Immune Evasion of Moraxella catarrhalis Involves Ubiquitous Surface Protein A-Dependent C3d Binding

Department of Laboratory Medicine Malmö, Lund University, Skåne University Hospital, Malmö, Sweden.
The Journal of Immunology (Impact Factor: 4.92). 03/2011; 186(5):3120-9. DOI: 10.4049/jimmunol.1002621
Source: PubMed

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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Available from: Kristian Riesbeck, Sep 28, 2015
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    • "Furthermore, it has been reported that UspA1 protein of M. catarrhalis induces CEACAM1-dependent apoptosis in alveolar epithelial cells and that this might contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD) [30]. In addition, UspA1 also helps M. catarrhalis evade host immunity through inhibiting both the alternative and classical pathways of the complement system [31]. It has also been reported that M. catarrhalis infected alveolar epithelium induced monocyte recruitment [32], but little is known about the potential effects of M. catarrhalis on the recruited monocyte differentiation after M. catarrhalis infection. "
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    ABSTRACT: Circulating monocytes in the bloodstream typically migrate to other tissues and differentiate into tissue resident macrophages, the process being determined by the constituents of the microenvironments encountered. These may include microbes and their products. In this study, we investigated whether Moraxella catarrhalis Ubiquitous Surface Protein A1 (UspA1), known to bind to a widely expressed human cell surface receptor CEACAM1, influences monocyte differentiation as receptor engagement has been shown to have profound effects on monocytes. We used the recombinant molecules corresponding to the regions of UspA1 which either bind (rD-7; UspA1527-665) or do not bind (r6-8; UspA1659-863) to CEACAM1 and investigated their effects on CD206, CD80 and CD86 expression on freshly isolated human CD14+ monocytes from peripheral blood mononuclear cells (PBMC). Exposure to rD-7, but not r6-8, biased monocyte differentiation towards a CD14+CD206+ phenotype, with reduced CD80 expression. Monocytes treated with rD-7 also secreted high levels of IL-1ra and chemokine IL-8 but not IL-10 or IL-12p70. The effects of rD-7 were independent of any residual endotoxin. Unexpectedly, these effects of rD-7 were also independent of its ability to bind to CEACAM1, as monocyte pre-treatment with the anti-CEACAM antibody A0115 known to inhibit rD-7 binding to the receptor, did not affect rD-7-driven differentiation. Further, another control protein rD-7/D (a mutant form of rD-7, known not to bind to CEACAMs), also behaved as the parent molecule. Our data suggest that specific regions of M. catarrhalis adhesin UspA1 may modulate inflammation during infection through a yet unknown receptor on monocytes.
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    ABSTRACT: Moraxella catarrhalis is a human-restricted commensal that over the last two decades has developed into an emerging respiratory tract pathogen. The bacterial species is equipped with various adhesins to facilitate its colonization. Successful evasion of the human immune system is a prerequisite for Moraxella infection. This strategy involves induction of an excessive proinflammatory response, intervention of granulocyte recruitment to the infection site, activation of selected pattern recognition receptors and cellular adhesion molecules to counteract the host bacteriolytic attack, as well as, finally, reprogramming of antigen presenting cells. Host immunomodulator molecules are also exploited by Moraxella to aid in resistance against complement killing and host bactericidal molecules. Thus, breaking the basis of Moraxella immune evasion mechanisms is fundamental for future invention of effective therapy in controlling Moraxella infection.
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