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von Pawel-Rammingen, Ulrich
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Publications (10 of 24) Show all publications
Seele, J., Hillermann, L.-M., Beineke, A., Seitz, M., von Pawel-Rammingen, U., Valentin-Weigand, P. & Baums, C. G. (2015). The immunoglobulin M-degrading enzyme of Streptococcus suis, Ide(Ssuis), is a highly protective antigen against serotype 2. Vaccine, 33(19), 2207-2212
Open this publication in new window or tab >>The immunoglobulin M-degrading enzyme of Streptococcus suis, Ide(Ssuis), is a highly protective antigen against serotype 2
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2015 (English)In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 33, no 19, p. 2207-2212Article in journal (Refereed) Published
Abstract [en]

Streptococcus suis (S. suis) is a major porcine pathogen causing meningitis, arthritis and several other pathologies. Recently, we identified a highly specific immunoglobulin M degrading enzyme of S. suis, designated IdeSsuis, which is expressed by various serotypes. The objective of this work was to access the immunogenicity and protective efficacy of a recombinant vaccine including IdeSsuis. Vaccination with rIdeSsuis elicited antibodies efficiently neutralizing the IgM protease activity. Importantly, 18 piglets vaccinated with rIdeSsuis alone or in combination with bacterin priming were completely protected against mortality and severe morbidity after S. suis serotype 2 challenge. In contrast, 12 of the 17 piglets either treated with the placebo or primed with the bacterin only, succumbed to S. suis disease. Immunity against Idessuis was associated with increased killing of S. suis wt in porcine blood ex vivo leading to a tenfold difference in the bacterial survival factor in blood of placebo-treated and rIdeSsuis-vaccinated piglets. In conclusion, the results of this study indicate that rIdeSsuis is a highly protective antigen in pigs.

Keyword
IgM protease, Streptococcus suis, Pigs, Bactericidal assay, Neutralizing antibodies
National Category
Medical Bioscience
Identifiers
urn:nbn:se:umu:diva-103720 (URN)10.1016/j.vaccine.2015.03.047 (DOI)000353734900003 ()25825330 (PubMedID)
Available from: 2015-06-11 Created: 2015-05-28 Last updated: 2017-12-04Bibliographically approved
Seele, J., Beineke, A., Hillermann, L.-M., Jaschok-Kentner, B., von Pawel-Rammingen, U., Valentin-Weigand, P. & Baums, C. G. (2015). The immunoglobulin M-degrading enzyme of Streptococcus suis, Ide(Ssuis), is involved in complement evasion. Veterinary research (Print), 46, Article ID 45.
Open this publication in new window or tab >>The immunoglobulin M-degrading enzyme of Streptococcus suis, Ide(Ssuis), is involved in complement evasion
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2015 (English)In: Veterinary research (Print), ISSN 0928-4249, E-ISSN 1297-9716, Vol. 46, article id 45Article in journal (Refereed) Published
Abstract [en]

Streptococcus (S.) suis is one of the most important pathogens in pigs causing meningitis, arthritis, endocarditis and serositis. Furthermore, it is also an emerging zoonotic agent. In our previous work we identified a highly specific IgM protease in S. suis, designated IdeSsuis. The objective of this study was to characterize the function of IdeSsuis in the host-pathogen interaction. Edman-sequencing revealed that Ide(Ssuis) cleaves the heavy chain of the IgM molecule between constant domain 2 and 3. As the C1q binding motif is located in the C3 domain, we hypothesized that IdeSsuis is involved in complement evasion. Complement-mediated hemolysis induced by porcine hyperimmune sera containing erythrocyte-specific IgM was abrogated by treatment of these sera with recombinant IdeSsuis. Furthermore, expression of IdeSsuis reduced IgM-triggered complement deposition on the bacterial surface. An infection experiment of prime-vaccinated growing piglets suggested attenuation in the virulence of the mutant 10 Delta IdeSsuis. Bactericidal assays confirmed a positive effect of IdeSsuis expression on bacterial survival in porcine blood in the presence of high titers of specific IgM. In conclusion, this study demonstrates that IdeSsuis is a novel complement evasion factor, which is important for bacterial survival in porcine blood during the early adaptive (IgM-dominated) immune response.

National Category
Medical Bioscience
Identifiers
urn:nbn:se:umu:diva-103733 (URN)10.1186/s13567-015-0171-6 (DOI)000353678100001 ()25928761 (PubMedID)
Available from: 2015-06-08 Created: 2015-05-28 Last updated: 2017-12-04Bibliographically approved
Seele, J., Singpiel, A., Spoerry, C., von Pawel-Rammingen, U., Valentin-Weigand, P. & Baums, C. G. (2013). Identification of a Novel Host-Specific IgM Protease in Streptococcus suis. Journal of Bacteriology, 195(5), 930-940
Open this publication in new window or tab >>Identification of a Novel Host-Specific IgM Protease in Streptococcus suis
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2013 (English)In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 195, no 5, p. 930-940Article in journal (Refereed) Published
Abstract [en]

Streptococcus suis serotype 2 is a highly invasive, extracellular pathogen in pigs with the capacity to cause severe infections in humans. This study was initiated by the finding that IgM degradation products are released after opsonization of S. suis. The objective of this work was to identify the bacterial factor responsible for IgM degradation. The results of this study showed that a member of the IdeS family, designated Ide(Ssuis) (Immunoglobulin M-degrading enzyme of S. suis), is responsible and sufficient for IgM cleavage. Recombinant Ide(Ssuis) was found to degrade only IgM but neither IgG nor IgA. Interestingly, Western blot analysis revealed that Ide(Ssuis) is host specific, as it exclusively cleaves porcine IgM but not IgM from six other species, including a closely related member of the Suidae family. As demonstrated by flow cytometry and immunofluorescence microscopy, Ide(Ssuis) modulates binding of IgM to the bacterial surface. Ide(Ssuis) is the first prokaryotic IgM-specific protease described, indicating that this enzyme is involved in a so-far-unknown mechanism of host-pathogen interaction at an early stage of the host immune response. Furthermore, cleavage of porcine IgM by Ide(Ssuis) is the first identified phenotype reflecting functional adaptation of S. suis to pigs as the main host.

Place, publisher, year, edition, pages
Washington: American society of microbiology, 2013
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-70155 (URN)10.1128/JB.01875-12 (DOI)000316961400003 ()
Available from: 2013-05-06 Created: 2013-05-06 Last updated: 2018-01-11Bibliographically approved
Seele, J., Singpiel, A., Spoerry, C., von Pawel-Rammingen, U., Valentin-Weigand, P. & Baums, C. G. (2013). Identification of a novel host-specific IgM protease in Streptococcus suis. Paper presented at 65th Annual Meeting of the German-Society-for-Hygiene-and-Microbiology (DGHM) e V / Annual Meeting of the German-Society-for-Infectious-Diseases (DGI) e V, SEP 22-25, 2013, Rostock, GERMANY. International Journal of Medical Microbiology, 303(Suppl. 1, MPP35), 58-58
Open this publication in new window or tab >>Identification of a novel host-specific IgM protease in Streptococcus suis
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2013 (English)In: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 303, no Suppl. 1, MPP35, p. 58-58Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Streptococcus (S.) suis is an important invasive, extracellular pathogen in pigs, which causes meningitis, arthritis, serositis and other diseases. Furthermore, it is also an emerging zoonotic agent. This study was initiated by the finding that IgM degradation products are released after opsonization of S. suis with porcine serum. The objective of this work was to identify and characterize the factor responsible for IgM cleavage. The results showed that a protein of S. suis with high homology to the well characterized IgG endopeptidase of S. pyogenes IdeS (or Mac1) [1, 2], designated IdeSsuis, degrades immunoglobulins (Ig) of the isotype M, but not IgG, IgA or other proteins present in porcine cerebrospinal fluid, joint fluid or serum. Western Blot analysis revealed that IdeSsuis is host-specific as it exclusively cleaves porcine IgM but not IgM from six other species. Flow cytometry and immunofluorescence microscopy demonstrated that this protein modulates binding of IgM to the bacterial surface. Furthermore the isogenic ideSsuis deletion mutant is significantly attenuated in survival in porcine blood [3]. IdeSsuis is the first prokaryotic IgM-specific protease described indicating a novel host-pathogen interaction at an early stage of the host immune response. Furthermore cleavage of porcine IgM by IdeSsuis is the first identified phenotype reflecting functional adaptation of S. suis to pigs as the main host.

Place, publisher, year, edition, pages
Elsevier, 2013
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-87426 (URN)10.1016/j.ijmm.2013.08.004 (DOI)000331497600197 ()
Conference
65th Annual Meeting of the German-Society-for-Hygiene-and-Microbiology (DGHM) e V / Annual Meeting of the German-Society-for-Infectious-Diseases (DGI) e V, SEP 22-25, 2013, Rostock, GERMANY
Available from: 2014-04-02 Created: 2014-03-31 Last updated: 2018-01-11Bibliographically approved
Okumura, C., Anderson, E. L., Döhrmann, S., Tran, D. N., Olson, J., von Pawel-Rammingen, U. & Nizet, V. (2013). IgG protease Mac/IdeS is not essential for phagocyte resistance or mouse virulence of M1T1 group A Streptococcus. mBio, 4(4), e00499-e00513
Open this publication in new window or tab >>IgG protease Mac/IdeS is not essential for phagocyte resistance or mouse virulence of M1T1 group A Streptococcus
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2013 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 4, no 4, p. e00499-e00513Article in journal (Refereed) Published
Abstract [en]

The Mac/IdeS protein of group A Streptococcus (GAS) is a secreted cysteine protease with cleavage specificity for IgG and is highly expressed in the GAS serotype M1T1 clone, which is the serotype most frequently isolated from patients with life-threatening invasive infections. While studies of Mac/IdeS with recombinant protein have shown that the protein can potentially prevent opsonophagocytosis of GAS by neutrophils, the role of the protein in immune evasion as physiologically produced by the living organism has not been studied. Here we examined the contribution of Mac/IdeS to invasive GAS disease by generating a mutant lacking Mac/IdeS in the hyperinvasive M1T1 background. While Mac/IdeS was highly expressed and proteolytically active in the hyperinvasive strain, elimination of the bacterial protease did not significantly influence GAS phagocytic uptake, oxidative-burst induction, cathelicidin sensitivity, resistance to neutrophil or macrophage killing, or pathogenicity in pre- or postimmune mouse infectious challenges. We conclude that in the highly virulent M1T1 background, Mac/IdeS is not essential for either phagocyte resistance or virulence. Given the conservation of Mac/IdeS and homologues across GAS strains, it is possible that Mac/IdeS serves another important function in GAS ecology or contributes to virulence in other strain backgrounds.

IMPORTANCE Group A Streptococcus (GAS) causes human infections ranging from strep throat to life-threatening conditions such as flesh-eating disease and toxic shock syndrome. Common disease-associated clones of GAS can cause both mild and severe infections because of a characteristic mutation and subsequent change in the expression of several genes that develops under host immune selection. One of these genes encodes Mac/IdeS, a protease that has been shown to cleave antibodies important to the immune defense system. In this study, we found that while Mac/IdeS is highly expressed in hypervirulent GAS, it does not significantly contribute to the ability of the bacteria to survive white blood cell killing or produce invasive infection in the mouse. These data underscore the importance of correlating studies on virulence factor function with physiologic expression levels and the complexity of streptococcal pathogenesis and contribute to our overall understanding of how GAS causes disease.

National Category
Microbiology
Identifiers
urn:nbn:se:umu:diva-81852 (URN)10.1128/mBio.00499-13 (DOI)000326881100050 ()23900173 (PubMedID)
Available from: 2013-10-22 Created: 2013-10-22 Last updated: 2018-02-09Bibliographically approved
Vindebro, R., Spoerry, C. & von Pawel-Rammingen, U. (2013). Rapid IgG heavy chain cleavage by the streptococcal IgG endopeptidase IdeS is mediated by IdeS monomers and is not due to enzyme dimerization. FEBS Letters, 587(12), 1818-1822
Open this publication in new window or tab >>Rapid IgG heavy chain cleavage by the streptococcal IgG endopeptidase IdeS is mediated by IdeS monomers and is not due to enzyme dimerization
2013 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 587, no 12, p. 1818-1822Article in journal (Refereed) Published
Abstract [en]

Streptococcus pyogenes employs an IgG specific endopeptidase, IdeS, to counteract the effector functions of specific IgG. The physiological significant step in disarming specific IgG is the cleavage of one IgG heavy chain. So far, characterizations of IdeS enzymatic activity have employed techniques that failed to differentiate between the first and the second cleavage step. The present data demonstrate that IdeS is active as a monomer and that IdeS activity follows classical Michaelis-Menten kinetics arguing against the previously proposed formation of a functional IdeS dimer. Our results show that IdeS inactivates IgG 100-fold faster than previously reported. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2013
Keyword
IgG, Cysteine protease, Monomer/dimer, GAS, Virulence factor, Streptococcus pyogenes
National Category
Cell and Molecular Biology Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-78961 (URN)10.1016/j.febslet.2013.04.039 (DOI)000320427400020 ()
Available from: 2013-07-29 Created: 2013-07-29 Last updated: 2018-01-11Bibliographically approved
Persson, H., Vindebro, R. & von Pawel-Rammingen, U. (2013). The streptococcal cysteine protease SpeB is not a natural immunoglobulin-cleaving enzyme. Infection and Immunity, 81(6), 2236-2241
Open this publication in new window or tab >>The streptococcal cysteine protease SpeB is not a natural immunoglobulin-cleaving enzyme
2013 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 81, no 6, p. 2236-2241Article in journal (Refereed) Published
Abstract [en]

The human bacterial pathogen Streptococcus pyogenes has developed a broad variety of virulence mechanisms to evade the actions of the host immune defense. One of the best-characterized factors is the streptococcal cysteine protease SpeB, an important multifunctional protease that contributes to group A streptococcal pathogenesis in vivo. Among many suggested activities, SpeB has been described to degrade various human plasma proteins, including immunoglobulins (Igs). In this study, we show that SpeB has no Ig-cleaving activity under physiological conditions and that only Igs in a reduced state, i.e., semimonomeric molecules, are cleaved and degraded by SpeB. Since reducing conditions outside eukaryotic cells have to be considered nonphysiological and IgG in a reduced state lacks biological effector functions, we conclude that SpeB does not contribute to S. pyogenes virulence through the proteolytic degradation of Igs.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-74504 (URN)10.1128/IAI.00168-13 (DOI)000318855100040 ()
Available from: 2013-07-02 Created: 2013-07-01 Last updated: 2018-01-11Bibliographically approved
Berggren, K., Vindebro, R., Bergström, C., Spoerry, C., Persson, H., Fex, T., . . . Luthman, K. (2012). 3-aminopiperidine-based peptide analogues as the first selective noncovalent inhibitors of the bacterial cysteine protease IdeS. Journal of Medicinal Chemistry, 55(6), 2549-2560
Open this publication in new window or tab >>3-aminopiperidine-based peptide analogues as the first selective noncovalent inhibitors of the bacterial cysteine protease IdeS
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2012 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 6, p. 2549-2560Article in journal (Refereed) Published
Abstract [en]

A series of eight peptides corresponding to the amino acid sequence of the hinge region of IgG and 17 newly synthesized peptide analogues containing a piperidine moiety as a replacement of a glycine residue were tested as potential inhibitors of the bacterial IgG degrading enzyme of Streptococcus pyogenes, IdeS. None of the peptides showed any inhibitory activity of IdeS, but several piperidine-based analogues were identified as inhibitors. Two different analysis methods were used: an SDS-PAGE based assay to detect IgG cleavage products and a surface plasmon resonance spectroscopy based assay to quantify the degree of inhibition. To investigate the selectivity of the inhibitors for IdeS, all compounds were screened against two other related cysteine proteases (SpeB and papain). The selectivity results show that larger analogues that are active inhibitors of IdeS are even more potent as inhibitors of papain, whereas smaller analogues that are active inhibitors of IdeS inhibit neither SpeB nor papain. Two compounds were identified that exhibit high selectivity against IdeS and will be used for further studies.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-55368 (URN)10.1021/jm201517a (DOI)000301767000004 ()
Available from: 2012-05-31 Created: 2012-05-14 Last updated: 2018-01-12Bibliographically approved
Brännström, K., Öhman, A., von Pawel-Rammingen, U., Olofsson, A. & Brattsand, M. (2012). Characterization of SPINK9, a KLK5-specific inhibitor expressed in palmo-plantar epidermis. Biological chemistry (Print), 393(5), 369-377
Open this publication in new window or tab >>Characterization of SPINK9, a KLK5-specific inhibitor expressed in palmo-plantar epidermis
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2012 (English)In: Biological chemistry (Print), ISSN 1431-6730, E-ISSN 1437-4315, Vol. 393, no 5, p. 369-377Article in journal (Refereed) Published
Abstract [en]

SPINK9, a Kazal-type serine protease inhibitor, is almost exclusively expressed in the palmo-plantar epidermis. SPINK9 selectively inhibits kallikrein-related peptidase 5 (KLK5), no other target enzyme is known at present. In this study, we defined the reactive loop to residues 48 and 49 of SPINK9 and characterized the inhibition and binding of different SPINK9 variants towards KLK5, KLK7, KLK8 and KLK14. Substitutions of single amino acids in the reactive loop had a large impact on both inhibitory efficiency and specificity. Binding studies showed that it is mainly the dissociation rate that is affected by the amino acid substitutions. The inhibitory effect of wild-type SPINK9 was clearly pH-dependent with an improved effect at a pH similar to that of the outer layers of the skin. Modeling of the enzyme-inhibitor complexes showed that the reactive loop of SPINK9 fits very well into the deep negatively charged binding pocket of KLK5. A decrease in pH protonates His48 of the wild-type protein resulting in a positively charged residue, thereby explaining the observed decreased dissociation rate. Interestingly, substitution with a positively charged amino acid at position 48 resulted in a more efficient inhibitor at higher pH.

Place, publisher, year, edition, pages
Walter de Gruyter, 2012
Keyword
binding studies, inhibition, kallikrein-related peptidases, Kazal-type inhibitor, KLK5, SPINK9
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-56422 (URN)10.1515/hsz-2011-0238 (DOI)000304334100007 ()
Available from: 2012-06-19 Created: 2012-06-18 Last updated: 2018-01-12Bibliographically approved
von Pawel-Rammingen, U. (2012). Streptococcal IdeS and Its Impact on Immune Response and Inflammation. JOURNAL OF INNATE IMMUNITY, 4(2), 132-140
Open this publication in new window or tab >>Streptococcal IdeS and Its Impact on Immune Response and Inflammation
2012 (English)In: JOURNAL OF INNATE IMMUNITY, ISSN 1662-811X, Vol. 4, no 2, p. 132-140Article in journal (Refereed) Published
Abstract [en]

Survival of the important bacterial pathogen Streptococcus pyogenes relies on its ability to circumvent the antimicrobial actions of innate and specific immune responses and to modulate the inflammatory responses induced during the course of an infection. Inflammatory processes play key roles during streptococcal pathogenesis and streptococcal infections are accompanied by an intense inflammatory state. As an exclusively human pathogen, S. pyogenes has adapted to the various countermeasures employed by its host to fight bacterial infections, in particular to interfere with the effector functions of immunoglobulin G (IgG). For this purpose, S. pyogenes has evolved an IgG-specific endopeptidase, IdeS, which is highly specific for the lower hinge region of IgG. This review summarizes the current knowledge about this intriguing enzyme as well as its role in inflammation and in the attenuation of human immune responses towards streptococcal infection.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-53269 (URN)10.1159/000332940 (DOI)000300758400003 ()
Available from: 2012-03-23 Created: 2012-03-19 Last updated: 2018-01-12Bibliographically approved
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