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The role of capsular antigens in Staphylococcus aureus immunity
Zbl. Bakt. 277,415-418 (1992) © Gustav Fischer Verlag, Stuttgart/New York
Editorial
The Role of Capsular Antigens Immunity
III
Staphylococcus aureus
WAL TER W. KARAKA W A Department of Molecular and Cell Biology, Pennsylvania State University, University Park, PA 16802, USA
Received September 30, 1992
Summary Most clinical blood isolates of Staphylococcus aureus have been shown to be encapsulated. Techniques are now available for the preparation of type-specific capsular antisera and to provide reliable serologic methods for the identification of clinical isolates of Staphylococcus aureus. Epidemiologic studies in the U.S.A. and Europe indicated the prevalence of capsular types 5 and 8 among clinical isolates from human, bovine, and poultry, Encapsulated types 5 and 8 resisted in vitro phagocytosis and specific anti-capsular serum facilitated type-specific opsonization of S. aureus by polymorphonuclear leukocytes (PMN). The structure of the prevalent types 5 and 8 capsular polysaccharides (CP) have been elucidated. Vaccines of CP conjugated to exotoxin A of Pseudomonas aeruginosa have been prepared and have been injected into animals and human volunteers. Antibodies elicated by these conjugates facilitated opsonization of specific S. aureus types by human PMN.
Zusammenfassung Die meisten aus dem Blur isolierten S. aureus-Stamme erwiesen sich als bekapselt. Jetzt verfugbare Antiseren gegen Kapselantigene errnoglichen eine serologische ldentifizierung klinischer S. aureus-Isolate. In USA und Europa wurden vorwiegend die Kapselrypen 5 und 8 von Mensch, Rind lind Gefliigel isoliert, die sich in vitro als Phagozytose-resistent erwiesen, wahrend Kapsel-spezifische Antiseren typspezifische Opsonisierung von S. aureus durch Granulozyten (PMN) forderten. Die Struktur der Kapselpolysaccharide (CP) der Typen 5 und 8 wurde aufgeklart. An Exotoxin A aus Pseudomonas aeruginosa gebundenes Kapselpolysaccharid (CP) wurde als Vaccine Tieren und mensch lichen Freiwilligen injiziert. Die erhaltenen Antikorper forderren die spezifische Opsonisierung von S. aureus durch menschliche Granulozyten (PMN). 27 Zbl. Bakr. 277/4
416
W.W.Karakawa
The classification of Staphylococcus aureus based on type-specific Polysaccharide capsules has been used in epidemiologic studies to identify the prevalent serotypes, 5 and 8 that cause most nosocomial infections. Antibodies to these capsular polysaccharides have been shown to promote phagocytosis and are undoubtedly an important factor in protective immunity. Several lines of evidence suggest that antibody-mediated phagocytosis is a critical process in immunity to Staphylococcus aureus. It is conceivable that immunization with a polysaccharide vaccine may be useful in preventing Staph. aureus infections (4). Despite a large body of work, immunity to Staph. aureus has been clouded in uncertainty for 80 years (7). Then a few clinical investigators began a series of studies that pointed to a possible solution. Quie observed, for example, that children with "chronic granulomatous disease of childhood" had frequent Staph. aureus infections (10). These occurrences were directly related to the dysfunction of the phagocytic cell. In many ways, this discovery was the most compelling evidence since the work of Wright and Douglas in 1905 that phagocytosis is the major line of defense against Staph. aureus infections (11). But it remained to identify the staphylococcal antigens that stimulate the production of opsonic antibodies. Between 1974 and 1985, Karakawa, Vann, and colleagues showed that the Staph. aureus strains isolated from community- and hospital-acquired infections could be classified into eight different serologic types based on type-specific capsular carbohydrate antigens (4). These surface polysaccharides have chemical similarities, although they can be distinguished serologically. Specific rabbit antisera as well as monoclonal antibodies have been prepared to each serologic type for immunologic identification of clinical isolates. The structure of these two prevalent polysaccharides are shown here. Type 5:
--->4)-~-D-ManNAcAP(1--->4)-a-L-FucNAcp(1--->3)-~-D-FucNAcp(l
3
i OAc Type 8:
--->3)-~-D-ManNAcAP(1--->3)-a-L-FucNAcp(1--->3)-~-D-FucNAcp(l
4
i OAc Serologic studies based on 246 isolated collected from patients in several different countries, confirmed that types 5 and 8 were the most prevalent types (4). Many of the strains were isolated from positive blood cultures: 26% of the strains were type 5, and 41 % were type 8. Included among the 246 isolates were strains from 49 consecutive cases of bacteremia in a single hospital over a 17-rnonth period. These patients had typical problems associated with Staph. aureus bacteremia, including those related to intravenous devices with resulting fatalities caused by septic shock and respiratory distress syndrome, as well as subsequent complications such as osteomyelitis and visceral abscesses. Subsequent clinical studies in other hospitals and other settings have revealed the continued worldwide predominance of types 5 and 8 as the cause of Staph. aureus sepsis and bacteremia. For example, in 1987, Hochkeppel and colleagues examined 821 isolates from patients; 26% were type 5 and 55% were type 8 (3). The possible importance of capsular types of Staph. aureus was first documented by a serologic analysis of strains isolated during an epidemic in the burn unit of a U.S.
The Role of Capsular Antigens in S.aureus Immunity
417
Army hospital in Tokyo in 1974 (5). AllIS strains isolated from patients proved to by type 4. Type 4 strains have not been found elsewhere since this occurrence, but the capsular-analysis of the strains from this early epidemic was an important first step in the recognition that invasive strains of Staph. aureus possess type-specific polysaccharide capsules. The possible immunological importance of antibodies to capsular polysaccharides is suggested by recent studies showing that type 5 and type 8 antibodies promote only type-specific phagocytosis (6). These results mimic the earlier studies done by Morse with strain Smith (8), and by Peterson and colleagues with strain M (9). These studies have prompted efforts to develop vaccines to type 5 and 8 capsular polysaccharides. Because these substances are of low molecular weight, they stimulate feeble immune responses. Thus, protein conjugate vaccines have been prepared, and mice immunized with these vaccines developed opsonic antibodies that promote phagocytosis of types 5 and 8 Staph. aureus (2). These vaccines have been recently employed in phase one trials in human volunteers (1). Most of the Staph. aureus strains isolated from the blood of patients with septicemia were encapsulated, suggesting that the capsule contributes in an important way to the invasiveness of Staph. aureus and therefore to the pathogenesis of a systemic infection. Studies demonstrating that antibodies to the polysaccharides promote phagocytosis suggest that these type-specific antibodies play an important role in immunity to Staph. aureus . If this is the case, it is possible that invasive infections occur because patients lack protective concentrations of specific antihodies in their serum before infection. It will be important to determine whether patients who develop type 5 or type 8 bacteremia are those who lack or have low concentrations of antibodies in their sera and thus are susceptihle to nosocomial infections and septicemia caused by these serotypes. If such proves to be the case, it is conceivable that patients known to be at high risk could be protected using either passive immunization with hyperimmune gamma globulin or active immunization with polysaccharide vaccines. Several population groups are likely candidates for clinical trials with a vaccine composed of types 5 and 8 capsular polysaccharides conjugated to Pseudomonas aeruginosa exotoxin A (1). Burn patients present a special challenge because of their susceptibility to severe Staph. aureus infections, which frequently results in loss of skin grafts, conversion of donor sites, septicemia, pneumonia, shock and death. Patients on renal dialysis are also very susceptible to these infections. Certainly all the work to date on Staph. aureus immunity suggests that efforts should be made to develop a vaccine for prevention of Staph. aureus infection. This possible mode of preventing staphylococcal infections is becoming more vital in light of the increase frequency of multiple antibiotic resistant strains of Staph. aureus. It is very likely that local infections - as opposed to severe systemic infections - of Staph. aureus will occur despite the presence of antibodies in the serum because of surgical manipulations, trauma, or burns that reduce local resistance, underlying systemic disease, or exposure to a large inoculum. Nevertheless, the local infection could conceivably be kept localized and invasion and septicemia prevented by substantially increasing the levels of types 5 and 8 antibodies in the patient's serum by using passive or active immunization. Any use of such immunization will require bacteriologic surveillance to determine that Staph. aureus types 5 and 8 remain the prevalent organisms causing nosocomial infections. Surveillance is also needed to detect the possible occurrence of new serotypes. These matters have yet to receive the attention they deserve. Bur there is now the
418
W. W. Karakawa
opportunity to understand the mechanisms of immunity to Staph .•tureus and to develop a rational method of immune treatment and prophylaxis. The argument for the development of immune methods of treatment and prevention is all the more persuasive in view of the widespread development of multiple antibiotic resistance by Staph. aureus.
References 1. Fattom, A., R. Schneeron, W. Karakawa, D. Fitzgerald, I. Pasten, X. Li, ]. Sbiloach, D. Bryla, and L. Robbins: Lab and clinical evaluation of conjugate vaccine composed of S. aureus type 5 and 8 capsules bound to P. aeruginosa exoprotein A. Infect. Immun. 1992, submitted for publication 2. Fattom, A., R. Schneerson, S. S. Szu, W. F. Vann, ]. Sbiloacb, W. Karakawa, and ]. B. Robbins: Synthesis and immunologic properties in mice of vaccines composed of Staphylococcus aureus type 5 and type 8 capsular polysaccharides conjugated to Pseudomonas (/(,nt~inIlS(/ exotoxin A. Infect. Immun. 58 (1990) 2367-2374 3. Hochkeppel, H. K., D. G. Braun, W. Vischer, S. Sutter, U. Staeubli, R. Guggenhein, E. Kaplan, A. Boutonnier and S. M. Fournier: Serotyping and electron microscopy studies of Staphylococcus aureus clinical isolates with monoclonal antibodies to capsular polysaccharide types 5 and 8. J. Clin. Microbiol. 25 (1987) 526-530 4. Karakawa, W. W., ]. M. Fournier, W. F. Vann, R. D. Arbeit, R. Schneerson, and ]. B. Robbins: Methods for the serological typing of the capsular polysaccharides of Staphylococcus aureus. J. Clin. Microbiol. 22 (1986) 445-447 5. Karakawa, W. W., j. A. Kane, and M. R. Smith: Isolation of an acidic surface antigen from a conventional strain of Staphylococcus aureus. Infect. Immun. 9 (1974) 511 6. Karakawa, W. W., A. Sutton, R. Schneerson, A. Karpas, and W. F. Vann: Capsular antibodies induce type-specific phagocytosis of Staphylococcus aureus by human polymorphonuclear leukocytes. Infect. Immun. 56 (1988) 1090-1095 7. Krause, R. M.: Immunity to Staphylococcus aureus, a persistent enigma. Emory Univ.]. Med. 3 (1989) 77-85 8. Morse, S. I.: Isolation and properties of surface antigen of Staphylococcus aureus. J. Exp. Med. 115 (1962) 295-311 9. Peterson, P. K., B. J. Wilkinson, Y. Kim, D. Schmeling, and P. G. Quie: Influence of encapsulation on staphylococcal opsonization and phagocytosis by human polymorphonuclear leukocytes. Infect. Immun, 19 (1978) 943-949 10. Quie, P. G.: Bacterial function of human polymorphonuclear leukocytes. Pediatrics 50
(1972) 264-270 11. Wright, A. E., and S. R. Douglas: An experimental investigation of the role of fluids in connection with phagocytosis. Proc. Roy. Soc. Lond. 73 (1904) 128-142 Dr. Walter W. Karakauia, Dept. of Molecular and Cell Biology, Pennsylvania State University, University Park, PA 16802, USA
Editorial
The Role of Capsular Antigens Immunity
III
Staphylococcus aureus
WAL TER W. KARAKA W A Department of Molecular and Cell Biology, Pennsylvania State University, University Park, PA 16802, USA
Received September 30, 1992
Summary Most clinical blood isolates of Staphylococcus aureus have been shown to be encapsulated. Techniques are now available for the preparation of type-specific capsular antisera and to provide reliable serologic methods for the identification of clinical isolates of Staphylococcus aureus. Epidemiologic studies in the U.S.A. and Europe indicated the prevalence of capsular types 5 and 8 among clinical isolates from human, bovine, and poultry, Encapsulated types 5 and 8 resisted in vitro phagocytosis and specific anti-capsular serum facilitated type-specific opsonization of S. aureus by polymorphonuclear leukocytes (PMN). The structure of the prevalent types 5 and 8 capsular polysaccharides (CP) have been elucidated. Vaccines of CP conjugated to exotoxin A of Pseudomonas aeruginosa have been prepared and have been injected into animals and human volunteers. Antibodies elicated by these conjugates facilitated opsonization of specific S. aureus types by human PMN.
Zusammenfassung Die meisten aus dem Blur isolierten S. aureus-Stamme erwiesen sich als bekapselt. Jetzt verfugbare Antiseren gegen Kapselantigene errnoglichen eine serologische ldentifizierung klinischer S. aureus-Isolate. In USA und Europa wurden vorwiegend die Kapselrypen 5 und 8 von Mensch, Rind lind Gefliigel isoliert, die sich in vitro als Phagozytose-resistent erwiesen, wahrend Kapsel-spezifische Antiseren typspezifische Opsonisierung von S. aureus durch Granulozyten (PMN) forderten. Die Struktur der Kapselpolysaccharide (CP) der Typen 5 und 8 wurde aufgeklart. An Exotoxin A aus Pseudomonas aeruginosa gebundenes Kapselpolysaccharid (CP) wurde als Vaccine Tieren und mensch lichen Freiwilligen injiziert. Die erhaltenen Antikorper forderren die spezifische Opsonisierung von S. aureus durch menschliche Granulozyten (PMN). 27 Zbl. Bakr. 277/4
416
W.W.Karakawa
The classification of Staphylococcus aureus based on type-specific Polysaccharide capsules has been used in epidemiologic studies to identify the prevalent serotypes, 5 and 8 that cause most nosocomial infections. Antibodies to these capsular polysaccharides have been shown to promote phagocytosis and are undoubtedly an important factor in protective immunity. Several lines of evidence suggest that antibody-mediated phagocytosis is a critical process in immunity to Staphylococcus aureus. It is conceivable that immunization with a polysaccharide vaccine may be useful in preventing Staph. aureus infections (4). Despite a large body of work, immunity to Staph. aureus has been clouded in uncertainty for 80 years (7). Then a few clinical investigators began a series of studies that pointed to a possible solution. Quie observed, for example, that children with "chronic granulomatous disease of childhood" had frequent Staph. aureus infections (10). These occurrences were directly related to the dysfunction of the phagocytic cell. In many ways, this discovery was the most compelling evidence since the work of Wright and Douglas in 1905 that phagocytosis is the major line of defense against Staph. aureus infections (11). But it remained to identify the staphylococcal antigens that stimulate the production of opsonic antibodies. Between 1974 and 1985, Karakawa, Vann, and colleagues showed that the Staph. aureus strains isolated from community- and hospital-acquired infections could be classified into eight different serologic types based on type-specific capsular carbohydrate antigens (4). These surface polysaccharides have chemical similarities, although they can be distinguished serologically. Specific rabbit antisera as well as monoclonal antibodies have been prepared to each serologic type for immunologic identification of clinical isolates. The structure of these two prevalent polysaccharides are shown here. Type 5:
--->4)-~-D-ManNAcAP(1--->4)-a-L-FucNAcp(1--->3)-~-D-FucNAcp(l
3
i OAc Type 8:
--->3)-~-D-ManNAcAP(1--->3)-a-L-FucNAcp(1--->3)-~-D-FucNAcp(l
4
i OAc Serologic studies based on 246 isolated collected from patients in several different countries, confirmed that types 5 and 8 were the most prevalent types (4). Many of the strains were isolated from positive blood cultures: 26% of the strains were type 5, and 41 % were type 8. Included among the 246 isolates were strains from 49 consecutive cases of bacteremia in a single hospital over a 17-rnonth period. These patients had typical problems associated with Staph. aureus bacteremia, including those related to intravenous devices with resulting fatalities caused by septic shock and respiratory distress syndrome, as well as subsequent complications such as osteomyelitis and visceral abscesses. Subsequent clinical studies in other hospitals and other settings have revealed the continued worldwide predominance of types 5 and 8 as the cause of Staph. aureus sepsis and bacteremia. For example, in 1987, Hochkeppel and colleagues examined 821 isolates from patients; 26% were type 5 and 55% were type 8 (3). The possible importance of capsular types of Staph. aureus was first documented by a serologic analysis of strains isolated during an epidemic in the burn unit of a U.S.
The Role of Capsular Antigens in S.aureus Immunity
417
Army hospital in Tokyo in 1974 (5). AllIS strains isolated from patients proved to by type 4. Type 4 strains have not been found elsewhere since this occurrence, but the capsular-analysis of the strains from this early epidemic was an important first step in the recognition that invasive strains of Staph. aureus possess type-specific polysaccharide capsules. The possible immunological importance of antibodies to capsular polysaccharides is suggested by recent studies showing that type 5 and type 8 antibodies promote only type-specific phagocytosis (6). These results mimic the earlier studies done by Morse with strain Smith (8), and by Peterson and colleagues with strain M (9). These studies have prompted efforts to develop vaccines to type 5 and 8 capsular polysaccharides. Because these substances are of low molecular weight, they stimulate feeble immune responses. Thus, protein conjugate vaccines have been prepared, and mice immunized with these vaccines developed opsonic antibodies that promote phagocytosis of types 5 and 8 Staph. aureus (2). These vaccines have been recently employed in phase one trials in human volunteers (1). Most of the Staph. aureus strains isolated from the blood of patients with septicemia were encapsulated, suggesting that the capsule contributes in an important way to the invasiveness of Staph. aureus and therefore to the pathogenesis of a systemic infection. Studies demonstrating that antibodies to the polysaccharides promote phagocytosis suggest that these type-specific antibodies play an important role in immunity to Staph. aureus . If this is the case, it is possible that invasive infections occur because patients lack protective concentrations of specific antihodies in their serum before infection. It will be important to determine whether patients who develop type 5 or type 8 bacteremia are those who lack or have low concentrations of antibodies in their sera and thus are susceptihle to nosocomial infections and septicemia caused by these serotypes. If such proves to be the case, it is conceivable that patients known to be at high risk could be protected using either passive immunization with hyperimmune gamma globulin or active immunization with polysaccharide vaccines. Several population groups are likely candidates for clinical trials with a vaccine composed of types 5 and 8 capsular polysaccharides conjugated to Pseudomonas aeruginosa exotoxin A (1). Burn patients present a special challenge because of their susceptibility to severe Staph. aureus infections, which frequently results in loss of skin grafts, conversion of donor sites, septicemia, pneumonia, shock and death. Patients on renal dialysis are also very susceptible to these infections. Certainly all the work to date on Staph. aureus immunity suggests that efforts should be made to develop a vaccine for prevention of Staph. aureus infection. This possible mode of preventing staphylococcal infections is becoming more vital in light of the increase frequency of multiple antibiotic resistant strains of Staph. aureus. It is very likely that local infections - as opposed to severe systemic infections - of Staph. aureus will occur despite the presence of antibodies in the serum because of surgical manipulations, trauma, or burns that reduce local resistance, underlying systemic disease, or exposure to a large inoculum. Nevertheless, the local infection could conceivably be kept localized and invasion and septicemia prevented by substantially increasing the levels of types 5 and 8 antibodies in the patient's serum by using passive or active immunization. Any use of such immunization will require bacteriologic surveillance to determine that Staph. aureus types 5 and 8 remain the prevalent organisms causing nosocomial infections. Surveillance is also needed to detect the possible occurrence of new serotypes. These matters have yet to receive the attention they deserve. Bur there is now the
418
W. W. Karakawa
opportunity to understand the mechanisms of immunity to Staph .•tureus and to develop a rational method of immune treatment and prophylaxis. The argument for the development of immune methods of treatment and prevention is all the more persuasive in view of the widespread development of multiple antibiotic resistance by Staph. aureus.
References 1. Fattom, A., R. Schneeron, W. Karakawa, D. Fitzgerald, I. Pasten, X. Li, ]. Sbiloach, D. Bryla, and L. Robbins: Lab and clinical evaluation of conjugate vaccine composed of S. aureus type 5 and 8 capsules bound to P. aeruginosa exoprotein A. Infect. Immun. 1992, submitted for publication 2. Fattom, A., R. Schneerson, S. S. Szu, W. F. Vann, ]. Sbiloacb, W. Karakawa, and ]. B. Robbins: Synthesis and immunologic properties in mice of vaccines composed of Staphylococcus aureus type 5 and type 8 capsular polysaccharides conjugated to Pseudomonas (/(,nt~inIlS(/ exotoxin A. Infect. Immun. 58 (1990) 2367-2374 3. Hochkeppel, H. K., D. G. Braun, W. Vischer, S. Sutter, U. Staeubli, R. Guggenhein, E. Kaplan, A. Boutonnier and S. M. Fournier: Serotyping and electron microscopy studies of Staphylococcus aureus clinical isolates with monoclonal antibodies to capsular polysaccharide types 5 and 8. J. Clin. Microbiol. 25 (1987) 526-530 4. Karakawa, W. W., ]. M. Fournier, W. F. Vann, R. D. Arbeit, R. Schneerson, and ]. B. Robbins: Methods for the serological typing of the capsular polysaccharides of Staphylococcus aureus. J. Clin. Microbiol. 22 (1986) 445-447 5. Karakawa, W. W., j. A. Kane, and M. R. Smith: Isolation of an acidic surface antigen from a conventional strain of Staphylococcus aureus. Infect. Immun. 9 (1974) 511 6. Karakawa, W. W., A. Sutton, R. Schneerson, A. Karpas, and W. F. Vann: Capsular antibodies induce type-specific phagocytosis of Staphylococcus aureus by human polymorphonuclear leukocytes. Infect. Immun. 56 (1988) 1090-1095 7. Krause, R. M.: Immunity to Staphylococcus aureus, a persistent enigma. Emory Univ.]. Med. 3 (1989) 77-85 8. Morse, S. I.: Isolation and properties of surface antigen of Staphylococcus aureus. J. Exp. Med. 115 (1962) 295-311 9. Peterson, P. K., B. J. Wilkinson, Y. Kim, D. Schmeling, and P. G. Quie: Influence of encapsulation on staphylococcal opsonization and phagocytosis by human polymorphonuclear leukocytes. Infect. Immun, 19 (1978) 943-949 10. Quie, P. G.: Bacterial function of human polymorphonuclear leukocytes. Pediatrics 50
(1972) 264-270 11. Wright, A. E., and S. R. Douglas: An experimental investigation of the role of fluids in connection with phagocytosis. Proc. Roy. Soc. Lond. 73 (1904) 128-142 Dr. Walter W. Karakauia, Dept. of Molecular and Cell Biology, Pennsylvania State University, University Park, PA 16802, USA