Jos A. G. van Strijp
Utrecht University
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Featured researches published by Jos A. G. van Strijp.
Journal of Experimental Medicine | 2004
Carla J. C. de Haas; Karin Ellen Veldkamp; Andreas Peschel; Floor Weerkamp; Willem Jan Bastiaan Van Wamel; Erik Heezius; Miriam J. J. G. Poppelier; Kok P. M. van Kessel; Jos A. G. van Strijp
Leukocyte migration is a key event both in host defense against invading pathogens as well as in inflammation. Bacteria generate chemoattractants primarily by excretion (formylated peptides), complement activation (C5a), and subsequently through activation of leukocytes (e.g., leukotriene B4, platelet-activating factor, and interleukin 8). Here we describe a new protein secreted by Staphylococcus aureus that specifically impairs the response of neutrophils and monocytes to formylated peptides and C5a. This chemotaxis inhibitory protein of S. aureus (CHIPS) is a 14.1-kD protein encoded on a bacteriophage and is found in >60% of clinical isolates. CHIPS reduces the neutrophil recruitment toward C5a in a mouse peritonitis model, even though its activity is much more potent on human than on mouse cells. These findings suggest a new immune escape mechanism of S. aureus and put forward CHIPS as a potential new antiinflammatory therapeutic compound.
Nature Immunology | 2005
Suzan H.M. Rooijakkers; Maartje Ruyken; Anja Roos; Mohamed R. Daha; Julia S. Presanis; Robert B. Sim; Willem Jan Bastiaan Van Wamel; Kok P. M. van Kessel; Jos A. G. van Strijp
The complement system is pivotal in host defense but also contributes to tissue injury in several diseases. The assembly of C3 convertases (C4b2a and C3bBb) is a prerequisite for complement activation. The convertases catalyze C3b deposition on activator surfaces. Here we describe the identification of staphylococcal complement inhibitor, an excreted 9.8-kilodalton protein that blocks human complement by specific interaction with C4b2a and C3bBb. Staphylococcal complement inhibitor bound and stabilized C3 convertases, interfering with additional C3b deposition through the classical, lectin and alternative complement pathways. This led to a substantial decrease in phagocytosis and killing of Staphylococcus aureus by human neutrophils. As a highly active and small soluble protein that acts exclusively on surfaces, staphylococcal complement inhibitor may represent a promising anti-inflammatory molecule.
Critical Care Medicine | 2003
Henk J van Leeuwen; Eric C. J. M. Heezius; Geesje M. Dallinga; Jos A. G. van Strijp; Jan Verhoef; Kok P. M. van Kessel
ObjectiveLipoproteins have been implicated to play a role in innate immunity. Changes in lipoprotein levels have been reported in a variety of inflammatory disorders. Not much is known about lipoprotein metabolism in patients with severe sepsis. We conducted an ancillary study in a multiple-center phase III sepsis trial to investigate the dynamics of plasma lipoproteins in patients with severe sepsis. DesignProspective analysis in patients meeting criteria for severe sepsis as part of a multiple-center sepsis study (KyberSept) with antithrombin III (Kybernin P). SettingUniversity hospital intensive care unit. PatientsSeventeen patients were included in the study. InterventionsRandomized patients received a loading dose of 6000 IU of antithrombin III (Kybernin P) or placebo followed by a 96-hr continuous infusion of 250 IU/hr antithrombin III (Kybernin P) or placebo. In each patient, serial blood samples for total cholesterol, lipoprotein cholesterol, triglycerides, apolipoprotein A-1, apolipoprotein B, and C-reactive protein determination as well as clinical data were collected over 28 days. Measurements and Main ResultsPlasma cholesterol levels rapidly decreased from 2.67 ± 2.02 mmol/L on day 0 to a nadir of 1.41 ± 0.70 mmol/L on day 3, followed by a slow increase to 4.18 ± 1.94 mmol/L on day 28. High-density lipoprotein (HDL) cholesterol concentrations decreased rapidly from 0.84 ± 0.92 mmol/L to a nadir of 0.42 ± 0.35 mmol/L on day 3, to show a slow increase during the following 4 wks to 0.84 ± 0.42 mmol/L. The low-density lipoprotein (LDL) cholesterol concentrations were already low (0.94 ± 0.81 mmol/L) at study entry, to show a progressive increase to subnormal values (2.01 ± 0.94 mmol/L) at 4 wks. Nadir and recovery lipoprotein concentrations were significantly different (paired Student’s t-test, p < .05). A significant correlation was found between HDL cholesterol and apolipoprotein A-1 (r = .714, p < .05) and between LDL cholesterol and apolipoprotein B (r = .733, p < .05). There was no statistical difference in lipoprotein concentrations either between survivors and nonsurvivors or between patients receiving antithrombin III or placebo.Serum amyloid A was a major apoprotein (45%) in HDL at the start of the sepsis and was slowly replaced by apolipoprotein A-1 during recovery. A positive correlation was found between plasma C-reactive protein concentrations and serum amyloid A concentrations in HDL (r = .684, p < .05). No other relevant correlations were found between inflammatory and lipoprotein parameters. ConclusionsIn patients with severe sepsis, lipoprotein concentrations rapidly change and can be reduced to 50% of recovery concentrations. The pattern of early rapid decline is found primarily in the HDL and a slow recovery in both HDL and LDL fractions. The correlation between apolipoprotein and lipoprotein cholesterol concentrations suggests a decline in lipoprotein particles. During severe sepsis, HDL is shifted to acute phase HDL, which is enriched in serum amyloid A and depleted of cholesterol and apolipoprotein A-1. Lipoprotein concentrations are unable to discriminate between survivors and nonsurvivors.
The Journal of Infectious Diseases | 2002
L. Vincent Collins; Sascha A. Kristian; Christopher Weidenmaier; Marion Faigle; Kok P. M. van Kessel; Jos A. G. van Strijp; Friedrich Götz; Birgid Neumeister; Andreas Peschel
Staphylococcus aureus is resistant to alpha-defensins, antimicrobial peptides that play an important role in oxygen-independent killing of human neutrophils. The dlt operon mediates d-alanine incorporation into teichoic acids in the staphylococcal cell envelope and is a determinant of defensin resistance. By using S. aureus wild-type (WT) and Dlt- bacteria, the relative contributions of oxygen-dependent and -independent antimicrobial phagocyte components were analyzed. The Dlt- strain was efficiently killed by human neutrophils even in the absence of a functional respiratory burst, whereas the killing of the WT organism was strongly diminished when the respiratory burst was inhibited. Human monocytes, which do not produce defensins, inactivated the WT and Dlt- bacteria with similar efficiencies. In addition, mice injected with the Dlt- strain had significantly lower rates of sepsis and septic arthritis and fewer bacteria in the kidneys, compared with mice infected with the WT strain.
Cell Host & Microbe | 2010
Dorothee Kretschmer; Anne-Kathrin Gleske; Maren Rautenberg; Rong Wang; Martin Köberle; Erwin Bohn; Torsten Schöneberg; Marie-Josèphe Rabiet; François Boulay; Seymour J. Klebanoff; Kok A. van Kessel; Jos A. G. van Strijp; Michael Otto; Andreas Peschel
Virulence of emerging community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and other highly pathogenic S. aureus strains depends on their production of phenol-soluble modulin (PSM) peptide toxins, which combine the capacities to attract and lyse neutrophils. The molecular basis of PSM-stimulated neutrophil recruitment has remained unclear. Here, we demonstrate that the human formyl peptide receptor 2 (FPR2/ALX), which has previously been implicated in control of endogenous inflammatory processes, senses PSMs at nanomolar concentrations and initiates proinflammatory neutrophil responses to CA-MRSA. Specific blocking of FPR2/ALX or deletion of PSM genes in CA-MRSA severely diminished neutrophil detection of CA-MRSA. Furthermore, a specific inhibitor of FPR2/ALX and of its functional mouse counterpart blocked PSM-mediated leukocyte infiltration in vivo in a mouse model. Thus, the innate immune system uses a distinct FPR2/ALX-dependent mechanism to specifically sense bacterial peptide toxins and detect highly virulent bacterial pathogens. FPR2/ALX represents an attractive target for new anti-infective or anti-inflammatory strategies.
Journal of Immunology | 2004
Bent Postma; Miriam J. J. G. Poppelier; Joost C. van Galen; Eric R. Prossnitz; Jos A. G. van Strijp; Carla J. C. de Haas; Kok P. M. van Kessel
Chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) is an exoprotein produced by several strains of S. aureus, and a potent inhibitor of neutrophil and monocyte chemotaxis toward C5a and formylated peptides like fMLP. These chemoattractants act on their target cells by binding and activating the C5aR and formylated peptide receptor (FPR), respectively. In the present report, we examined the mechanism by which CHIPS affects both of these receptors. We showed that CHIPS blocked binding of anti-C5aR mAb and formylated peptide to human neutrophils as efficiently at temperatures of 0 and 37°C, implying that it is independent of signal transducing systems. This was confirmed by showing that CHIPS acts completely independently of ATP. Additionally, CHIPS was not internalized upon binding to neutrophils. Furthermore, we showed that CHIPS binds specifically to the C5aR and FPR expressed on U937 cells. This binding was functional in blocking C5a- and fMLP-induced calcium mobilization in these cell lines. These results suggest that CHIPS binds directly to the C5aR and FPR, thereby preventing the natural ligands from activating these receptors. The apparent Kd values of CHIPS for the C5aR and FPR were 1.1 ± 0.2 nM and 35.4 ± 7.7 nM, respectively. Moreover, after screening a wide variety of other G protein-coupled receptors, CHIPS was found to affect exclusively the C5aR and FPR. This selectivity and high-affinity binding with potent antagonistic effects makes CHIPS a promising lead for the development of new anti-inflammatory compounds for diseases in which damage by neutrophils plays a key role.
Nature Immunology | 2009
Suzan H.M. Rooijakkers; Jin Wu; Maartje Ruyken; Robert van Domselaar; Karel L. Planken; Apostolia Tzekou; Daniel Ricklin; John D. Lambris; Bert J. C. Janssen; Jos A. G. van Strijp; Piet Gros
Activation of the complement system generates potent chemoattractants and leads to the opsonization of cells for immune clearance. Short-lived protease complexes cleave complement component C3 into anaphylatoxin C3a and opsonin C3b. Here we report the crystal structure of the C3 convertase formed by C3b and the protease fragment Bb, which was stabilized by the bacterial immune-evasion protein SCIN. The data suggest that the proteolytic specificity and activity depend on the formation of dimers of C3 with C3b of the convertase. SCIN blocked the formation of a productive enzyme-substrate complex. Irreversible dissociation of the complex of C3b and Bb is crucial to complement regulation and was determined by slow binding kinetics of the Mg2+-adhesion site in Bb. Understanding the mechanistic basis of the central complement-activation step and microbial immune evasion strategies targeting this step will aid in the development of complement therapeutics.
Annual Review of Microbiology | 2013
András N. Spaan; Bas G. J. Surewaard; Reindert Nijland; Jos A. G. van Strijp
The pathogen Staphylococcus aureus is well adapted to its human host. Neutrophil-mediated killing is a crucial defense system against S. aureus; however, the pathogen has evolved many strategies to resist killing. We first describe the discrete steps of neutrophil activation and migration to the site of infection and the killing of microbes by neutrophils in general. We then highlight the different approaches utilized by S. aureus to resist the different steps of neutrophil attack. Various molecules are discussed in their evolutionary context. Most of the molecules secreted by S. aureus to combat neutrophil attacks at the site of infection show clear human specificity. Many elements of human neutrophil defenses appear redundant, and so the evasion strategies of staphylococci display redundant functions as well. All efforts by S. aureus to resist neutrophil-mediated killing stress the importance of these mechanisms in the pathophysiology of staphylococcal diseases. However, the highly human-specific nature of most host-pathogen interactions hinders the in vivo establishment of their contribution to staphylococcal pathophysiology.
Journal of Immunology | 2001
Philipp Henneke; Osamu Takeuchi; Jos A. G. van Strijp; Hilde-Kari Guttormsen; Jason A. Smith; Andra B. Schromm; Terje Espevik; Shizuo Akira; Victor Nizet; Dennis L. Kasper; Douglas T. Golenbock
Group B streptococcus (GBS) imposes a major health threat to newborn infants. Little is known about the molecular basis of GBS-induced sepsis. Both heat-inactivated whole GBS bacteria and a heat-labile soluble factor released by GBS during growth (GBS-F) induce nuclear translocation of NF-κB, the secretion of TNF-α, and the formation of NO in mouse macrophages. Macrophages from mice with a targeted disruption of MyD88 failed to secrete TNF-α in response to both heat-inactivated whole bacteria and GBS-F, suggesting that Toll-like receptors (TLRs) are involved in different aspects of GBS recognition. Immune cell activation by whole bacteria differed profoundly from that by secreted GBS-F. Whole GBS activated macrophages independently of TLR2 and TLR6, whereas a response to the secreted GBS-F was not observed in macrophages from TLR2-deficient animals. In addition to TLR2, TLR6 and CD14 expression were essential for GBS-F responses, whereas TLR1 and TLR4 or MD-2 did not appear to be involved. Heat lability distinguished GBS-F from peptidoglycan and lipoproteins. GBS mutants deficient in capsular polysaccharide or β-hemolysin had GBS-F activity comparable to that of wild-type streptococci. We suggest that CD14 and TLR2 and TLR6 function as coreceptors for secreted microbial products derived from GBS and that cell wall components of GBS are recognized by TLRs distinct from TLR1, 2, 4, or 6.
BMC Genomics | 2010
Maarten Schijffelen; C. H. Edwin Boel; Jos A. G. van Strijp; Ad C. Fluit
BackgroundRecently, a new livestock-associated methicillin-resistant Staphylococcus aureus (MRSA) Sequence Type 398 (ST398) isolate has emerged worldwide. Although there have been reports of invasive disease in humans, MRSA ST398 colonization is much more common in livestock and demonstrates especially high prevalence rates in pigs and calves. The aim of this study was to compare the genome sequence of an ST398 MRSA isolate with other S. aureus genomes in order to identify genetic traits that may explain the success of this particular lineage. Therefore, we determined the whole genome sequence of S0385, an MRSA ST398 isolate from a human case of endocarditis.ResultsThe entire genome sequence of S0385 demonstrated considerable accessory genome content differences relative to other S. aureus genomes. Several mobile genetic elements that confer antibiotic resistance were identified, including a novel composite of an type V (5C2&5) Staphylococcal Chromosome Cassette mec (SCCmec) with distinct joining (J) regions. The presence of multiple integrative conjugative elements combined with the absence of a type I restriction and modification system on one of the two νSa islands, could enhance horizontal gene transfer in this strain. The ST398 MRSA isolate carries a unique pathogenicity island which encodes homologues of two excreted virulence factors; staphylococcal complement inhibitor (SCIN) and von Willebrand factor-binding protein (vWbp). However, several virulence factors such as enterotoxins and phage encoded toxins, including Panton-Valentine leukocidin (PVL), were not identified in this isolate.ConclusionsUntil now MRSA ST398 isolates did not cause frequent invasive disease in humans, which may be due to the absence of several common virulence factors. However, the proposed enhanced ability of these isolates to acquire mobile elements may lead to the rapid acquisition of determinants which contribute to virulence in human infections.