Staphylococcus aureus secretes the SSL7 protein as part of its immune evasion strategy. The protein binds both complement C5 and IgA, yet it is unclear whether SSL7 cross-links these two proteins and, if so, what purpose this serves the pathogen. We have isolated a stable IgA-SSL7-C5 complex, and our crystal structure of the C5-SSL7 complex confirms that binding to C5 occurs exclusively through the C-terminal β-grasp domain of SSL7 leaving the OB domain free to interact with IgA. SSL7 interacts with C5 >70 Å from the C5a cleavage site without inducing significant conformational changes in C5, and efficient inhibition of convertase cleavage of C5 is shown to be IgA dependent. Inhibition of C5a production and bacteriolysis are all shown to require C5 and IgA binding while inhibition of hemolysis is achieved by the C5 binding SSL7 β-grasp domain alone. These results provide a conceptual and structural basis for the development of a highly specific complement inhibitor preventing only the formation of the lytic membrane attack complex without affecting the important signaling functions of C5a. Complement activation triggers cleavage of the three homologous 185-to 200-kDa proteins C3, C4, and C5. Three activation pathways converge on C3 cleavage to C3b (6). Activation by the alternative pathway (AP) results from spontaneous hydrolysis of an internal thioester bond in C3 or by deposition of properdin on an appropriate surface (7), whereas the classical pathway (CP) and lectin-mediated pathways are activated by surface-bound immune complexes or mannan binding lectins/ficolins, respectively. Activation of the CP or the lectin pathway generates the surface-bound C3 convertase (a proteolytic enzyme cleaving C3) C4b2a, whereas the AP generates the C3 convertase C3bBb. Both may recruit an additional C3b molecule to form the CP C5 convertase C4b2a3b or the AP C5 convertase C3bBb3b (8, 9), which cleaves C5 to generate the large fragment C5b and the anaphylatoxin C5a. This binds with high affinity to the C5a receptor (CD88) on myeloid cells triggering G protein (Gα I and Gα 16 )-mediated cell activation, chemotaxis, respiratory burst, and release of proinflammatory mediators (10). C5b quickly associates with C6, C7, C8, and multiple molecules of C9 to form the membrane attack complex (MAC) that results in rapid cell lysis (11). Elevated levels of C5a are implicated in a wide range of inflammatory disorders, such as rheumatoid arthritis, ischemia/reperfusion injury, sepsis, and fibrotic conditions (12). MAC deposition through C5b on erythrocytes results in destruction of these cells in the hemolytic disease paroxysmal nocturnal hemoglobinuria (PNH) (13). In addition, excessive MAC formation is linked with the pathophysiology of conditions such as antibody-mediated transplant rejection (14), inflammatory neuropathies (15) and multiple sclerosis (16).Given its importance to innate immune clearance, pathogens have developed many strategies to prevent complement activation (17). The Staphylococcal Superantigen-Like protein 7 (SSL7)...
Dermatophagoides pteronyssinus is the European dust mite and a major source of human allergens. Here, we present the first draft genome sequence of the mite, as well as the ab initio gene prediction and functional analyses that will facilitate comparative genomic analyses with other mite species.
The European house dust mite Dermatophagoides pteronyssinus is of significant medical importance as it is a major elicitor of allergic illnesses. In this analysis we have undertaken comprehensive bioinformatic and proteomic examination of Dermatophagoides pteronyssinus airmid, identified 12,530 predicted proteins and validated the expression of 4,002 proteins. Examination of homology between predicted proteins and allergens from other species revealed as much as 2.6% of the D . pteronyssinus airmid proteins may cause an allergenic response. Many of the potential allergens have evidence for expression ( n = 259) and excretion ( n = 161) making them interesting targets for future allergen studies. Comparative proteomic analysis of mite body and spent growth medium facilitated qualitative assessment of mite group allergen localisation. Protein extracts from house dust contain a substantial number of uncharacterised D . pteronyssinus proteins in addition to known and putative allergens. Novel D . pteronyssinus proteins were identified to be highly abundant both in house dust and laboratory cultures and included numerous carbohydrate active enzymes that may be involved in cuticle remodelling, bacteriophagy or mycophagy. These data may have clinical applications in the development of allergen-specific immunotherapy that mimic natural exposure. Using a phylogenomic approach utilising a supermatrix and supertree methodologies we also show that D . pteronyssinus is more closely related to Euroglyphus maynei than Dermatophagoides farinae .
The European house dust mite, Dermatophagoides pteronyssinus is a major source of airborne allergens worldwide and is found in half of European homes. Interactions between microbes and house dust mites (HDM) are considered important factors that allow them to persist in the home. Laboratory studies indicate the European HDM, D. pteronyssinus is a mycophagous mite, capable of utilising a variety of fungi for nutrients, however specific mycolytic digestive enzymes are unknown. Our previous work identified a number of putative glycosyl hydrolases present in the predicted proteome of D. pteronyssinus airmid and validated the expression of 42 of these. Of note, three GH16 proteins with predicted β-1,3 glucanase activity were found to be consistently present in the mite body and excretome. Here, we performed an extensive bioinformatic, proteomic and biochemical study to characterize three-novel β-1,3 glucanases from this medically important house dust mite. The genes encoding novel β-1,3 glucanases designated Glu1, Glu2 and Glu3 were identified in D. pteronyssinus airmid, each exhibited more than 59% amino acid identity to one another. These enzymes are encoded by Glu genes present in a tri-gene cluster and protein homologs are found in other acari. The patchy phyletic distribution of Glu proteins means their evolutionary history remains elusive, however horizontal gene transfer cannot be completely excluded. Recombinant Glu1 and Glu2 exhibit hydrolytic activity toward laminarin, pachyman and barley glucan. Excreted β-1,3 glucanase activity was increased in response to D. pteronyssinus airmid feeding on baker's yeast. Active β-1,3 glucanases are expressed and excreted in the faeces of D. pteronyssinus airmid indicating they are digestive enzymes capable of breaking down β-1,3 glucans of fungi present in house dust.
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