| 1. |
- Hallström, Teresia, et al.
(författare)
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Immune Evasion of Moraxella catarrhalis Involves Ubiquitous Surface Protein A-Dependent C3d Binding.
- 2011
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Ingår i: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 186, s. 3120-3129
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Tidskriftsartikel (refereegranskat)abstract
- The complement system plays an important role in eliminating invading pathogens. Activation of complement results in C3b deposition (opsonization), phagocytosis, anaphylatoxin (C3a, C5a) release, and consequently cell lysis. Moraxella catarrhalis is a human respiratory pathogen commonly found in children with otitis media and in adults with chronic obstructive pulmonary disease. The species has evolved multiple complement evasion strategies, which among others involves the ubiquitous surface protein (Usp) family consisting of UspA1, A2, and A2 hybrid. In the present study, we found that the ability of M. catarrhalis to bind C3 correlated with UspA expression and that C3 binding contributed to serum resistance in a large number of clinical isolates. Recombinantly expressed UspA1 and A2 inhibit both the alternative and classical pathways, C3b deposition, and C3a generation when bound to the C3 molecule. We also revealed that the M. catarrhalis UspA-binding domain on C3b was located to C3d and that the major bacterial C3d-binding domains were within UspA1(299-452) and UspA2(165-318). The interaction with C3 was not species specific since UspA-expressing M. catarrhalis also bound mouse C3 that resulted in inhibition of the alternative pathway of mouse complement. Taken together, the binding of C3 to UspAs is an efficient strategy of Moraxella to block the activation of complement and to inhibit C3a-mediated inflammation.
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| 2. |
- Manolov, Taras, et al.
(författare)
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Moraxella-Dependent {alpha}1-Antichymotrypsin Neutralization - A Unique Virulence Mechanism.
- 2008
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - 1535-4989. ; 38:5, s. 609-617
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Tidskriftsartikel (refereegranskat)abstract
- The acute phase reactant and protease inhibitor alpha1-antichymotrypsin is considered to play a protective role in the airways, but it is not known. Objectives: We analyzed whether the common respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis interact with antichymotrypsin. Methods: We compared a series of clinical isolates in addition to wild type and ubiquitous surface protein-deficient Moraxella to study the nature of antichymotrypsin binding by the bacteria. Measurements and Main Results: M. catarrhalis was the only species that bound antichymotrypsin among 25 bacterial species tested by flow cytometry and a direct binding assay. Experiments with Moraxella mutants revealed that ubiquitous surface proteins A1 and A2 were responsible for the interaction, and using recombinant fragments, a consensus sequence within ubiquitous surface proteins A1 and A2 was defined. Binding of iodine labeled antichymotrypsin was dose dependent and strong (d
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| 3. |
- Nordström, Therése, et al.
(författare)
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Ionic binding of C3 to the human pathogen Moraxella catarrhalis is a unique mechanism for combating innate immunity
- 2005
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Ingår i: Journal of Immunology. - 1550-6606. ; 175:6, s. 3628-3636
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Tidskriftsartikel (refereegranskat)abstract
- Moraxella catarrhalis ubiquitous surface proteins A1 and A2 (UspA1/A2) interfere with the classical pathway of the complement system by binding C4b-binding protein. In this study we demonstrate that M. catarrhalis UspA1 and A2 noncovalently and in a dose-dependent manner bind both the third component of complement (C3) from EDTA-treated serum and methylamine-treated C3. In contrast, related Moraxella subspecies (n = 13) or other human pathogenic bacteria (n = 13) do not bind C3 or methylamine-treated C3. Experiments with recombinant proteins and M. catarrhalis mutants devoid of UspA1/A2 revealed that UspA1/A2 exert their actions by absorbing and neutralizing C3 from serum and restrain complement activation. UspA2 was responsible for most of the effect, and the Moraxella mutant lacking UspA2 was more sensitive to the lytic effect of human serum compared with the wild type. Interestingly, among the large number of bacteria analyzed, only M. catarrhalis has this unique ability to interfere with the innate immune system of complement by binding C3.
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| 4. |
- Tan, Thuan Tong, et al.
(författare)
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Current progress of adhesins as vaccine candidates for Moraxella catarrhalis
- 2007
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Ingår i: Expert Review of Vaccines. - : Informa UK Limited. - 1744-8395 .- 1476-0584. ; 6:6, s. 949-956
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Forskningsöversikt (refereegranskat)abstract
- Moraxello catorrhalis is an emerging pathogen and all isolates are now considered beta-lactamase producing. Potential further use of vaccines against Streptococcus pneumoniae and nontypeable Haemophilus influenzae means that M. catarrhalis might be thrust further into the limelight. However, a vaccine has not yet been designed. In this review, the progress of M. catarrhalis adhesins as vaccine candidates is discussed with a focus on various candidate antigens that spanned those discovered more than 10 years ago, for example, the ubiquitous surface proteins to newer antigens, such as the Moraxella IgD-binding hemagglutinin.
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| 5. |
- Tan, Thuan Tong, et al.
(författare)
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Haemophilus influenzae Survival during Complement-Mediated Attacks Is Promoted by Moraxella catarrhalis Outer Membrane Vesicles.
- 2007
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 195:11, s. 1661-1670
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Tidskriftsartikel (refereegranskat)abstract
- Moraxella catarrhalis causes respiratory tract infections in children and in adults with chronic obstructive pulmonary disease. It is often isolated as a copathogen with Haemophilus influenzae. The underlying mechanism for this cohabitation is unclear. Here, in clinical specimens from a patient with M. catarrhalis infection, we document that outer membrane vesicles (OMVs) carrying ubiquitous surface protein (Usp) A1 and UspA2 (hereafter, UspA1/A2) were secreted. Further analyses revealed that OMVs isolated in vitro also contained UspA1/A2, which mediate interactions with, among other proteins, the third component of the complement system (C3). OMVs from M. catarrhalis wild-type clinical strains bound to C3 and counteracted the complement cascade to a larger extent than did OMVs without UspA1/A2. In contrast, UspA1/A2-deficient OMVs were significantly weaker inhibitors of complement-dependent killing of H. influenzae. Thus, our results suggest that a novel strategy exists in which pathogens collaborate to conquer innate immunity and that the M. catarrhalis vaccine candidates UspA1/A2 play a major role in this interaction.
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| 6. |
- Tan, Thuan Tong
(författare)
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MORAXELLA CATARRHALIS OUTER MEMBRANE PROTEINS AND THEIR INTERACTIONS WITH THE HUMAN HOST
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Moraxella catarrhalis is an airway pathogen whose role in infection has been increasingly recognized in recent years. Most authorities in this field now agree that M. catarrhalis causes significant morbidity and is not just a harmless commensal. The universal prevalence of BRO ?-lactamases in this pathogen is a serious concern. In addition, M. catarrhalis may be further propelled into a more prominent position in the hierarchy of respiratory infectious agents due to the phenomenon of ?non-vaccine type replacement? as a result of the wider usage of vaccines against other pathogens in the same ecological niche, such as Haemophilus influenzae and Streptococcus pneumoniae. There is currently no available vaccine against M. catarrhalis. A detailed analysis of the interactions of this bacterium with the human host is necessary to identify ways to interfere with its colonization and infection. To this end, we have focused on the interactions via three outer membrane proteins, namely UspA1 (ubiquitous surface protein A1), UspA2 and MID (Moraxella catarrhalis IgD binding protein). We found that UspA1 and A2 could bind fibronectin and laminin, and characterized these interactions. We also detailed a novel interaction of UspA1 and A2 with the complement protein C3. The UspA1/A2-dependent C3 binding contributes to its serum resistant phenotype and is a way in which M. catarrhalis combat the innate immunity. Furthermore, we showed that this interaction could contribute to the survival of copathogens. An analysis of naturally acquired serological responses to these two proteins and those of MID showed that the functional domains identified here (fibronectin binding region in UspA1299-452 and UspA2165-318, C3 binding region in UspA2) and those identified in other studies (CEACAM binding region of UspA1, the MID764-913 adhesive domain) evoked significant immune responses. The better understanding of the interactions and the identification of important domains in these three proteins represent significant advances in the quest for a suitable vaccine against M. catarrhalis.
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| 7. |
- Tan, Thuan Tong, et al.
(författare)
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Serological Response to M. catarrhalis Outer Membrane Protein MID as Compared to UspA1 and A2.
- 2006
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Ingår i: Infection and Immunity. - 1098-5522. ; 74:11, s. 6377-6386
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Tidskriftsartikel (refereegranskat)abstract
- Morarella catarrhalis immunoglobulin D-binding protein (MID) is a complex antigen with unique immunoglobulin D (IgD)-binding, adhesion, and hernagglutination properties. Previous studies have shown that antibodies raised against MID764-111 in rabbits inhibited M. catarrhalis adhesion to human alveolar epithelial cells, and immunization with MID764-913 resulted in an increased pulmonary clearance in a murine model. Strong immune responses against MID have also consistently been shown in humans. Here, the MID-specified IgG responses were compared to those of ubiquitous surface proteins A1 and A2 (UspA1/A2) using a series of recombinant fragments that spanned all three proteins. Sera were obtained from young children, aged 6 months to 1 year (n = 8) and 2 to 3 years (n = 15), and healthy adults (n = 16). Acute- and convalescent-phase sera from chronic obstructive pulmonary disease (COPD) patients with M. catarrhalis infective exacerbations (n = 23) were also analyzed. Young children, who are at risk of M. catarrhalis infection, had low levels of anti-MID and anti-UspA1/A2 antibodies. Healthy adults and the majority of COPD patients (16/23) had high levels of antibodies directed against, among others, the adhesive domain of MID and the fibronectin- and C3-binding domains of UspA1/A2. Among eight COPD patients in whom a rise in antibody levels could be detected, these functional domains were also the main regions targeted by the antibodies. In addition, human IgG directed against MID was bactericidal and anti-MID antibodies were additive to antibodies targeting UspA1/A2. Hence, the functional domains in these three antigens may have significant potential in a future vaccine against M. catarrhalis.
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