Molecular Aspects of<i>Moraxella catarrhalis</i>Pathogenesis

Vries, Stefan P. W. de; Bootsma, Hester J.; Hays, John P.; Hermans, Peter W. M.

doi:10.1128/mmbr.00007-09

Cited by 88 publications

(64 citation statements)

References 160 publications

(256 reference statements)

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“…catarrhalis has the ability to overcome host innate immunity and to evade complement-mediated lysis. To facilitate its serum resistance, M. catarrhalis uses an arsenal of membrane proteins to counteract complement attack (10). For example, the ubiquitous surface protein A (UspA)1 and UspA2 of M. catarrhalis directly bind and incapacitate C3 and further recruit complement inhibitors, such as C4b-binding protein (C4BP) and vitronectin (11)(12)(13).…”

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confidence: 99%

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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confidence: 99%

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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“…Additionally, M. catarrhalis is one of the most common inhabitants of the pharynx of healthy preschool children, and within this group it becomes pathogenic upon simultaneous viral infection. During the first year of life, the carrier rate of M. catarrhalis is ∼67% of all children and the species colonizes oropharynx and nasopharynx (7). This implies that M. catarrhalis as a commensal has numerous strategies to survive in the host (1).…”

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confidence: 99%

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

Hallström

Nordström

Tan

et al. 2011

The Journal of Immunology

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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 UspA1299–452 and UspA2165–318. 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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“…The socioeconomic burden of otitis media and COPD is significant, with an estimated $50 billion dollars annually in health care expenses globally (5,9,12). In view of the morbidity and health care cost associated with M. catarrhalis, it is important to understand the mechanisms of pathogenesis in order to guide development of novel approaches to treatment and prevention (2,13,14). In previous work, we identified OppA as a promising vaccine antigen and a nutritional virulence factor for M. catarrhalis (15,16).…”

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confidence: 99%

Expression of the Oligopeptide Permease Operon of Moraxella catarrhalis Is Regulated by Temperature and Nutrient Availability

Jones

Murphy

2015

Infect Immun

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Moraxella catarrhalis causes otitis media in children and exacerbations of chronic obstructive pulmonary disease in adults. Together, these two conditions contribute to enormous morbidity and mortality worldwide. The oligopeptide permease (opp) ABC transport system is a nutritional virulence factor important for the utilization of peptides. The substrate binding protein OppA, which binds peptides for uptake, is a potential vaccine antigen, but little was known about the regulation of gene expression. The five opp genes oppB, oppC, oppD, oppF, and oppA are in the same open reading frame. Sequence analysis predicted two promoters, one located upstream of oppB and one within the intergenic region between oppF and oppA. We have characterized the gene cluster as an operon with two functional promoters and show that cold shock at 26°C for <0.5 h and the presence of a peptide substrate increase gene transcript levels. Additionally, the putative promoter upstream of oppA contributes to the transcription of oppA but is not influenced by the same environmental cues as the promoter upstream of oppB. We conclude that temperature and nutrient availability contribute to the regulation of the Opp system, which is an important nutritional virulence factor in M. catarrhalis. Moraxella catarrhalis is an increasingly important human-specific pathogen contributing to worldwide morbidity and mortality that has transitioned from an emerging to an established pathogen (1-3). Otitis media in children is the primary cause of new antibiotic prescriptions and pediatric office visits, with M. catarrhalis accounting for 10% to 20% of acute otitis media episodes (2, 4-6). Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States, with M. catarrhalis contributing to at least 10% of exacerbations (7-11). The socioeconomic burden of otitis media and COPD is significant, with an estimated $50 billion dollars annually in health care expenses globally (5, 9, 12). In view of the morbidity and health care cost associated with M. catarrhalis, it is important to understand the mechanisms of pathogenesis in order to guide development of novel approaches to treatment and prevention (2,13,14). In previous work, we identified OppA as a promising vaccine antigen and a nutritional virulence factor for M. catarrhalis (15,16).We previously characterized the oligopeptide permease (opp) gene cluster as an ABC transport system vital for the utilization of peptide substrates. The gene cluster encodes two permeases, OppB and OppC; two ATPases, OppD and OppF; and a substrate binding protein, OppA (16). We hypothesized that this gene cluster was transcribed as an operon and that environmental factors, temperature and essential nutrients available as peptides, would alter the rate of transcription.The lower respiratory tract has a normal body temperature of 37°C, while the upper airways, specifically the nasopharynx, where M. catarrhalis first colonizes, ranges from 34°C at room temperature (25°C) down to 26°C after a short...

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Molecular Aspects ofMoraxella catarrhalisPathogenesis

Cited by 88 publications

References 160 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

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

Expression of the Oligopeptide Permease Operon of Moraxella catarrhalis Is Regulated by Temperature and Nutrient Availability

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