Binding of human C4BP to the hypervariable region of M protein: a molecular mechanism of phagocytosis resistance in <i>Streptococcus pyogenes</i>

Berggård, Karin; Johnsson, Eskil; Morfeldt, Eva; Persson, Jenny; Stålhammar‐Carlemalm, Margaretha; Lindahl, Gunnar

doi:10.1046/j.1365-2958.2001.02664.x

Cited by 92 publications

(114 citation statements)

References 73 publications

(112 reference statements)

Supporting

Mentioning

106

Contrasting

Unclassified

Order By: Relevance

“…This showed for the first time, to our knowledge, that CFH binding via domains 5-7 is a very important innate immuneevasion strategy for GAS. This probably was not shown previously, because the impact of CFH binding to the bacteria cannot be measured by removing CFH from serum or blood because of the resulting vigorous C activation, and removal of the M protein by bacterial mutagenesis could also impair its other functions, such as C4BP binding (40). Our approach of showing the impact of CFH acquisition for the bacteria is novel and free of these biases.…”

Section: Discussionmentioning

confidence: 93%

Acquisition of Complement Factor H Is Important for Pathogenesis ofStreptococcus pyogenesInfections: Evidence from Bacterial In Vitro Survival and Human Genetic Association

Haapasalo

Vuopio

Syrjänen

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

Streptococcus pyogenes (or group A streptococcus [GAS]) is a major human pathogen causing infections, such as tonsillitis, erysipelas, and sepsis. Several GAS strains bind host complement regulator factor H (CFH) via its domain 7 and, thereby, evade complement attack and C3b-mediated opsonophagocytosis. Importance of CFH binding for survival of GAS has been poorly studied because removal of CFH from plasma or blood causes vigorous complement activation, and specific inhibitors of the interaction have not been available. In this study, we found that activation of human complement by different GAS strains (n = 38) correlated negatively with binding of CFH via its domains 5–7. The importance of acquisition of host CFH for survival of GAS in vitro was studied next by blocking the binding with recombinant CFH5–7 lacking the regulatory domains 1–4. Using this fragment in full human blood resulted in death or radically reduced multiplication of all of the studied CFH-binding GAS strains. To study the importance of CFH binding in vivo (i.e., for pathogenesis of streptococcal infections), we used our recent finding that GAS binding to CFH is diminished in vitro by polymorphism 402H, which is also associated with age-related macular degeneration. We showed that allele 402H is suggested to be associated with protection from erysipelas (n = 278) and streptococcal tonsillitis (n = 209) compared with controls (n = 455) (p < 0.05). Taken together, the bacterial in vitro survival data and human genetic association revealed that binding of CFH is important for pathogenesis of GAS infections and suggested that inhibition of CFH binding can be a novel therapeutic approach in GAS infections.

show abstract

Section: Discussionmentioning

confidence: 93%

Acquisition of Complement Factor H Is Important for Pathogenesis ofStreptococcus pyogenesInfections: Evidence from Bacterial In Vitro Survival and Human Genetic Association

Haapasalo

Vuopio

Syrjänen

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…In addition to inhibition of the alternative pathway, several bacteria (e.g., Moraxella catarrhalis, S. pyogenes, E. coli K1, and H. influenzae) bind C4BP and are shielded against the classical and lectin pathways (49 -51). Interestingly, many species, C. albicans, Borrelia recurrentis, and S. pyogenes, among others, have been shown to bind both FH and C4BP (26,(52)(53)(54)(55). We have recently demonstrated that non-typeable H. influenzae binds C4BP (30).…”

Section: Discussionmentioning

confidence: 96%

Haemophilus influenzae Interacts with the Human Complement Inhibitor Factor H

Hallström

Zipfel

Blom

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

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 ∼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.

show abstract

“…Binding of FH has been demonstrated for strains of S. pyogenes (group A streptococcus) (40), Neisseria gonorrhoeae (41,42), Streptococcus pneumoniae (43)(44)(45), and Borrelia burgdorferi (46,47), while binding of C4BP has been demonstrated for strains of S. pyogenes (48 -50), Bordetella pertussis (51,52), and N. gonorrhoeae (53,54). In at least two of these cases, there is strong evidence that the bound FH or C4BP contributes to bacterial virulence (41,55). The role of the bacteria-bound RCA protein is most simply explained by its ability to down-regulate complement activation, but it also seems possible that the RCA protein contributes to virulence by mechanisms that are independent of the effect on complement activation (e.g.…”

Section: Discussionmentioning

confidence: 99%

Streptococcal β Protein Has Separate Binding Sites for Human Factor H and IgA-Fc

Areschoug

Stålhammar‐Carlemalm

Karlsson

et al. 2002

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The group B streptococcus (GBS) is the most important cause of life-threatening bacterial infections in newborn infants. Protective immunity to GBS infection is elicited by several surface proteins, one of which, the ␤ protein, is known to bind human IgA-Fc. Here, we show that the ␤ protein also binds human factor H (FH), a negative regulator of complement activation. Absorption experiments with whole human plasma demonstrated binding of FH to a GBS strain expressing ␤ protein but not to an isogenic ␤-negative mutant. This binding was due to a direct interaction between ␤ and FH, as shown by experiments with purified proteins. Inhibition tests and studies with ␤ fragments demonstrated that FH and IgA-Fc bind to separate and nonoverlapping regions in ␤. Heparin, a known ligand for FH, specifically inhibited the binding between ␤ and FH, suggesting that FH has overlapping binding sites for ␤ and heparin. Bacteria-bound FH retained its complement regulatory activity, implying that ␤-expressing GBS may use bound FH to evade complement attack. The finding that ␤ protein binds FH adds to a growing list of interactions between human pathogens and complement regulatory proteins, supporting the notion that these interactions are of general importance in bacterial pathogenesis.

show abstract

Binding of human C4BP to the hypervariable region of M protein: a molecular mechanism of phagocytosis resistance in Streptococcus pyogenes

Cited by 92 publications

References 73 publications

Acquisition of Complement Factor H Is Important for Pathogenesis ofStreptococcus pyogenesInfections: Evidence from Bacterial In Vitro Survival and Human Genetic Association

Acquisition of Complement Factor H Is Important for Pathogenesis ofStreptococcus pyogenesInfections: Evidence from Bacterial In Vitro Survival and Human Genetic Association

Haemophilus influenzae Interacts with the Human Complement Inhibitor Factor H

Streptococcal β Protein Has Separate Binding Sites for Human Factor H and IgA-Fc

Contact Info

Product

Resources

About