binding Proteins mentioning

confidence: 99%

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Moraxella catarrhalis Binds Plasminogen To Evade Host Innate Immunity

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“…The central component of all complement activation pathways is C3b, and therefore, all pathogens causing invasive diseases would benefit from inhibiting deposition or function of C3b on their surface, either by attracting host FH or by inhibiting C3b directly (20,21). Increasing numbers of microbes have been shown to acquire FH onto their surfaces to protect themselves from complement attack (21).…”

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confidence: 99%

Staphylococcal Ecb Protein and Host Complement Regulator Factor H Enhance Functions of Each Other in Bacterial Immune Evasion

Amdahl

Jongerius

Meri

et al. 2013

The Journal of Immunology

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Staphylococcus aureus is a major human pathogen causing more than a tenth of all septicemia cases and often superficial and deep infections in various tissues. One of the immune evasion strategies of S. aureus is to secrete proteins that bind to the central complement opsonin C3b. One of these, extracellular complement binding protein (Ecb), is known to interfere directly with functions of C3b. Because C3b is also the target of the physiological plasma complement regulator, factor H (FH), we studied the effect of Ecb on the complement regulatory functions of FH. We show that Ecb enhances acquisition of FH from serum onto staphylococcal surfaces. Ecb and FH enhance mutual binding to C3b and also the function of each other in downregulating complement activation. Both Ecb and the C-terminal domains 19–20 of FH bind to the C3d part of C3b. We show that the mutual enhancing effect of Ecb and FH on binding to C3b depends on binding of the FH domain 19 to the C3d part of C3b next to the binding site of Ecb on C3d. Our results show that Ecb, FH, and C3b form a tripartite complex. Upon exposure of serum-sensitive Haemophilus influenzae to human serum, Ecb protected the bacteria, and this effect was enhanced by the addition of the C-terminal domains 19–20 of FH. This finding indicates that the tripartite complex formation could give additional protection to bacteria and that S. aureus is thereby able to use host FH and bacterial Ecb in a concerted action to eliminate C3b at the site of infection.

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Complement evasion by the human respiratory tract pathogens Haemophilus influenzae and Moraxella catarrhalis

Riesbeck

2020

FEBS Letters

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All infective bacterial species need to conquer the innate immune system in order to colonize and survive in their hosts. The human respiratory pathogens Haemophilus influenzae and Moraxella catarrhalis are no exceptions and have developed sophisticated mechanisms to evade complement-mediated killing. Both bacterial species carry lipooligosaccharides preventing complement attacks and attract and utilize host complement regulators C4b binding protein and factor H to inhibit the classical and alternative pathways of complement activation, respectively. In addition, the regulator of the terminal pathway of complement activation, vitronectin, is hijacked by both bacteria. An array of different outer membrane proteins (OMP) in H. influenzae and M. catarrhalis simultaneously binds complement regulators, but also plasminogen. Several of the bacterial complement-binding proteins are important adhesins and contain highly conserved regions for interactions with the host. Thus, some of the OMP are viable targets for new therapeutics, including vaccines aimed at preventing respiratory tract diseases such as otitis media in children and exacerbations in patients suffering from chronic obstructive pulmonary disease.

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Immune Evasion ofMoraxella catarrhalisInvolves Ubiquitous Surface Protein A-Dependent C3d Binding

Cited by 25 publications

References 85 publications

Moraxella catarrhalis Binds Plasminogen To Evade Host Innate Immunity

Moraxella catarrhalis Binds Plasminogen To Evade Host Innate Immunity

Staphylococcal Ecb Protein and Host Complement Regulator Factor H Enhance Functions of Each Other in Bacterial Immune Evasion

Complement evasion by the human respiratory tract pathogens Haemophilus influenzae and Moraxella catarrhalis

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