- Email: [email protected]
Septic shock caused by Gram-positive bacteria*
COMMENT
peptide. This finding might shed light on some previously unexplained observations. The fusion peptide is the most conserved part of HA among all influenza viruses, and it has long been known that minor deviations from its correct structure, for example the absence of the amino-terminal glycine and substitution of other glycine residues by glutamic acid, prevent fusion or affect pH dependance14,15. It therefore appears that exact fitting of the amino-terminal part of HA2 into the cavity is an essential step in the sequence of events leading to fusion. This concept is also supported by the observation that the infectivity of paramyxoviruses can be inhibited
by peptides mimicking the fusion domain of these viruses16. It will be interesting to see if such peptide analogues will also interfere with influenza virus replication. If so, they might become useful for the treatment of influenza, as has already been suggested for protease inhibitors1. References 1 Klenk, H.D. and Garten, W. (1994) Trends Microbiol. 2, 39–43 2 Bullough, P.A. et al. (1994) Nature 371, 37–43 3 Carr, C.M. and Kim, P.S. (1993) Cell 7, 823–832 4 Wiley, D.C. and Skehel, J.J. (1987) Annu. Rev. Biochem. 56, 365–394 5 Chen, J. et al. (1998) Cell 95, 409–417 6 Horimoto, T. and Kawaoka, Y. (1994)
J. Virol. 68, 3120–3128 7 Klenk, H.D. and Rott, R. (1988) Adv. Virus Res. 34, 247–281 8 Kido, H. et al. (1992) J. Biol. Chem. 267, 13573–13579 9 Tashiro, M. et al. (1987) Nature 325, 536–537 10 Subbarao, K. et al. (1998) Science 279, 393–396 11 Goto, H. and Kawaoka, Y. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 10224–10228 12 Morsy, J. et al. (1994) Virology 202, 988–991 13 Ohuchi, R. et al. (1991) J. Virol. 65, 3530–3537 14 Garten, W. et al. (1981) Virology 115, 361–374 15 Gething, M.J. et al. (1986) J. Cell Biol. 102, 11–23 16 Richardson, C.D. et al. (1980) Virology 105, 205–222
Event
Septic shock caused by Gram-positive bacteria Giuseppe Teti
T
he incidence of sepsis and septic shock caused by Gram-positive bacteria has been increasing over the past two decades, whereas the incidence of Gram-negative sepsis has remained fairly constant. Consequently, between a third and a half of all cases of sepsis (~2 per year per 1000 population) are currently caused by Gram-positive microorganisms. The clinical manifestations of septic shock are caused by the elevated release of inflammatory mediators and cytokines by host cells upon interaction with bacterial products. Gram-positive microorganisms do not contain lipopolysaccharide (LPS), which is mainly responsible for the initiation of Gram-negative shock. Relative to the many studies conducted with LPS, much less is known of bacterial initiators and the cell activation mechanisms involved in Gram-positive shock. This information is crucial to the development of alternative strat-
Septic Shock Caused by Grampositive Bacteria, organized by James Cook and Giuseppe Teti, was held at Vibo Valentia, Italy, 10–12 October 1998. G. Teti is in the Institute of Microbiology, University of Messina, Policlinico Universitario, Via Consolare Valeria 1, Messina, I-98125, Italy. tel: 139 090 221 3310, fax: 139 090 221 3312, e-mail: [email protected]
egies aimed at reducing sepsis lethality, which is still high (~35%) despite adequate therapy. The meeting in Vibo Valentia represents the first organized attempt to address these issues. Bacterial initiators Gram-positive cocci remain a leading cause of sepsis in adults (Janusz Jelijaszewicz, National Institute of Hygiene, Warsaw, Poland) and children (Patricia Ferrieri, University of Minnesota Medical School,
0966-842X/99/$ - see front matter © 1999 Elsevier Science. All rights reserved. TRENDS
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Minneapolis, MN, USA). In many cases, superantigenic exotoxins are likely to play an important pathogenic role (Joseph Alouf, Pasteur Institute, Lille, France) and might be useful targets for passive immunotherapy (Malak Kotb, University of Tennessee, Memphis, TN, USA). However, many sepsis-causing strains do not produce superantigens. Therefore, the meeting was also devoted to common bacterial cell components. Peptidoglycan (PG) or lipoteichoic acids (LTA) can induce the production of proinflammatory mediators and, importantly, have strong synergistic activities in inducing organ failure in a rat model (Christoph Thiemermann, St Bartholomew’s Hospital Medical College, London, UK). PG also synergizes with LPS, which might be relevant to the pathogenesis of Gram-negative shock. As with LPS, maximal cytokine stimulation by PG, LTA or bacterial polysaccharides seems to require PII: S0966-842X(99)01453-5
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COMMENT
certain supramolecular configurations and/or multiple receptor aggregation. Linkage to particles of low-molecular-weight polymannuronan increases cytokine-inducing potency by up to 60 000-fold (Terje Espevik, Institute of Cancer Research and Molecular Biology, Trondeim, Norway). Similarly, optimal cytokine stimulation by LTA requires receptor crosslinking on monocytes by anti-LTA antibodies (Itzhak Ofek, Tel Aviv University, Tel Aviv, Israel). Disruption of the three-dimensional structure of PG by high-energy sonication or by solubilization with enzymes markedly decreases the activity of PG (Jos Van Srijp, Utrecht University, Utrecht, The Netherlands). Peptide structures appear to play a role in the proinflammatory activities of PG, as shown by studies using pneumococcal amino-sugarfree branched stem peptides (Didier Heumann, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland) or peptidefree amino-sugar backbone analogs (Arthur Ulmer, Research Center Borstel, Borstel, Germany). Although traditionally considered immunologically inert, bacterial DNA can strongly induce activation of macrophages and a lethal cytokine syndrome in sensitized mice (Klaus Heeg, Philipps University, Marburg, Germany). These effects are related to the recognition of specific CG-containing oligonucleotides, which occur infrequently in mammalian DNA. Furthermore, hemolysins might play a role in streptococcal shock, as they are able to induce nitrous oxide production (Jerry Shenep, St Jude Children’s Research Hospital, Memphis, TN, USA). The potential role of bacterial adhesins in activating host cells was also reviewed (David Hasty, University of Tennessee). Pattern recognition Innate, non-clonal recognition of invading pathogens must rely on common structures, or patterns, present on microorganisms. Pattern recognition molecules are capable of binding PG and other fundamental bacterial components, and there was much interest in the independ-
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IN
ent cloning and characterization of two insect PG recognition proteins (PGRPs) that are strongly induced by bacterial stimuli and are conserved in humans (Hakan Steiner, Stockholm University, Stockholm, Sweden; Masaaki Ashida, Hokkaido University, Sapporo, Japan). Short amino-terminal sequences of these 19-kDa proteins share 60–65% sequence identity. The function of PGRPs in mammals is still under study, but their highlevel expression in organs of the immune system appears significant. CD14, a glycosylphosphatidylinositol-anchored protein lacking an intra-cytoplasmic portion, is also considered to be a pattern recognition receptor, as it binds PG and a large array of bacterial polysaccharides and glycolipids. Binding of LPS or PG to CD14 on phagocytes initiates signal transduction and activation, although PG is considerably less potent in these activities than LPS. Soluble PG binds to conformational, rather than linear, CD14 epitopes that are only partially identical (amino acids 51–64) to those recognized by LPS (Roman Dziarski, Indiana University School of Medicine, Gary, IN, USA). CD14 might not be involved in cytokine responses to whole Gram-positive bacteria (Giuseppe Teti). Moreover, it does not seem to play a prominent role in murine septic shock induced by Staphylococcus aureus, as suggested by similar survival rates in CD14-deficient and control mice (Sanna Goyert, Cornell University, New York, NY, USA). b2 integrins, including complement receptor type 3 and type 4, do play a role in cytokine responses to particulate stimuli, such as whole Gram-positive bacteria (Giuseppe Teti) or particle-bound polysaccharides (Terje Espevik), but not to soluble polysaccharides. Signal transduction Although signaling pathways initiated by Gram-positive bacteria and their components might diverge from the LPS pathway early in the signal transduction cascade, similarities between the pathways have also been documented. For example, cardiovascular dysfunctions and the response to anti-inflamma-
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tory therapies are similar in Grampositive and Gram-negative shock, suggesting common pathways of activation (Charles Natanson, National Institutes of Health, Bethesda, MD, USA). This conclusion is also supported by observations that LPS tolerance induces partial cross-tolerance to Grampositive sepsis (James Cook, Medical University of South Carolina, Charleston, SC, USA). Marked similarities have been found between LPS and PG signal transduction pathways, including the activation of several tyrosine kinases (Lyn, ERK1/2, JNK) and transcription factors (NF-kB, ATF-1, CREB and c-Jun) (Roman Dziarski). Moreover, tyrosine kinase inhibitors protect equally against shock induced by LPS, Gram-positive bacteria or cecal ligation incision (Shingji Ogura, Kagawa Medical School, Kagawa, Japan). Douglas Golenbock (Boston University School of Medicine, Boston, MA, USA) described the construction of mutant cell lines that lack the ability to respond to LPS. Identification of the genes affected in these cells should lead to the characterization of novel and important components of the signaling cascade involved in responses to LPS and Gram-positive bacteria. Conclusions The continuing high mortality rate of sepsis and septic shock underscores the need to increase our understanding of the pathogenesis of these conditions in order to develop innovative therapeutic measures (Mohammed Sayeed, Kansas City Hospital, Kansas City, KA, USA). Models of Gram-positive shock are providing invaluable information not only on the pathogenesis of sepsis in general but also on the mechanisms underlying innate immune recognition. A followup meeting, also to be held in Vibo Valentia, is planned for 2001. Acknowledgements The symposium was supported mainly by the Amministrazione Provinciale di Vibo Valentia, Vibo Valentia, Italy. The organizers also gratefully acknowledge funding from the City of Vibo Valentia, the Regione Calabria and the University of Messina.
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peptide. This finding might shed light on some previously unexplained observations. The fusion peptide is the most conserved part of HA among all influenza viruses, and it has long been known that minor deviations from its correct structure, for example the absence of the amino-terminal glycine and substitution of other glycine residues by glutamic acid, prevent fusion or affect pH dependance14,15. It therefore appears that exact fitting of the amino-terminal part of HA2 into the cavity is an essential step in the sequence of events leading to fusion. This concept is also supported by the observation that the infectivity of paramyxoviruses can be inhibited
by peptides mimicking the fusion domain of these viruses16. It will be interesting to see if such peptide analogues will also interfere with influenza virus replication. If so, they might become useful for the treatment of influenza, as has already been suggested for protease inhibitors1. References 1 Klenk, H.D. and Garten, W. (1994) Trends Microbiol. 2, 39–43 2 Bullough, P.A. et al. (1994) Nature 371, 37–43 3 Carr, C.M. and Kim, P.S. (1993) Cell 7, 823–832 4 Wiley, D.C. and Skehel, J.J. (1987) Annu. Rev. Biochem. 56, 365–394 5 Chen, J. et al. (1998) Cell 95, 409–417 6 Horimoto, T. and Kawaoka, Y. (1994)
J. Virol. 68, 3120–3128 7 Klenk, H.D. and Rott, R. (1988) Adv. Virus Res. 34, 247–281 8 Kido, H. et al. (1992) J. Biol. Chem. 267, 13573–13579 9 Tashiro, M. et al. (1987) Nature 325, 536–537 10 Subbarao, K. et al. (1998) Science 279, 393–396 11 Goto, H. and Kawaoka, Y. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 10224–10228 12 Morsy, J. et al. (1994) Virology 202, 988–991 13 Ohuchi, R. et al. (1991) J. Virol. 65, 3530–3537 14 Garten, W. et al. (1981) Virology 115, 361–374 15 Gething, M.J. et al. (1986) J. Cell Biol. 102, 11–23 16 Richardson, C.D. et al. (1980) Virology 105, 205–222
Event
Septic shock caused by Gram-positive bacteria Giuseppe Teti
T
he incidence of sepsis and septic shock caused by Gram-positive bacteria has been increasing over the past two decades, whereas the incidence of Gram-negative sepsis has remained fairly constant. Consequently, between a third and a half of all cases of sepsis (~2 per year per 1000 population) are currently caused by Gram-positive microorganisms. The clinical manifestations of septic shock are caused by the elevated release of inflammatory mediators and cytokines by host cells upon interaction with bacterial products. Gram-positive microorganisms do not contain lipopolysaccharide (LPS), which is mainly responsible for the initiation of Gram-negative shock. Relative to the many studies conducted with LPS, much less is known of bacterial initiators and the cell activation mechanisms involved in Gram-positive shock. This information is crucial to the development of alternative strat-
Septic Shock Caused by Grampositive Bacteria, organized by James Cook and Giuseppe Teti, was held at Vibo Valentia, Italy, 10–12 October 1998. G. Teti is in the Institute of Microbiology, University of Messina, Policlinico Universitario, Via Consolare Valeria 1, Messina, I-98125, Italy. tel: 139 090 221 3310, fax: 139 090 221 3312, e-mail: [email protected]
egies aimed at reducing sepsis lethality, which is still high (~35%) despite adequate therapy. The meeting in Vibo Valentia represents the first organized attempt to address these issues. Bacterial initiators Gram-positive cocci remain a leading cause of sepsis in adults (Janusz Jelijaszewicz, National Institute of Hygiene, Warsaw, Poland) and children (Patricia Ferrieri, University of Minnesota Medical School,
0966-842X/99/$ - see front matter © 1999 Elsevier Science. All rights reserved. TRENDS
IN
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100
Minneapolis, MN, USA). In many cases, superantigenic exotoxins are likely to play an important pathogenic role (Joseph Alouf, Pasteur Institute, Lille, France) and might be useful targets for passive immunotherapy (Malak Kotb, University of Tennessee, Memphis, TN, USA). However, many sepsis-causing strains do not produce superantigens. Therefore, the meeting was also devoted to common bacterial cell components. Peptidoglycan (PG) or lipoteichoic acids (LTA) can induce the production of proinflammatory mediators and, importantly, have strong synergistic activities in inducing organ failure in a rat model (Christoph Thiemermann, St Bartholomew’s Hospital Medical College, London, UK). PG also synergizes with LPS, which might be relevant to the pathogenesis of Gram-negative shock. As with LPS, maximal cytokine stimulation by PG, LTA or bacterial polysaccharides seems to require PII: S0966-842X(99)01453-5
VOL. 7 NO. 3 MARCH 1999
COMMENT
certain supramolecular configurations and/or multiple receptor aggregation. Linkage to particles of low-molecular-weight polymannuronan increases cytokine-inducing potency by up to 60 000-fold (Terje Espevik, Institute of Cancer Research and Molecular Biology, Trondeim, Norway). Similarly, optimal cytokine stimulation by LTA requires receptor crosslinking on monocytes by anti-LTA antibodies (Itzhak Ofek, Tel Aviv University, Tel Aviv, Israel). Disruption of the three-dimensional structure of PG by high-energy sonication or by solubilization with enzymes markedly decreases the activity of PG (Jos Van Srijp, Utrecht University, Utrecht, The Netherlands). Peptide structures appear to play a role in the proinflammatory activities of PG, as shown by studies using pneumococcal amino-sugarfree branched stem peptides (Didier Heumann, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland) or peptidefree amino-sugar backbone analogs (Arthur Ulmer, Research Center Borstel, Borstel, Germany). Although traditionally considered immunologically inert, bacterial DNA can strongly induce activation of macrophages and a lethal cytokine syndrome in sensitized mice (Klaus Heeg, Philipps University, Marburg, Germany). These effects are related to the recognition of specific CG-containing oligonucleotides, which occur infrequently in mammalian DNA. Furthermore, hemolysins might play a role in streptococcal shock, as they are able to induce nitrous oxide production (Jerry Shenep, St Jude Children’s Research Hospital, Memphis, TN, USA). The potential role of bacterial adhesins in activating host cells was also reviewed (David Hasty, University of Tennessee). Pattern recognition Innate, non-clonal recognition of invading pathogens must rely on common structures, or patterns, present on microorganisms. Pattern recognition molecules are capable of binding PG and other fundamental bacterial components, and there was much interest in the independ-
TRENDS
IN
ent cloning and characterization of two insect PG recognition proteins (PGRPs) that are strongly induced by bacterial stimuli and are conserved in humans (Hakan Steiner, Stockholm University, Stockholm, Sweden; Masaaki Ashida, Hokkaido University, Sapporo, Japan). Short amino-terminal sequences of these 19-kDa proteins share 60–65% sequence identity. The function of PGRPs in mammals is still under study, but their highlevel expression in organs of the immune system appears significant. CD14, a glycosylphosphatidylinositol-anchored protein lacking an intra-cytoplasmic portion, is also considered to be a pattern recognition receptor, as it binds PG and a large array of bacterial polysaccharides and glycolipids. Binding of LPS or PG to CD14 on phagocytes initiates signal transduction and activation, although PG is considerably less potent in these activities than LPS. Soluble PG binds to conformational, rather than linear, CD14 epitopes that are only partially identical (amino acids 51–64) to those recognized by LPS (Roman Dziarski, Indiana University School of Medicine, Gary, IN, USA). CD14 might not be involved in cytokine responses to whole Gram-positive bacteria (Giuseppe Teti). Moreover, it does not seem to play a prominent role in murine septic shock induced by Staphylococcus aureus, as suggested by similar survival rates in CD14-deficient and control mice (Sanna Goyert, Cornell University, New York, NY, USA). b2 integrins, including complement receptor type 3 and type 4, do play a role in cytokine responses to particulate stimuli, such as whole Gram-positive bacteria (Giuseppe Teti) or particle-bound polysaccharides (Terje Espevik), but not to soluble polysaccharides. Signal transduction Although signaling pathways initiated by Gram-positive bacteria and their components might diverge from the LPS pathway early in the signal transduction cascade, similarities between the pathways have also been documented. For example, cardiovascular dysfunctions and the response to anti-inflamma-
MICROBIOLOGY
101
tory therapies are similar in Grampositive and Gram-negative shock, suggesting common pathways of activation (Charles Natanson, National Institutes of Health, Bethesda, MD, USA). This conclusion is also supported by observations that LPS tolerance induces partial cross-tolerance to Grampositive sepsis (James Cook, Medical University of South Carolina, Charleston, SC, USA). Marked similarities have been found between LPS and PG signal transduction pathways, including the activation of several tyrosine kinases (Lyn, ERK1/2, JNK) and transcription factors (NF-kB, ATF-1, CREB and c-Jun) (Roman Dziarski). Moreover, tyrosine kinase inhibitors protect equally against shock induced by LPS, Gram-positive bacteria or cecal ligation incision (Shingji Ogura, Kagawa Medical School, Kagawa, Japan). Douglas Golenbock (Boston University School of Medicine, Boston, MA, USA) described the construction of mutant cell lines that lack the ability to respond to LPS. Identification of the genes affected in these cells should lead to the characterization of novel and important components of the signaling cascade involved in responses to LPS and Gram-positive bacteria. Conclusions The continuing high mortality rate of sepsis and septic shock underscores the need to increase our understanding of the pathogenesis of these conditions in order to develop innovative therapeutic measures (Mohammed Sayeed, Kansas City Hospital, Kansas City, KA, USA). Models of Gram-positive shock are providing invaluable information not only on the pathogenesis of sepsis in general but also on the mechanisms underlying innate immune recognition. A followup meeting, also to be held in Vibo Valentia, is planned for 2001. Acknowledgements The symposium was supported mainly by the Amministrazione Provinciale di Vibo Valentia, Vibo Valentia, Italy. The organizers also gratefully acknowledge funding from the City of Vibo Valentia, the Regione Calabria and the University of Messina.
VOL. 7 NO. 3 MARCH 1999