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103. The post-vaccine microevolution of invasive Streptococcus pneumoniae

Author

Cremers, Amelieke J H, Mobegi, Fredrick M, de Jonge, Marien I, van Hijum, Sacha A F T, Meis, Jacques F, Hermans, Peter W M, Ferwerda, Gerben, Bentley, Stephen D, Zomer, Aldert L, Cremers, Amelieke J H, Mobegi, Fredrick M, de Jonge, Marien I, van Hijum, Sacha A F T, Meis, Jacques F, Hermans, Peter W M, Ferwerda, Gerben, Bentley, Stephen D, and Zomer, Aldert L

Abstract

The 7-valent pneumococcal conjugated vaccine (PCV7) has affected the genetic population of Streptococcus pneumoniae in pediatric carriage. Little is known however about pneumococcal population genomics in adult invasive pneumococcal disease (IPD) under vaccine pressure. We sequenced and serotyped 349 strains of S. pneumoniae isolated from IPD patients in Nijmegen between 2001 and 2011. Introduction of PCV7 in the Dutch National Immunization Program in 2006 preluded substantial alterations in the IPD population structure caused by serotype replacement. No evidence could be found for vaccine induced capsular switches. We observed that after a temporary bottleneck in gene diversity after the introduction of PCV7, the accessory gene pool re-expanded mainly by genes already circulating pre-PCV7. In the post-vaccine genomic population a number of genes changed frequency, certain genes became overrepresented in vaccine serotypes, while others shifted towards non-vaccine serotypes. Whether these dynamics in the invasive pneumococcal population have truly contributed to invasiveness and manifestations of disease remains to be further elucidated. We suggest the use of whole genome sequencing for surveillance of pneumococcal population dynamics that could give a prospect on the course of disease, facilitating effective prevention and management of IPD.

Published
2015

104. The post-vaccine microevolution of invasive Streptococcus pneumoniae

Author

dI&I I&I-4, Sub Bioinformatics, LS Klinisch Onderzoek Wagenaar, Infection & Immunity, Cremers, Amelieke J H, Mobegi, Fredrick M, de Jonge, Marien I, van Hijum, Sacha A F T, Meis, Jacques F, Hermans, Peter W M, Ferwerda, Gerben, Bentley, Stephen D, Zomer, Aldert L, dI&I I&I-4, Sub Bioinformatics, LS Klinisch Onderzoek Wagenaar, Infection & Immunity, Cremers, Amelieke J H, Mobegi, Fredrick M, de Jonge, Marien I, van Hijum, Sacha A F T, Meis, Jacques F, Hermans, Peter W M, Ferwerda, Gerben, Bentley, Stephen D, and Zomer, Aldert L

Published
2015

105. Olfactomedin 4 serves as a marker for disease severity in pediatric Respiratory Syncytial Virus (RSV) infection

Author

Brand, Kim H., Ahout, Ingle M., de Ridder, Dick, van Diepen, Angela, Li, Yunlei, Zaalberg, Marike, Andeweg, Arno, Roeleveld, Nel, de Groot, Ronald, Warris, Adilia, Hermans, Peter W., Ferwerda, Gerben, Staal, Frank J., Brand, Kim H., Ahout, Ingle M., de Ridder, Dick, van Diepen, Angela, Li, Yunlei, Zaalberg, Marike, Andeweg, Arno, Roeleveld, Nel, de Groot, Ronald, Warris, Adilia, Hermans, Peter W., Ferwerda, Gerben, and Staal, Frank J.

Abstract

Respiratory viral infections follow an unpredictable clinical course in young children ranging from a common cold to respiratory failure. The transition from mild to severe disease occurs rapidly and is difficult to predict. The pathophysiology underlying disease severity has remained elusive. There is an urgent need to better understand the immune response in this disease to come up with biomarkers that may aid clinical decision making. In a prospective study, flow cytometric and genome-wide gene expression analyses were performed on blood samples of 26 children with a diagnosis of severe, moderate or mild Respiratory Syncytial Virus (RSV) infection. Differentially expressed genes were validated using Q-PCR in a second cohort of 80 children during three consecutive winter seasons. FACS analyses were also performed in the second cohort and on recovery samples of severe cases in the first cohort. Severe RSV infection was associated with a transient but marked decrease in CD4+ T, CD8+ T, and NK cells in peripheral blood. Gene expression analyses in both cohorts identified Olfactomedin4 (OLFM4) as a fully discriminative marker between children with mild and severe RSV infection, giving a PAM cross-validation error of 0%. Patients with an OLFM4 gene expression level above -7.5 were 6 times more likely to develop severe disease, after correction for age at hospitalization and gestational age. In conclusion, by combining genome-wide expression profiling of blood cell subsets with clinically well-annotated samples, OLFM4 was identified as a biomarker for severity of pediatric RSV infection., Respiratory viral infections follow an unpredictable clinical course in young children ranging from a common cold to respiratory failure. The transition from mild to severe disease occurs rapidly and is difficult to predict. The pathophysiology underlying disease severity has remained elusive. There is an urgent need to better understand the immune response in this disease to come up with biomarkers that may aid clinical decision making. In a prospective study, flow cytometric and genome-wide gene expression analyses were performed on blood samples of 26 children with a diagnosis of severe, moderate or mild Respiratory Syncytial Virus (RSV) infection. Differentially expressed genes were validated using Q-PCR in a second cohort of 80 children during three consecutive winter seasons. FACS analyses were also performed in the second cohort and on recovery samples of severe cases in the first cohort. Severe RSV infection was associated with a transient but marked decrease in CD4+ T, CD8+ T, and NK cells in peripheral blood. Gene expression analyses in both cohorts identified Olfactomedin4 (OLFM4) as a fully discriminative marker between children with mild and severe RSV infection, giving a PAM cross-validation error of 0%. Patients with an OLFM4 gene expression level above -7.5 were 6 times more likely to develop severe disease, after correction for age at hospitalization and gestational age. In conclusion, by combining genome-wide expression profiling of blood cell subsets with clinically well-annotated samples, OLFM4 was identified as a biomarker for severity of pediatric RSV infection.

Published
2015

106. Aptasensors for viral diagnostics

Author

van den Kieboom, Corné H., primary, van der Beek, Samantha L., additional, Mészáros, Tamás, additional, Gyurcsányi, Róbert E., additional, Ferwerda, Gerben, additional, and de Jonge, Marien I., additional

Published
2015
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107. FC GAMMA RECEPTORS IN RESPIRATORY SYNCYTIAL VIRUS INFECTIONS: IMPLICATIONS FOR INNATE IMMUNITY

Author

Jans, Jop, Vissers, Marloes, Heldens, Jacco G.M., de Jonge, Marien I., Levy, Ofer, and Ferwerda, Gerben

Subjects
viruses, Respiratory Syncytial Virus, Human, Receptors, IgG, Infant, Newborn, Humans, Infant, Respiratory Syncytial Virus Infections, Antibodies, Viral, Article, Immunity, Innate
Abstract

Respiratory syncytial virus infections are a major burden in infants less than 3 months of age. Newborns and infants express a distinct immune system that is largely dependent on innate immunity and passive immunity from maternal antibodies. Antibodies can regulate immune responses against viruses through interaction with Fc gamma receptors leading to enhancement or neutralization of viral infections. The mechanisms underlying the immunomodulatory effect of Fc gamma receptors on viral infections have yet to be elucidated in infants. Herein, we will discuss current knowledge of the effects of antibodies and Fc gamma receptors on infant innate immunity to RSV. A better understanding of the pathogenesis of RSV infections in young infants may provide insight into novel therapeutic strategies like vaccination.

Published
2013

110. Bacterial lipopolysaccharide inhibits influenza virus infection of human macrophages and the consequent induction of CD8+ T cell immunity

Author

LS Klinisch Onderzoek Wagenaar, Short, Kirsty R, Vissers, Marloes, de Kleijn, Stan, Zomer, Aldert L, Kedzierska, Katherine, Grant, Emma, Reading, Patrick C, Hermans, Peter W M, Ferwerda, Gerben, Diavatopoulos, Dimitri A, LS Klinisch Onderzoek Wagenaar, Short, Kirsty R, Vissers, Marloes, de Kleijn, Stan, Zomer, Aldert L, Kedzierska, Katherine, Grant, Emma, Reading, Patrick C, Hermans, Peter W M, Ferwerda, Gerben, and Diavatopoulos, Dimitri A

Published
2014

112. The adult nasopharyngeal microbiome as a determinant of pneumococcal acquisition

Author

Sub Bioinformatics, LS Klinisch Onderzoek Wagenaar, Cremers, Amelieke Jh, Zomer, Aldert L, Gritzfeld, Jenna F, Ferwerda, Gerben, van Hijum, Sacha Aft, Ferreira, Daniela M, Shak, Joshua R, Klugman, Keith P, Boekhorst, Jos, Timmerman, Harro M, de Jonge, Marien I, Gordon, Stephen B, Hermans, Peter Wm, Sub Bioinformatics, LS Klinisch Onderzoek Wagenaar, Cremers, Amelieke Jh, Zomer, Aldert L, Gritzfeld, Jenna F, Ferwerda, Gerben, van Hijum, Sacha Aft, Ferreira, Daniela M, Shak, Joshua R, Klugman, Keith P, Boekhorst, Jos, Timmerman, Harro M, de Jonge, Marien I, Gordon, Stephen B, and Hermans, Peter Wm

Published
2014

114. Defective acute inflammation in Crohn's disease

Author

Netea, Mihai G., van der Meer, Jos W.M., Ferwerda, Gerben, Kullberg, Bart Jan, van Lierop, P.P.E., Damen, G.M., Escher, J.C., Samsom, J.N., and Nieuwenhuis, E.E.S.

Published
2006

120. Bacterial Lipopolysaccharide Inhibits Influenza Virus Infection of Human Macrophages and the Consequent Induction of CD8+ T Cell Immunity

Author

Short, Kirsty R., primary, Vissers, Marloes, additional, de Kleijn, Stan, additional, Zomer, Aldert L., additional, Kedzierska, Katherine, additional, Grant, Emma, additional, Reading, Patrick C., additional, Hermans, Peter W.M., additional, Ferwerda, Gerben, additional, and Diavatopoulos, Dimitri A., additional

Published
2013
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121. Decreased Cell Wall Galactosaminogalactan in Aspergillus nidulans Mediates Dysregulated Inflammation in the Chronic Granulomatous Disease Host.

Author

Henriet, Stefanie S. V., van de Sande, Wendy W. J., Lee, Mark J., Simonetti, Elles, Momany, Michelle, Verweij, Paul E., Rijs, Antonius J. M. M., Ferwerda, Gerben, Sheppard, Donald C., de Jonge, Marien I., and Warris, Adilia

Subjects
GALACTANS, POLYSACCHARIDES, ASPERGILLUS nidulans, ASPERGILLUS, CHRONIC granulomatous disease, LEUCOCYTE disorders
Abstract

Invasive aspergillosis is a major threat to patients suffering from impaired neutrophil function, with Aspergillus fumigatus being the most common species causing this life-threatening condition. Patients with chronic granulomatous disease (CGD) not only develop infections with A. fumigatus, but also exhibit a unique susceptibility to infection with the normally nonpathogenic species Aspergillus nidulans. In this study, we compared the inflammatory cytokine response of peripheral blood mononuclear cells (PBMCs) from healthy and CGD patients to these two fungal species. CGD patients displayed evidence for a chronic hyperinflammatory state as indicated by elevated plasma IL-1β and TNF-α levels. PBMCs isolated from CGD patients secreted higher levels of IL-1β and TNF-α in response to A. nidulans as compared with A. fumigatus. The presence or absence of melanin in the cell wall of A. nidulans did not alter the cytokine release by healthy or CGD PBMCs. In contrast, A. fumigatus mutants lacking melanin stimulated higher levels of proinflammatory cytokine release from healthy, but not CGD PBMCs. Purified cell wall polysaccharides of A. nidulans induced a much higher level of IL-1β secretion by CGD PBMCs than did cell wall polysaccharides isolated from A. fumigatus. Using modified A. nidulans strains overexpressing galactosaminogalactan, we were able to show that the increased secretion of inflammatory cytokines by CGD PBMCs in response to A. nidulans are a consequence of low levels of cell wall-associated galactosaminogalactan in this species. [ABSTRACT FROM AUTHOR]

Published
2016
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126. Recognition and Blocking of Innate Immunity Cells by Candida albicans Chitin

Author

Mora-Montes, Héctor M., primary, Netea, Mihai G., additional, Ferwerda, Gerben, additional, Lenardon, Megan D., additional, Brown, Gordon D., additional, Mistry, Anita R., additional, Kullberg, Bart Jan, additional, O'Callaghan, Chris A., additional, Sheth, Chirag C., additional, Odds, Frank C., additional, Brown, Alistair J. P., additional, Munro, Carol A., additional, and Gow, Neil A. R., additional

Published
2011
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128. Differential requirement for the activation of the inflammasome for processing and release of IL-1β in monocytes and macrophages

Author

Netea, Mihai G., primary, Nold-Petry, Claudia A., additional, Nold, Marcel F., additional, Joosten, Leo A. B., additional, Opitz, Bastian, additional, van der Meer, Jonathan H. M., additional, van de Veerdonk, Frank L., additional, Ferwerda, Gerben, additional, Heinhuis, Bas, additional, Devesa, Isabel, additional, Funk, C. Joel, additional, Mason, Robert J., additional, Kullberg, Bart Jan, additional, Rubartelli, Anna, additional, van der Meer, Jos W. M., additional, and Dinarello, Charles A., additional

Published
2009
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130. Differential function of the NACHT-LRR (NLR) members Nod1 and Nod2 in arthritis

Author

Joosten, Leo A. B., primary, Heinhuis, Bas, additional, Abdollahi-Roodsaz, Shahla, additional, Ferwerda, Gerben, additional, LeBourhis, Lionel, additional, Philpott, Dana J., additional, Nahori, Marie-Anne, additional, Popa, Calin, additional, Morre, Servaas A., additional, van der Meer, Jos W. M., additional, Girardin, Stephen E., additional, Netea, Mihai G., additional, and van den Berg, Wim B., additional

Published
2008
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131. Syk kinase is required for collaborative cytokine production induced through Dectin-1 and Toll-like receptors

Author

Dennehy, Kevin M., primary, Ferwerda, Gerben, additional, Faro-Trindade, Inês, additional, Pyż, Elwira, additional, Willment, Janet A., additional, Taylor, Philip R., additional, Kerrigan, Ann, additional, Tsoni, S. Vicky, additional, Gordon, Siamon, additional, Meyer-Wentrup, Friederike, additional, Adema, Gosse J., additional, Kullberg, Bart-Jan, additional, Schweighoffer, Edina, additional, Tybulewicz, Victor, additional, Mora-Montes, Hector M., additional, Gow, Neil A. R., additional, Williams, David L., additional, Netea, Mihai G., additional, and Brown, Gordon D., additional

Published
2008
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132. Engagement of NOD2 has a dual effect on proIL-1β mRNA transcription and secretion of bioactive IL-1β

Author

Ferwerda, Gerben, primary, Kramer, Matthijs, additional, de Jong, Dirk, additional, Piccini, Alessandra, additional, Joosten, Leo A., additional, DevesaGiner, Isabel, additional, Girardin, Stephen E., additional, Adema, Gosse J., additional, van der Meer, Jos W. M., additional, Kullberg, Bart-Jan, additional, Rubartelli, Anna, additional, and Netea, Mihai G., additional

Published
2008
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133. Immune Recognition ofCandida albicansβ‐glucan by Dectin‐1

Author

Gow, Neil A. R., primary, Netea, Mihai G., additional, Munro, Carol A., additional, Ferwerda, Gerben, additional, Bates, Steven, additional, Mora‐Montes, Héctor M., additional, Walker, Louise, additional, Jansen, Trees, additional, Jacobs, Liesbeth, additional, Tsoni, Vicky, additional, Brown, Gordon D., additional, Odds, Frank C., additional, Van der Meer, Jos W. M., additional, Brown, Alistair J. P., additional, and Kullberg, Bart Jan, additional

Published
2007
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136. To the Editor

Author

Ferwerda, Gerben, primary, Girardin, Stephen E., additional, van der Meer, Jos W. M., additional, and Netea, Mihai G., additional

Published
2006
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139. NOD2 and Toll-Like Receptors Are Nonredundant Recognition Systems of Mycobacterium tuberculosis

Author

Ferwerda, Gerben, primary, Girardin, Stephen E, additional, Kullberg, Bart-Jan, additional, Le Bourhis, Lionel, additional, de Jong, Dirk J., additional, Langenberg, Dennis M. L, additional, van Crevel, Reinout, additional, Adema, Gosse J, additional, Ottenhoff, Tom H. M, additional, Van der Meer, Jos W. M., additional, and Netea, Mihai G, additional

Published
2005
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140. The Frameshift Mutation in Nod2 Results in Unresponsiveness Not Only to Nod2- but Also Nod1-activating Peptidoglycan Agonists

Author

Netea, Mihai G., primary, Ferwerda, Gerben, additional, de Jong, Dirk J., additional, Werts, Catherine, additional, Boneca, Ivo G., additional, Jéhanno, Muguette, additional, Van Der Meer, Jos W.M., additional, Mengin-Lecreulx, Dominique, additional, Sansonetti, Philippe J., additional, Philpott, Dana J., additional, Dharancy, Sébastien, additional, and Girardin, Stephen E., additional

Published
2005
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141. Nucleotide-Binding Oligomerization Domain-2 Modulates Specific TLR Pathways for the Induction of Cytokine Release

Author

Netea, Mihai G., primary, Ferwerda, Gerben, additional, de Jong, Dirk J., additional, Jansen, Trees, additional, Jacobs, Liesbeth, additional, Kramer, Matthijs, additional, Naber, Ton H. J., additional, Drenth, Joost P. H., additional, Girardin, Stephen E., additional, Jan Kullberg, Bart, additional, Adema, Gosse J., additional, and Van der Meer, Jos W. M., additional

Published
2005
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143. The role of ZmpC in the clinical manifestation of invasive pneumococcal disease.

Author

Cremers, Amelieke J.H., Kokmeijer, Ishana, Groh, Laszlo, de Jonge, Marien I., and Ferwerda, Gerben

Subjects
STREPTOCOCCUS pneumoniae, METALLOPROTEINASES, BACTERIAL proteins, NEUTROPHILS, INFLAMMATION, TISSUE remodeling, SEROTYPES
Abstract

Introduction The clinical severity and course of invasive pneumococcal disease (IPD) differs substantially between patients. Streptococcus pneumoniae harbors large genetic variability. Zinc metalloproteinase C (ZmpC), a secreted pneumococcal protein involved in neutrophil extravasation, inflammation and tissue remodeling, is present in a minority of IPD isolates. We investigated whether the presence of zmpC was associated with the clinical manifestation of IPD. Material and methods IPD patients admitted to two Dutch hospitals between 2000 and 2013 were included in the study. Detailed clinical data were collected and the serotype and presence of zmpC were determined in the corresponding blood culture isolates. Results ZmpC was present in 21% of the 542 included IPD cases and was mainly associated with serotypes 8, 4, 33A/F and 11A/D. Infection with S. pneumoniae positive for zmpC was more frequently observed in females ( p = 0.048) and patients with a history of smoking ( p = 0.033). Although no relation to clinical syndrome was observed, zmpC positive cases more often presented with cough, dyspnea and sepsis ( p -values 0.026, 0.001 and 0.018), and more frequently required ICU admission ( p = 0.011) compared to zmpC negative cases. Conclusion The presence of zmpC was associated with a more severe clinical manifestation of IPD. This study demonstrates that information on pneumococcal genetic background may be useful to identify vulnerable individuals, to monitor clinical presentation and to predict the course of IPD. [ABSTRACT FROM AUTHOR]

Published
2014
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144. Fc gamma receptors in respiratory syncytial virus infections: implications for innate immunity.

Author

Jans, Jop, Vissers, Marloes, Heldens, Jacco G.M., Jonge, Marien I., Levy, Ofer, and Ferwerda, Gerben

Abstract

SUMMARY RSV infections are a major burden in infants less than 3 months of age. Newborns and infants express a distinct immune system that is largely dependent on innate immunity and passive immunity from maternal antibodies. Antibodies can regulate immune responses against viruses through interaction with Fc gamma receptors leading to enhancement or neutralization of viral infections. The mechanisms underlying the immunomodulatory effect of Fc gamma receptors on viral infections have yet to be elucidated in infants. Herein, we will discuss current knowledge of the effects of antibodies and Fc gamma receptors on infant innate immunity to RSV. A better understanding of the pathogenesis of RSV infections in young infants may provide insight into novel therapeutic strategies such as vaccination. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Published
2014
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146. Immune recognition of Candida albicans beta-glucan by dectin-1.

Author

Grow NAR, Netea MG, Munro CA, Ferwerda G, Bates S, Moras-Mentes HM, Walker L, Jansen T, Jacobs L, Tsoni V, Brown GD, Odds FC, Van der Meer JWM, Brown AJP, Kullberg BJ, Gow, Neil A R, Netea, Mihai G, Munro, Carol A, Ferwerda, Gerben, and Bates, Steven

Abstract

Beta (1,3)-glucans represent 40% of the cell wall of the yeast Candida albicans. The dectin-1 lectin-like receptor has shown to recognize fungal beta (1,3)-glucans and induce innate immune responses. The importance of beta-glucan-dectin-1 pathways for the recognition of C. albicans by human primary blood cells has not been firmly established. In this study we demonstrate that cytokine production by both human peripheral blood mononuclear cells and murine macrophages is dependent on the recognition of beta-glucans by dectin-1. Heat killing of C. albicans resulted in exposure of beta-glucans on the surface of the cell wall and subsequent recognition by dectin-1, whereas live yeasts stimulated monocytes mainly via recognition of cell-surface mannans. Dectin-1 induced cytokine production through the following 2 pathways: Syk-dependent production of the T-helper (Th) 2-type anti-inflammatory cytokine interleukin-10 and Toll-like receptor-Myd88-dependent stimulation of monocyte-derived proinflammatory cytokines, such as tumor necrosis factor-alpha . In contrast, stimulation of Th1-type cytokines, such as interferon-gamma , by C. albicans was independent of the recognition of beta-glucans by dectin-1. In conclusion, C. albicans induces production of monocyte-derived and T cell-derived cytokines through distinct pathways dependent on or independent of dectin-1. [ABSTRACT FROM AUTHOR]

Published
2007

147. Immune Recognition of Candida albicans β-glucan by Dectin-1.

Author

Gow, Neil A. R., Netea, Mihai G., Munro, Carol A., Ferwerda, Gerben, Bates, Steven, Mora-Montes, Héctor M., Walker, Louise, Jansen, Trees, Jacobs, Liesbeth, Tsoni, Vicky, Brown, Gordon D., Odds, Frank C., van der Meer, Jos W. M., Brown, Alistair J. P., and Kullberg, Bart Jan

Subjects
CANDIDA albicans, IMMUNOREGULATION, ANTINEOPLASTIC agents, LEUCOCYTES, GLYCOPROTEINS, MONOCYTES, BLOOD cells, CYTOKINES, MACROPHAGES
Abstract

β(1,3)-glucans represent 40% of the cell wall of the yeast Candida albicans. The dectin-1 lectin-like receptor has shown to recognize fungal β(1,3)-glucans and induce innate immune responses. The importance of β-glucan-dectin-1 pathways for the recognition of C. albicans byhumanprimary blood cells has not been firmly established. In this study we demonstrate that cytokine production by both human peripheral blood mononuclear cells and murine macrophages is dependent on the recognition of β-glucans by dectin-1. Heat killing of C. albicans resulted in exposure of β-glucans on the surface of the cell wall and subsequent recognition by dectin-1, whereas live yeasts stimulated monocytes mainly via recognition of cell-surface mannans. Dectin-1 induced cytokine production through the following 2 pathways: Syk-dependent production of the T-helper (Th) 2-type anti-inflammatory cytokine interleukin-10 and Toll-like receptor-Myd88-dependent stimulation of monocyte-derived proinflammatory cytokines, such as tumor necrosis factor-α. In contrast, stimulation of Th1-type cytokines, such as interferon-γ, by C. albicans was independent of the recognition of β-glucans by dectin-1. In conclusion, C. albicans induces production of monocyte-derived and T cell-derived cytokines through distinct pathways dependent on or independent of dectin-1. [ABSTRACT FROM AUTHOR]

Published
2007
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148. Recognition of Streptococcus pneumoniaeand Muramyl Dipeptide by NOD2 Results in Potent Induction of MMP-9, Which Can Be Controlled by Lipopolysaccharide Stimulation

Author

Vissers, Marloes, Hartman, Yvonne, Groh, Laszlo, de Jong, Dirk J., de Jonge, Marien I., and Ferwerda, Gerben

Abstract

ABSTRACTMatrix metallopeptidase 9 (MMP-9) is a protease involved in the degradation of extracellular matrix collagen. Evidence suggests that MMP-9 is involved in pathogenesis during Streptococcus pneumoniaeinfection. However, not much is known about the induction of MMP-9 and the regulatory processes involved. We show here that the Gram-positive bacteria used in this study induced large amounts of MMP-9, in contrast to the Gram-negative bacteria that were used. An important pathogen-associated molecular pattern (PAMP) for Gram-positive bacteria is muramyl dipeptide (MDP). MDP is a very potent inducer of MMP-9 and showed a dose-dependent MMP-9 induction. Experiments using peripheral blood mononuclear cells (PBMCs) from Crohn's disease patients with nonfunctional NOD2 showed that MMP-9 induction by Streptococcus pneumoniaeand MDP is NOD2 dependent. Increasing amounts of lipopolysaccharide (LPS), an important PAMP for Gram-negative bacteria, resulted in decreasing amounts of MMP-9. Moreover, the induction of MMP-9 by MDP could be counteracted by simultaneously adding LPS. The inhibition of MMP-9 expression by LPS was found to be regulated posttranscriptionally, independently of tissue inhibitor of metalloproteinase 1 (TIMP-1), an endogenous inhibitor of MMP-9. Collectively, these data show that Streptococcus pneumoniaeis able to induce large amounts of MMP-9. These high MMP-9 levels are potentially involved in Streptococcus pneumoniaepathogenesis.

Published
2014
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149. CD4+T-cell counts and interleukin-8 and CCL-5 plasma concentrations discriminate disease severity in children with RSV infection

Author

Brand, Hanne K., Ferwerda, Gerben, Preijers, Frank, de Groot, Ronald, Neeleman, Chris, Staal, Frank J.T., Warris, Adilia, and Hermans, Peter W.M.

Abstract

Background:Current tools to predict the severity of respiratory syncytial virus (RSV) infection might be improved by including immunological parameters. We hypothesized that a combination of inflammatory markers would differentiate between severe and mild disease in RSV-infected children.Methods:Blood and nasopharyngeal samples from 52 RSV-infected children were collected during acute infection and after recovery. Retrospectively, patients were categorized into three groups based on disease severity: mild (no supportive treatment), moderate (supplemental oxygen and/or nasogastric feeding), and severe (mechanical ventilation). Clinical data, number of flow-defined leukocyte subsets, and cytokine concentrations were compared.Results:Children with severe RSV infection were characterized by young age; lymphocytopenia; increased interleukin (IL)-8, granulocyte colony-stimulating factor (G-CSF), and IL-6 concentrations; and decreased chemokine (C-C motif) ligand (CCL-5) concentrations in plasma. The combination of plasma levels of IL-8 and CCL-5, and CD4+T-cell counts, with cutoff values of 67 pg/ml, 13?ng/ml, and 2.3 × 106/ml, respectively, discriminated severe from mild RSV infection with 82% sensitivity and 96% specificity.Conclusion:This study demonstrates that the combination of CD4+T-cell counts and IL-8 and CCL-5 plasma concentrations correlates with disease severity in RSV-infected children. In addition to clinical features, these immunological markers may be used to assess severity of RSV infection and guide clinical management.

Published
2013
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150. A combination of immune cell types identified through ensemble machine learning strategy detects altered profile in recurrent pregnancy loss: a pilot study

Author

Benner, Marilen, Feyaerts, Dorien, Lopez-Rincon, Alejandro, van der Heijden, Olivier WH., van der Hoorn, Marie-Louise, Joosten, Irma, Ferwerda, Gerben, and van der Molen, Renate G.

Abstract

To compare the immunological profiles of peripheral and menstrual blood of women who experience recurrent pregnancy loss (RPL) and women without pregnancy complications.

Published
2022
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