- Email: [email protected]
Surviving innate immunity
News & Comment
TRENDS in Microbiology Vol.10 No.8 August 2002
had allegedly been harmed or even killed by vaccines. All of the web sites said that vaccines cause idiopathic illness. Other common claims were that vaccines wear away immunity and that profit motivates vaccination policy. For someone who is negatively affected by a vaccine, the consequences can mean a lifetime of suffering, however, in the developing world, the benefits of vaccination clearly outweigh the risks. The Global Alliance for Vaccines and Immunisation and the Vaccine Fund aspire to provide vaccines to every child in need. In a recently launched project, the coalition of organisations will provide US$4.1 million to immunise children in impoverished areas of India against hepatitis B. AV http://jama.ama-assn.org/ http://www.vaccinealliance.org
non-paralytic case in Georgia, all caused by poliovirus originating from the Indian subcontinent. It has taken 14 years for Europe to reach this landmark, since the campaign to eradicate polio worldwide began in 1988. CK http://www.who.int
and antibiotic use on echocardiogram reports, as suggested by a recent US study. AV http://www.cdc.gov/ncidod/EID/ vol8no8/01-0458.htm http://www.eurekalert.org
Reducing infection risk in heart patients
Researchers in Greece have found a link between the gastrointestinal bacterium Helicobacter pylori and glaucoma. Jannis Kountouras, from Aristotle University of Thessaloniki, Greece, and colleagues found that H. pylori was detected in 88% of glaucoma cases, compared with just 47% of controls. They studied the effect of H. pylori eradication on intraocular pressure and visual field, the two most commonly used parameters in glaucoma. Treatment was successful in 83% of cases and improvement in both glaucoma parameters was seen in these patients. However, no such improvements were seen in untreated patients. Although the group gave a cautious interpretation of their results, they did suggest that H. pylori might induce synthesis of various mediators, such as cytokines, which could be detrimental to the outflow system of eyes suffering from glaucoma. CK http://www.mediscover.net
358
Europe declared polio-free Europe reached a historic milestone in June 2002 when the continent was declared polio-free at a meeting of the European Regional Commission for the Certification of Poliomyelitis Eradication in Copenhagen. The European Region has been free of indigenous poliomyelitis for over three years. The last case of indigenous wild poliomyelitis occurred in eastern Turkey in 1998, when a two-year-old unvaccinated boy was paralysed by the virus. Despite the success, poliovirus imported from polioendemic countries will remain a threat until global eradication of the disease is completed. In 2001, there were three polio cases among children in Bulgaria and one
Body piercing carries a serious infection risk and could put heart patients at risk for endocarditis. Bacterial infection of the heart lining or valves can occur when bacteria enter the bloodstream, a common occurrence with dental procedures. The American Heart Association recommends that vulnerable individuals take antibiotics before undergoing procedures that cause bleeding, however many patients are unaware of this recommendation. One case study (Emerging Infectious Diseases, August 2002), reports on a 25-year-old man with a history of heart disease, who began to suffer from endocarditis two months after having his tongue pierced. Haemophilus aphrophilus growing around the piercing apparently caused the infection. Although more research is needed to establish a clear link between endocarditis and piercing, prophylactic measures seem prudent. One way to ensure the message reaches heart patients would be to include comments about endocarditis risk
H. pylori linked with glaucoma
In Brief compiled by Cathel Kerr ([email protected]) and Alexandra Venter ([email protected])
Letters
Surviving innate immunity In a complex environment, higher organisms face the constant threat of microbial infection. To defend against this onslaught of potential pathogens, all known members of the plant and animal kingdoms use an innate immune system. A key component of innate immunity is the production of small, cationic antimicrobial peptides (CAMPs). In mammals, recent discoveries from gene therapy and gene-knockout studies have confirmed that CAMPs play a crucial role in defense against invasive bacterial http://tim.trends.com
disease [1,2]. As is increasingly the case with pharmaceutical antibiotics, bacteria exposed to human CAMPs appear to have evolved under selective pressure to develop mechanisms of resistance. Although these selective pressures existed before the dawn of modern medicine, and indeed have existed throughout evolution, CAMPs still exhibit a broad spectrum of activity against diverse Gram-positive and Gramnegative bacterial species. The ability to resist killing by CAMPs, as discussed by Andreas Peschel in a recent issue of Trends in Microbiology [3], is likely to be a discriminating feature of several bacterial pathogens.
In humans, CAMPs are elaborated by skin keratinocytes and mucosal epithelial cells at low levels under baseline conditions, but can be induced specifically in response to injury or infectious stimuli [4,5]. CAMPs are also concentrated in the granules of circulating bone-marrowderived cells and are recruited to the sites of epithelial inflammation. Bacteria such as Staphylococcus aureus and Salmonella spp. that generally exhibit intrinsic CAMP resistance should possess a survival advantage on damaged epithelium, in deeper body tissues and in the phagocytic vacuoles of leukocytes. This is supported by the observations that S. aureus is the most common cause of
0966-842X/02/$ – see front matter © 2002 Published by Elsevier Science Ltd. PII: S0966-842X(02)02406-X
News & Comment
TRENDS in Microbiology Vol.10 No.8 August 2002
359
human wound infections and deep-tissue abscesses and Salmonella spp. are leading agents of chronic systemic infections, including enteric fever. Bacterial species generally more sensitive to CAMPs, such as Escherichia coli, can occupy a niche on mucosal surfaces with local or toxin-mediated disease effects, invading deep tissues only in groups with broader defects in innate or acquired immunity (e.g. neonates, the elderly or chemotherapy patients). As discussed by Dr Peschel, the genetic approach of generating and screening bacterial mutants for alterations in CAMP sensitivity has been fruitful in elucidating a feature common to several resistant species – and supports an unattractive (sic) hypothesis: bacteria that can successfully modify the normal anionic constituents of their cell walls with cationic substitutions repulse rather than attract positively charged natural antibiotics. These charge alterations have been achieved in diverse fashions such as modifications of lipoteichoic acid polymers with D-alanine (S. aureus), phosphotidylglycerol with L-lysine (S. aureus), or lipopolysaccharide lipid A with aminoarabinose (Salmonella enterica and Legionella pneumophila). Alternative resistance mechanisms include proteolytic digestion of the antimicrobial peptide (S. enterica) or proton-motive-forcedependent efflux pumps (Neisseria gonorrhoeae). Confirming the importance of CAMP in host defense, isogenic bacterial mutants with decreased CAMP resistance are less virulent than their wild-type parent strains in animal models of invasive bacterial infection [6–8]. A puzzling consideration is how some bacterial species that are sensitive to killing by human CAMPs in vitro sometimes produce invasive infections in healthy individuals. The intestinal pathogen Shigella spp. and the skin and respiratory tract pathogen group A Streptococcus (GAS) are examples. For Shigella, the solution could lie in the ability of the organism to suppress the production of CAMPs by intestinal epithelial cells [9]. Resistant GAS mutants can be identified in the laboratory upon serial exposure to increasing concentrations of CAMPs, and these mutants are hypervirulent upon challenge of animals [2]. It is interesting to speculate that a mutation conferring CAMP resistance might not prove
advantageous to the organism in epithelial colonization or host–host transmission where even greater evolutionary selective pressures exist. For many human bacterial pathogens, the number of individuals colonized asymptomatically greatly exceeds the low incidence of invasive infection. Is it possible that in rare events a quantum ‘switch’ to higher CAMP resistance allows invasion? Alternatively, do some patients have congenital or acquired defects in their specific ability to mount an appropriate CAMP response to minor injury? When considering the pathogenesis of infections through epithelial barriers, the ability of the microorganism to avoid or resist CAMPmediated defenses must be considered. The defining quality of some important human pathogens thus could be an ‘innate immunity to innate immunity’. Such a strategy will require mechanisms to circumvent multiple immune defense events, both soluble and cellular, that have evolved at the epithelial interface with our environment. Increased appreciation of the molecular and genetic basis of CAMP resistance offers fundamental new insights into pathogen–host interactions and could reveal several promising new targets for antibiotic therapy.
necessary for lipopolysaccharide modification, antimicrobial peptide resistance, and oral virulence of Salmonella enterica serovar Typhimurium. Infect. Immun. 68, 6139–6146 7 Robey, M. et al. (2001) Identification of Legionella pneumophila rcp, a pagP-like gene that confers resistance to cationic antimicrobial peptides and promotes intracellular infection. Infect. Immun. 69, 4276–4286 8 Peschel, A. et al. (2001) Staphylococcus aureus resistance to human defensins and evasion of neutrophil killing via the novel virulence factor MprF is based on modification of membrane lipids with L-lysine. J. Exp. Med. 193, 1067–1076 9 Islam, D. et al. (2001) Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat. Med. 7, 180–185
http://tim.trends.com
Victor Nizet Dept of Pediatrics, Richard L. Gallo* Depts of Pediatrics and Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA. *e-mail: [email protected] References 1 Bals, R. et al. (1999) Augmentation of innate host defense by expression of a cathelicidin antimicrobial peptide. Infect. Immun. 67, 6084–6089 2 Nizet, V. et al. (2001) Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414, 454–457 3 Peschel, A. (2002) How do bacteria resist human antimicrobial peptides? Trends Microbiol. 10, 179–186 4 Diamond, G. et al. (1996) Inducible expression of an antibiotic peptide gene in lipopolysaccharidechallenged tracheal epithelial cells. Proc. Natl. Acad. Sci. U. S. A. 93, 5156–5160 5 Dorschner, R.A. et al. (2001) Cutaneous injury induces the release of cathelicidin anti-microbial peptides active against group A Streptococcus. J. Invest. Dermatol. 117, 91–97 6 Gunn, J.S. et al. (2000) Genetic and functional analysis of a PmrA–PmrB-regulated locus
Published online: 10 July 2002
The multiple faces of the immune response to Mycobacterium tuberculosis Recent research indicates that the host response to Mycobacterium tuberculosis is multifaceted, and can simultaneously include elements that are beneficial and detrimental to the infectious process. A hallmark of tuberculosis (TB) is a progressive granulomatous response, which, when exuberant, is tissue damaging and probably contributes to the perpetuation of infection, at least in immunocompetent hosts. However, the role of tissue damage in the pathogenesis of TB has been hard to appreciate. In their recent article in Trends in Microbiology, Cooper et al. analyzed and compared pathological findings from four different mycobacterial infections in the mouse model [1]. Data from gene-deleted mice indicate that interferon (IFN)-γ and nitric oxide (NO), both deemed to be indispensable for protective immunity against M. tuberculosis [2,3], might participate in the resolution of the inflammatory response at sites of infection, thereby decreasing tissue damage. If mycobacterial models with less dependence on IFN-γ and NO for containing mycobacterial growth are used, the role of these molecules in controlling immunopathology can be distinguished more convincingly [1]. Thus, in the Mycobacterium avium infection model, IFN-γ is mainly necessary to initiate an organized granulomatous response [4],
0966-842X/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S0966-842X(02)02407-1
TRENDS in Microbiology Vol.10 No.8 August 2002
had allegedly been harmed or even killed by vaccines. All of the web sites said that vaccines cause idiopathic illness. Other common claims were that vaccines wear away immunity and that profit motivates vaccination policy. For someone who is negatively affected by a vaccine, the consequences can mean a lifetime of suffering, however, in the developing world, the benefits of vaccination clearly outweigh the risks. The Global Alliance for Vaccines and Immunisation and the Vaccine Fund aspire to provide vaccines to every child in need. In a recently launched project, the coalition of organisations will provide US$4.1 million to immunise children in impoverished areas of India against hepatitis B. AV http://jama.ama-assn.org/ http://www.vaccinealliance.org
non-paralytic case in Georgia, all caused by poliovirus originating from the Indian subcontinent. It has taken 14 years for Europe to reach this landmark, since the campaign to eradicate polio worldwide began in 1988. CK http://www.who.int
and antibiotic use on echocardiogram reports, as suggested by a recent US study. AV http://www.cdc.gov/ncidod/EID/ vol8no8/01-0458.htm http://www.eurekalert.org
Reducing infection risk in heart patients
Researchers in Greece have found a link between the gastrointestinal bacterium Helicobacter pylori and glaucoma. Jannis Kountouras, from Aristotle University of Thessaloniki, Greece, and colleagues found that H. pylori was detected in 88% of glaucoma cases, compared with just 47% of controls. They studied the effect of H. pylori eradication on intraocular pressure and visual field, the two most commonly used parameters in glaucoma. Treatment was successful in 83% of cases and improvement in both glaucoma parameters was seen in these patients. However, no such improvements were seen in untreated patients. Although the group gave a cautious interpretation of their results, they did suggest that H. pylori might induce synthesis of various mediators, such as cytokines, which could be detrimental to the outflow system of eyes suffering from glaucoma. CK http://www.mediscover.net
358
Europe declared polio-free Europe reached a historic milestone in June 2002 when the continent was declared polio-free at a meeting of the European Regional Commission for the Certification of Poliomyelitis Eradication in Copenhagen. The European Region has been free of indigenous poliomyelitis for over three years. The last case of indigenous wild poliomyelitis occurred in eastern Turkey in 1998, when a two-year-old unvaccinated boy was paralysed by the virus. Despite the success, poliovirus imported from polioendemic countries will remain a threat until global eradication of the disease is completed. In 2001, there were three polio cases among children in Bulgaria and one
Body piercing carries a serious infection risk and could put heart patients at risk for endocarditis. Bacterial infection of the heart lining or valves can occur when bacteria enter the bloodstream, a common occurrence with dental procedures. The American Heart Association recommends that vulnerable individuals take antibiotics before undergoing procedures that cause bleeding, however many patients are unaware of this recommendation. One case study (Emerging Infectious Diseases, August 2002), reports on a 25-year-old man with a history of heart disease, who began to suffer from endocarditis two months after having his tongue pierced. Haemophilus aphrophilus growing around the piercing apparently caused the infection. Although more research is needed to establish a clear link between endocarditis and piercing, prophylactic measures seem prudent. One way to ensure the message reaches heart patients would be to include comments about endocarditis risk
H. pylori linked with glaucoma
In Brief compiled by Cathel Kerr ([email protected]) and Alexandra Venter ([email protected])
Letters
Surviving innate immunity In a complex environment, higher organisms face the constant threat of microbial infection. To defend against this onslaught of potential pathogens, all known members of the plant and animal kingdoms use an innate immune system. A key component of innate immunity is the production of small, cationic antimicrobial peptides (CAMPs). In mammals, recent discoveries from gene therapy and gene-knockout studies have confirmed that CAMPs play a crucial role in defense against invasive bacterial http://tim.trends.com
disease [1,2]. As is increasingly the case with pharmaceutical antibiotics, bacteria exposed to human CAMPs appear to have evolved under selective pressure to develop mechanisms of resistance. Although these selective pressures existed before the dawn of modern medicine, and indeed have existed throughout evolution, CAMPs still exhibit a broad spectrum of activity against diverse Gram-positive and Gramnegative bacterial species. The ability to resist killing by CAMPs, as discussed by Andreas Peschel in a recent issue of Trends in Microbiology [3], is likely to be a discriminating feature of several bacterial pathogens.
In humans, CAMPs are elaborated by skin keratinocytes and mucosal epithelial cells at low levels under baseline conditions, but can be induced specifically in response to injury or infectious stimuli [4,5]. CAMPs are also concentrated in the granules of circulating bone-marrowderived cells and are recruited to the sites of epithelial inflammation. Bacteria such as Staphylococcus aureus and Salmonella spp. that generally exhibit intrinsic CAMP resistance should possess a survival advantage on damaged epithelium, in deeper body tissues and in the phagocytic vacuoles of leukocytes. This is supported by the observations that S. aureus is the most common cause of
0966-842X/02/$ – see front matter © 2002 Published by Elsevier Science Ltd. PII: S0966-842X(02)02406-X
News & Comment
TRENDS in Microbiology Vol.10 No.8 August 2002
359
human wound infections and deep-tissue abscesses and Salmonella spp. are leading agents of chronic systemic infections, including enteric fever. Bacterial species generally more sensitive to CAMPs, such as Escherichia coli, can occupy a niche on mucosal surfaces with local or toxin-mediated disease effects, invading deep tissues only in groups with broader defects in innate or acquired immunity (e.g. neonates, the elderly or chemotherapy patients). As discussed by Dr Peschel, the genetic approach of generating and screening bacterial mutants for alterations in CAMP sensitivity has been fruitful in elucidating a feature common to several resistant species – and supports an unattractive (sic) hypothesis: bacteria that can successfully modify the normal anionic constituents of their cell walls with cationic substitutions repulse rather than attract positively charged natural antibiotics. These charge alterations have been achieved in diverse fashions such as modifications of lipoteichoic acid polymers with D-alanine (S. aureus), phosphotidylglycerol with L-lysine (S. aureus), or lipopolysaccharide lipid A with aminoarabinose (Salmonella enterica and Legionella pneumophila). Alternative resistance mechanisms include proteolytic digestion of the antimicrobial peptide (S. enterica) or proton-motive-forcedependent efflux pumps (Neisseria gonorrhoeae). Confirming the importance of CAMP in host defense, isogenic bacterial mutants with decreased CAMP resistance are less virulent than their wild-type parent strains in animal models of invasive bacterial infection [6–8]. A puzzling consideration is how some bacterial species that are sensitive to killing by human CAMPs in vitro sometimes produce invasive infections in healthy individuals. The intestinal pathogen Shigella spp. and the skin and respiratory tract pathogen group A Streptococcus (GAS) are examples. For Shigella, the solution could lie in the ability of the organism to suppress the production of CAMPs by intestinal epithelial cells [9]. Resistant GAS mutants can be identified in the laboratory upon serial exposure to increasing concentrations of CAMPs, and these mutants are hypervirulent upon challenge of animals [2]. It is interesting to speculate that a mutation conferring CAMP resistance might not prove
advantageous to the organism in epithelial colonization or host–host transmission where even greater evolutionary selective pressures exist. For many human bacterial pathogens, the number of individuals colonized asymptomatically greatly exceeds the low incidence of invasive infection. Is it possible that in rare events a quantum ‘switch’ to higher CAMP resistance allows invasion? Alternatively, do some patients have congenital or acquired defects in their specific ability to mount an appropriate CAMP response to minor injury? When considering the pathogenesis of infections through epithelial barriers, the ability of the microorganism to avoid or resist CAMPmediated defenses must be considered. The defining quality of some important human pathogens thus could be an ‘innate immunity to innate immunity’. Such a strategy will require mechanisms to circumvent multiple immune defense events, both soluble and cellular, that have evolved at the epithelial interface with our environment. Increased appreciation of the molecular and genetic basis of CAMP resistance offers fundamental new insights into pathogen–host interactions and could reveal several promising new targets for antibiotic therapy.
necessary for lipopolysaccharide modification, antimicrobial peptide resistance, and oral virulence of Salmonella enterica serovar Typhimurium. Infect. Immun. 68, 6139–6146 7 Robey, M. et al. (2001) Identification of Legionella pneumophila rcp, a pagP-like gene that confers resistance to cationic antimicrobial peptides and promotes intracellular infection. Infect. Immun. 69, 4276–4286 8 Peschel, A. et al. (2001) Staphylococcus aureus resistance to human defensins and evasion of neutrophil killing via the novel virulence factor MprF is based on modification of membrane lipids with L-lysine. J. Exp. Med. 193, 1067–1076 9 Islam, D. et al. (2001) Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat. Med. 7, 180–185
http://tim.trends.com
Victor Nizet Dept of Pediatrics, Richard L. Gallo* Depts of Pediatrics and Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA. *e-mail: [email protected] References 1 Bals, R. et al. (1999) Augmentation of innate host defense by expression of a cathelicidin antimicrobial peptide. Infect. Immun. 67, 6084–6089 2 Nizet, V. et al. (2001) Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414, 454–457 3 Peschel, A. (2002) How do bacteria resist human antimicrobial peptides? Trends Microbiol. 10, 179–186 4 Diamond, G. et al. (1996) Inducible expression of an antibiotic peptide gene in lipopolysaccharidechallenged tracheal epithelial cells. Proc. Natl. Acad. Sci. U. S. A. 93, 5156–5160 5 Dorschner, R.A. et al. (2001) Cutaneous injury induces the release of cathelicidin anti-microbial peptides active against group A Streptococcus. J. Invest. Dermatol. 117, 91–97 6 Gunn, J.S. et al. (2000) Genetic and functional analysis of a PmrA–PmrB-regulated locus
Published online: 10 July 2002
The multiple faces of the immune response to Mycobacterium tuberculosis Recent research indicates that the host response to Mycobacterium tuberculosis is multifaceted, and can simultaneously include elements that are beneficial and detrimental to the infectious process. A hallmark of tuberculosis (TB) is a progressive granulomatous response, which, when exuberant, is tissue damaging and probably contributes to the perpetuation of infection, at least in immunocompetent hosts. However, the role of tissue damage in the pathogenesis of TB has been hard to appreciate. In their recent article in Trends in Microbiology, Cooper et al. analyzed and compared pathological findings from four different mycobacterial infections in the mouse model [1]. Data from gene-deleted mice indicate that interferon (IFN)-γ and nitric oxide (NO), both deemed to be indispensable for protective immunity against M. tuberculosis [2,3], might participate in the resolution of the inflammatory response at sites of infection, thereby decreasing tissue damage. If mycobacterial models with less dependence on IFN-γ and NO for containing mycobacterial growth are used, the role of these molecules in controlling immunopathology can be distinguished more convincingly [1]. Thus, in the Mycobacterium avium infection model, IFN-γ is mainly necessary to initiate an organized granulomatous response [4],
0966-842X/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S0966-842X(02)02407-1