CD44 as a receptor for colonization of the pharynx by group A Streptococcus

Cywes, Colette; Stamenkovic, Ivan; Wessels, Michael R.

doi:10.1172/jci10195

Cited by 122 publications

(85 citation statements)

References 39 publications

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“…As for CD44, it has been shown to act as a receptor for group A Streptococcus (Cywes et al 2000), Mycobacterium tuberculosis (Leemans et al 2003), and Escherichia coli in urinary tract infections (Rouschop et al 2006).…”

Section: Resultsmentioning

confidence: 99%

Widespread balancing selection and pathogen-driven selection at blood group antigen genes

Fumagalli¹,

Cagliani²,

Pozzoli³

et al. 2008

Genome Res.

152

141

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Historically, allelic variations in blood group antigen (BGA) genes have been regarded as possible susceptibility factors for infectious diseases. Since host-pathogen interactions are major determinants in evolution, BGAs can be thought of as selection targets. In order to verify this hypothesis, we obtained an estimate of pathogen richness for geographic locations corresponding to 52 populations distributed worldwide; after correction for multiple tests and for variables different from selective forces, significant correlations with pathogen richness were obtained for multiple variants at 11 BGA loci out of 26. In line with this finding, we demonstrate that three BGA genes, namely CD55, CD151, and SLC14A1, have been subjected to balancing selection, a process, rare outside MHC genes, which maintains variability at a locus. Moreover, we identified a gene region immediately upstream the transcription start site of FUT2 which has undergone non-neutral evolution independently from the coding region. Finally, in the case of BSG, we describe the presence of a highly divergent haplotype clade and the possible reasons for its maintenance, including frequency-dependent balancing selection, are discussed. These data indicate that BGAs have been playing a central role in the host-pathogen arms race during human evolutionary history and no other gene category shows similar levels of widespread selection, with the only exception of loci involved in antigen recognition.

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Section: Resultsmentioning

confidence: 99%

Widespread balancing selection and pathogen-driven selection at blood group antigen genes

Fumagalli¹,

Cagliani²,

Pozzoli³

et al. 2008

Genome Res.

152

141

View full text Add to dashboard Cite

show abstract

“…Among them, the hyaluronate receptors CD44, CD98, and CD99 were the most prominent. CD44 mediates human cellcell-and cell-extracellular matrix-binding interactions and has also been described to function as a receptor for group A streptococcus colonization of the pharynx in vivo (10). Internalization of piliated capsulated meningococci has been shown to be triggered by the formation of microvillus-like membrane protrusion, containing eszin, moesin, and the integral membrane proteins CD44 and ICAM-1 (24).…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Pattern in Human Brain Endothelial Cells in Response to Neisseria meningitidis

et al. 2007

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To extend our knowledge of target proteins in endothelial cells infected with the meningitis-causing pathogen Neisseria meningitidis, we characterized the interaction between the bacterial and human brain microvascular endothelial cell (HBMEC) monolayers. By use of human cDNA microarrays, transcriptional analysis revealed distinct responses to 4 and 8 h of infection. We also addressed the question of whether the major virulence factor of meningococci, i.e., the capsule, influences the host cell response. Of the 1,493 (at 4 h postinfection) and 1,246 (at 8 h postinfection) genes with altered expression upon bacterial contact, about 49.4% and 45%, respectively, depended on capsule expression. In particular, we identified an increase of expression for genes encoding proteins involved in bacterial adhesion and invasion. High levels of apoptosis-related gene (bad, bak, asp, and immediate-early response gene 1) expression could also be detected in infected cells. Further analyses confirmed that HBMECs displayed several hallmarks of apoptosis in response to N. meningitidis infection, namely, phosphatidylserine translocation and activation of caspase 3 and AMP-activated protein kinase ␣. Moreover, several differentially regulated genes not previously known to respond to meningococcal infection were identified. Of these, genes encoding cell adhesion proteins (CD44, CD98, and CD99), genes involved in downstream signaling of integrins (integrin-linked kinase, mitogen-activated protein kinase kinase 1, and mitogen-activated protein kinase kinase kinase 10) as well as negative regulators of these pathways (dualspecificity phosphatases 1, 5, and 14 and G protein pathway suppressor 2), and genes involved in cytoskeleton reorganization (those encoding Arp2/3, p34-arc, actinin alpha 1, vasodilatator-stimulated protein, and Wiskott-Aldrich syndrome protein) were the most prominent. This global transcriptional analysis creates a new platform for further molecular and cellular analysis of the interaction between N. meningitidis and target cells.

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“…Our approach to designing anthrax-toxin receptor-directed inhibitors may be broadly applicable to receptors used by other pathogens and toxins (3,(30)(31)(32)(33). Membrane proteins are currently the most highly represented class of drug targets for noninfectious diseases.…”

Section: Resultsmentioning

confidence: 99%

Polyvalent inhibitors of anthrax toxin that target host receptors

Basha

Rai

Poon

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Resistance of pathogens to antimicrobial therapeutics has become a widespread problem. Resistance can emerge naturally, but it can also be engineered intentionally, which is an important consideration in designing therapeutics for bioterrorism agents. Blocking host receptors used by pathogens represents a powerful strategy to overcome this problem, because extensive alterations to the pathogen may be required to enable it to switch to a new receptor that can still support pathogenesis. Here, we demonstrate a facile method for producing potent receptor-directed antitoxins. We used phage display to identify a peptide that binds both anthraxtoxin receptors and attached this peptide to a synthetic scaffold. Polyvalency increased the potency of these peptides by >50,000-fold in vitro and enabled the neutralization of anthrax toxin in vivo. This work demonstrates a receptor-directed anthrax-toxin inhibitor and represents a promising strategy to combat a variety of viral and bacterial diseases.antimicrobial resistance ͉ phage display ͉ therapeutics P athogens can develop resistance to drugs directed against microbial targets by modifying the drug, by lowering the concentration of drug that reaches the target, or by mutating the target (1, 2). There is also an increasing concern that therapeutics developed for bioterrorism agents may be rendered ineffective if the microbial target is altered intentionally. This problem could be overcome, however, by designing inhibitors that block host proteins used by the pathogen or its toxins to cause disease.Microbial pathogens and their products interact with host structures to facilitate colonization or to promote cellular uptake. Many of these interactions are polyvalent, meaning that they involve the simultaneous binding of multiple ligands on one entity to multiple receptors on another (3). The design of synthetic polyvalent (4-8) or oligovalent (9, 10) molecules also represents a promising approach to enhance the potency of inhibitors of microbial pathogens and toxins. Current examples of this approach have involved the design of molecules that bind directly to the pathogen or toxin. Inhibitors that bind host proteins would represent an effective way to attenuate virulence that may be less susceptible to resistance mechanisms, and the use of polyvalency could provide a significant enhancement in the potency of these inhibitors.ANTXR1 and ANTXR2 are host receptors that bind and internalize anthrax toxin (11,12). These proteins are likely important for anthrax pathogenesis because the toxin impairs the immune response and is responsible for the major symptoms and death associated with anthrax. Thus, blocking these receptors could represent a promising approach to anthrax therapy.ANTXR1 and ANTXR2 are widely expressed type I membrane proteins that bind components of the extracellular matrix (13). They both contain an extracellular I domain, which binds the protective antigen (PA) component of anthrax toxin. The two proteins are 40% identical overall and share 60% identity within ...

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CD44 as a receptor for colonization of the pharynx by group A Streptococcus

Cited by 122 publications

References 39 publications

Widespread balancing selection and pathogen-driven selection at blood group antigen genes

Widespread balancing selection and pathogen-driven selection at blood group antigen genes

Gene Expression Pattern in Human Brain Endothelial Cells in Response to Neisseria meningitidis

Polyvalent inhibitors of anthrax toxin that target host receptors

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