| 1. |
- Blom, Anna, et al.
(författare)
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Complement evasion strategies of pathogens-Acquisition of inhibitors and beyond.
- 2009
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Ingår i: Molecular Immunology. - : Elsevier BV. - 1872-9142 .- 0161-5890. ; 46, s. 2808-2817
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Tidskriftsartikel (refereegranskat)abstract
- Activation of the complement system and resulting opsonisation with C3b are key events of the innate immune defense against infections. However, a wide variety of bacterial pathogens subvert complement attack by binding host complement inhibitors such as C4b-binding protein, factor H and vitronectin, which results in diminished opsonophagocytosis and killing of bacteria by lysis. Another widely used strategy is production of proteases, which can effectively degrade crucial complement components. Furthermore, bacterial pathogens such as Moraxella catarrhalis and Staphylococcus aureus capture and incapacitate the key complement component C3. The current review describes examples of these three strategies. Targeting binding sites for complement inhibitors on bacterial surfaces and complement-degrading proteases with vaccine-induced antibodies may be used to enhance a common vaccine design strategy that depends on the generation of complement-dependent bactericidal and opsonophagocytic antibody activities.
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| 2. |
- Fleury, Christophe, et al.
(författare)
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Identification of a Haemophilus influenzae Factor H-Binding Lipoprotein Involved in Serum Resistance.
- 2014
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 192:12, s. 5913-5923
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Tidskriftsartikel (refereegranskat)abstract
- Haemophilus influenzae is a Gram-negative human pathogen that resides in the upper respiratory tract. Encapsulated H. influenzae type b (Hib) and type f (Hif) are the most common serotypes associated with invasive disease. H. influenzae displays various strategies to circumvent the host innate immune response, including the bactericidal effect of the complement system. In this study, we identified an H. influenzae lipoprotein having the ability to bind factor H (FH), the major regulator of the alternative pathway of complement activation. This protein, named protein H (PH), was surface exposed and was found in all clinical Hib and Hif isolates tested. Deletion of the gene encoding for PH (lph) in Hib and Hif significantly reduced the interaction between bacteria and FH. When Hib and Hif PH variants were separately expressed in nontypeable (unencapsulated) H. influenzae, which did not bind FH, an increased FH affinity was observed. We recombinantly expressed the two PH variants in Escherichia coli, and despite sharing only 56% identical amino acids, both FH-binding Haemophilus proteins similarly interacted with the complement regulator FH short consensus repeats 7 and 18-20. Importantly, Hib and Hif resistance against the bactericidal effect of human serum was significantly reduced when bacterial mutants devoid of PH were tested. In conclusion, we have characterized a hitherto unknown bacterial protein that is crucial for mediating an interaction between the human pathogen H. influenzae and FH. This novel interaction is important for H. influenzae resistance against complement activation and will consequently promote bacterial pathogenesis.
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| 3. |
- Hallström, Teresia, et al.
(författare)
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Binding of complement regulators to invasive nontypeable Haemophilus influenzae is not increased compared to nasopharyngeal isolates, but serum resistance is linked to disease severity.
- 2010
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Ingår i: Journal of Clinical Microbiology. - 1098-660X. ; 48:3, s. 921-927
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to analyse the importance for non-typeable Haemophilus influenzae (NTHi) isolated from patients with sepsis (invasive isolates) compared to nasopharyngeal isolates from patients with upper respiratory tract infection to resist the complement-mediated attack in human serum and to correlate this to disease severity. We in detail studied and characterized cases of invasive NTHi disease. All patients with invasive NTHi isolates were adults and 35 % had a clinical presentation of severe sepsis according to the ACCP/SCCM classification of sepsis grading. Moreover, 41 % of the cases had evidence of immune deficiency. The different isolates were analyzed for survival in human serum, for binding of [(125)I]-labeled purified human complement inhibitors C4b-binding protein (C4BP), Factor H and vitronectin in addition to binding of regulators directly from serum. No significant differences were found when blood and nasopharyngeal isolates were compared, suggesting that interactions with the complement system are equally important for NTHi strains irrespectively of isolation site. Interestingly, a correlation between serum resistance and invasive disease severity was found. The ability to resist the attack of the complement system seems to be important for NTHi strains infecting the respiratory tract as well as the blood stream.
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| 4. |
- Hallström, Teresia, et al.
(författare)
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Conserved Patterns of Microbial Immune Escape: Pathogenic Microbes of Diverse Origin Target the Human Terminal Complement Inhibitor Vitronectin via a Single Common Motif.
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Pathogenicity of many microbes relies on their capacity to resist innate immunity, and to survive and persist in an immunocompetent human host microbes have developed highly efficient and sophisticated complement evasion strategies. Here we show that different human pathogens including Gram-negative and Gram-positive bacteria, as well as the fungal pathogen Candida albicans, acquire the human terminal complement regulator vitronectin to their surface. By using truncated vitronectin fragments we found that all analyzed microbial pathogens (n = 13) bound human vitronectin via the same C-terminal heparin-binding domain (amino acids 352-374). This specific interaction leaves the terminal complement complex (TCC) regulatory region of vitronectin accessible, allowing inhibition of C5b-7 membrane insertion and C9 polymerization. Vitronectin complexed with the various microbes and corresponding proteins was thus functionally active and inhibited complement-mediated C5b-9 deposition. Taken together, diverse microbial pathogens expressing different structurally unrelated vitronectin-binding molecules interact with host vitronectin via the same conserved region to allow versatile control of the host innate immune response.
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| 5. |
- Hallström, Teresia, et al.
(författare)
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Haemophilus influenzae and the complement system.
- 2010
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Ingår i: Trends in Microbiology. - : Elsevier BV. - 1878-4380 .- 0966-842X. ; Mar 4, s. 258-265
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Tidskriftsartikel (refereegranskat)abstract
- The respiratory tract pathogen Haemophilus influenzae is responsible for a variety of infections in humans including septicemia, bronchitis, pneumonia, and acute otitis media. The pathogenesis of H. influenzae relies on its capacity to resist human host defenses including the complement system, and thus H. influenzae has developed several efficient strategies to circumvent complement attack. In addition to attracting specific host complement regulators directly to the bacterial surface, the capsule, lipooligosaccharides, and several outer membrane proteins contribute to resistance against complement-mediated attacks and hence increased bacterial survival. Insights into the mechanisms of complement evasion by H. influenzae are important for understanding pathogenesis and for developing vaccines and new therapies aimed at patients with, for example, chronic obstructive pulmonary disease. Here we overview current knowledge on the different mechanisms by which H. influenzae evades attack by the host complement system.
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| 6. |
- Hallström, Teresia, et al.
(författare)
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Haemophilus influenzae interacts with the human complement inhibitor factor H
- 2008
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Ingår i: Journal of Immunology. - 1550-6606. ; 181:1, s. 537-545
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Tidskriftsartikel (refereegranskat)abstract
- Pathogenic microbes acquire human complement inhibitors to circumvent the innate immune system. In this study, we identify two novel host-pathogen interactions, factor H (FH) and factor H-like protein 1 (FHL-1), the inhibitors of the alternative pathway that binds to Hib. A collection of clinical Haemophilus influenzae isolates was tested and the majority of encapsulated and unencapsulated bound FH. The isolate Hib 541 with a particularly high FH-binding was selected for detailed analysis. An increased survival in normal human serum was observed with Hib 541 as compared with the low FH-binding Hib 568. Interestingly, two binding domains were identified within FH; one binding site common to both FH and FHL-1 was located in the N-terminal short consensus repeat domains 6-7, whereas the other, specific for FH, was located in the C-terminal short consensus repeat domains 18-20. Importantly, both FH and FHL-1, when bound to the surface of Hib 541, retained cofactor activity as determined by analysis of C3b degradation. Two H. influenzae outer membrane proteins of similar to 32 and 40 kDa were detected with radiolabeled FH in Far Western blot. Taken together, in addition to interactions with the classical, lectin, and terminal pathways, H. influenzae interferes with the alternative complement activation pathway by binding FH and FHL-1, and thereby reducing the complement-mediated bactericidal activity resulting in an increased survival. In contrast to incubation with active complement, H. influenzae had a reduced survival in FH-depleted human serum, thus demonstrating that FH mediates a protective role at the bacterial surface.
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| 7. |
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| 8. |
- 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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| 9. |
- Hallström, Teresia, et al.
(författare)
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Interaction with C4b-binding protein contributes to nontypeable Haemophilus influenzae serum resistance.
- 2007
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Ingår i: Journal of Immunology. - 1550-6606. ; 178:10, s. 6359-6366
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Tidskriftsartikel (refereegranskat)abstract
- Complement evasion by various mechanisms is important for microbial virulence and survival in the host. One strategy used by some pathogenic bacteria is to bind the complement inhibitor of the classical pathway, C4b-binding protein (C4BP). In this study, we have identified a novel interaction between nontypeable Haemophilus influenzae (NTHi) and C4BP, whereas the majority of the typeable H. influenzae (a-f) tested showed no binding. One of the clinical isolates, NTHi 506, displayed a particularly high binding of C4BP and was used for detailed analysis of the interaction. Importantly, a low C4BP-binding isolate (NTHi 69) showed an increased deposition of C3b followed by reduced survival as compared with NTHi 506 when exposed to normal human serum. The main isoform of C4BP contains seven identical a-chains and one beta-chain linked together with disulfide bridges. Each a-chain is composed of eight complement control protein (CCP) modules and we have found that the NTHi 506 strain did not interact with rC4BP lacking CCP2 or CCP7 showing that these two CCPs are important for the binding. Importantly, C4BP bound to the surface of H. influenzae retained its cofactor activity as determined by analysis of C3b and C4b degradation. Taken together, NTHi interferes with the classical complement activation pathway by binding to C4BP.
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| 10. |
- Hallström, Teresia, et al.
(författare)
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Nontypeable Haemophilus influenzae Protein E Binds Vitronectin and Is Important for Serum Resistance
- 2009
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 183:4, s. 2593-2601
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Tidskriftsartikel (refereegranskat)abstract
- Nontypeable Haemophilus influenzae (NTHi) commonly causes local disease in the upper and lower respiratory tract and has recently been shown to interfere with both the classical and alternative pathways of complement activation. The terminal pathway of the complement system is regulated by vitronectin that is a component of both plasma and the extracellular matrix. In this study, we identify protein E (PE; 16 kDa), which is a recently characterized ubiquitous outer membrane protein, as a vitronectin-binding protein of NTHi. A PE-deficient NTHi mutant had a markedly reduced survival in serum compared with the PE-expressing isogenic NTHi wild type. Moreover, the PE-deficient mutant showed a significantly decreased binding to both soluble and immobilized vitronectin. In parallel, PE-expressing Escherichia coli bound soluble vitronectin and adhered to immobilized vitronectin compared with controls. Surface plasmon resonance technology revealed a K-D of 0.4 mu M for the interaction between recombinant PE and immobilized vitronectin. Moreover, the PE-dependent vitronectin-binding site was located at the heparin-binding domains of vitronectin and the major vitronectin-binding domain was found in the central core of PE (aa 84-108). Importantly, vitronectin bound to the surface of NTHi 3655 reduced membrane attack complex-induced hemolysis. In contrast to incubation with normal human serum, NTHi 3655 showed a reduced survival in vitronectin-depleted human serum, thus demonstrating that vitronectin mediates a protective role at the bacteria] surface. Our findings show that PE, by binding vitronectin, may play an important role in NTHi pathogenesis. The Journal of Immunology, 2009, 183: 2593-2601.
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