Impact of sequence diversity in the Moraxella catarrhalis UspA2/UspA2H head domain on vitronectin binding and antigenic variation

Su, Yu-Ching; Hallström, Björn M.; Bernhard, Sara; Singh, Birendra; Riesbeck, Kristian

doi:10.1016/j.micinf.2013.02.004

Cited by 27 publications

(29 citation statements)

References 50 publications

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“…5A). We previously assessed serum sensitivity of these isolates (31) and found that binding of [ 125 I]COMP correlates with survival of M. catarrhalis in human serum (Spearman r = +0.4912, p = 0.0001) (Fig. 5B).…”

Section: Comp Binds To the Majority Of Clinical Isolates Of M Catarrmentioning

confidence: 97%

“…To further dissect the binding between COMP and UspA2, we attempted to determine the specific regions of UspA2 and COMP that are involved in the interaction. To this end, we used a number of truncated recombinant variants of both proteins (22,31). After subtracting background binding to BSA, we found that the stalk domain of UspA2 bound more [ 125 I]COMP than the head (Fig.…”

Section: Comp Interacts Directly With Uspa2 Of M Catarrhalismentioning

confidence: 99%

“…The N-terminal head of UspA2 is highly diverse and can be classified into N-terminal repeats (NTERs) 2A, 2B, 2C, and "nontypeable," according to domain distribution and sequence similarity (31). Moreover, the NTER found in the UspA2 hybrid is divergent from the ones in UspA2 and, hence, are classified as NTER2H.…”

Section: Comp Binds To the Majority Of Clinical Isolates Of M Catarrmentioning

confidence: 99%

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Moraxella catarrhalis Evades Host Innate Immunity via Targeting Cartilage Oligomeric Matrix Protein

Liu

Gradstedt

Ermert

et al. 2016

The Journal of Immunology

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Moraxella catarrhalis is a respiratory tract pathogen commonly causing otitis media in children and acute exacerbations in patients suffering from chronic obstructive pulmonary disease. Cartilage oligomeric matrix protein (COMP) functions as a structural component in cartilage, as well as a regulator of complement activity. Importantly, COMP is detected in resident macrophages and monocytes, alveolar fluid, and the endothelium of blood vessels in lung tissue. We show that the majority of clinical isolates of M. catarrhalis (n = 49), but not other tested bacterial pathogens, bind large amounts of COMP. COMP interacts directly with the ubiquitous surface protein A2 of M. catarrhalis. Binding of COMP correlates with survival of M. catarrhalis in human serum by inhibiting bactericidal activity of the complement membrane attack complex. Moreover, COMP inhibits phagocytic killing of M. catarrhalis by human neutrophils. We further observed that COMP reduces bacterial adhesion and uptake by human lung epithelial cells, thus protecting M. catarrhalis from intracellular killing by epithelial cells. Taken together, our findings uncover a novel mechanism that M. catarrhalis uses to evade host innate immunity.

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Section: Comp Binds To the Majority Of Clinical Isolates Of M Catarrmentioning

confidence: 97%

Section: Comp Interacts Directly With Uspa2 Of M Catarrhalismentioning

confidence: 99%

Section: Comp Binds To the Majority Of Clinical Isolates Of M Catarrmentioning

confidence: 99%

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Moraxella catarrhalis Evades Host Innate Immunity via Targeting Cartilage Oligomeric Matrix Protein

Liu

Gradstedt

Ermert

et al. 2016

The Journal of Immunology

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“…M. catarrhalis clinical isolates are highly serum resistant, and this is accomplished mainly by hijacking complement regulators in order to inhibit the formation of the MAC (4). M. catarrhalis recruits vitronectin from serum and ultimately inhibits the assembly of the C5b-C7 complex and polymerization of C9 (7)(8)(9)(10). In addition, C4b-binding protein (C4BP) is utilized by M. catarrhalis for inhibition of the classical pathway of complement activation (11).…”

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confidence: 99%

“…Both UspA1 and UspA2 function as adhesins and interact with extracellular matrix (ECM) proteins such as laminin and fibronectin (17,18). In addition, UspA1 and UspA2 neutralize C3 and C3d and attract C4BP and vitronectin to protect M. catarrhalis from the bactericidal activity of serum (8,11).…”

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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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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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Impact of sequence diversity in the Moraxella catarrhalis UspA2/UspA2H head domain on vitronectin binding and antigenic variation

Cited by 27 publications

References 50 publications

Moraxella catarrhalis Evades Host Innate Immunity via Targeting Cartilage Oligomeric Matrix Protein

Moraxella catarrhalis Evades Host Innate Immunity via Targeting Cartilage Oligomeric Matrix Protein

Moraxella catarrhalis Binds Plasminogen To Evade Host Innate Immunity

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

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