Targeting Bacterial Virulence
Morbidity and mortality due to certain bacterial pathogens have not declined despite the availability of effective antimicrobial treatments. Staphylococcus aureus and Streptococcus pyogenes cause a number of serious infections, such as necrotizing fasciitis and toxic shock syndrome, which are associated with the release of bacterial toxins. Animal studies have demonstrated clindamycin, a protein synthesis inhibitor, to be more effective in treating these severe infections than other more susceptible antimicrobial treatments. Linezolid, another protein synthesis inhibitor, also has shown efficacy in in vitro studies. Human trials to validate the effects of antibiotic therapies on bacterial virulence have not been performed. Future animal and human studies are needed to help elucidate the immunomodulatory mechanisms of protein synthesis inhibitors in order to optimize antimicrobial treatment and decrease the morbidity and mortality associated with severe bacterial infections.
Despite the availability of effective antibacterial therapies, morbidity and mortality due to certain bacterial pathogens have not declined. Sepsis due to virulent gram-negative bacteria such as Pseudomonas aeruginosa and Escherichia coli is responsible for approximately 50% of cases of septicemia in the United States. Gram-positive organisms, most notably Staphylococcus aureus, are often the culprit in a number of serious infections, such as pneumonia, bacteremia, scalded skin syndrome, and toxic shock syndrome. Streptococcal toxic shock syndrome and necrotizing fasciitis due to Streptococcus pyogenes (group A streptococcus) increasingly have been reported in the community.
Current approaches to antimicrobial therapy for most infections revolve around the ability of an antibiotic regimen to eradicate the offending organism rapidly. At the onset of infection, bacteria rapidly replicate and release various bacterial virulence factors that can directly cause tissue damage. In addition, these bacterial toxins stimulate the immune system, leading to cytokine release and further tissue injury, making bacterial eradication imperative (Figure 1). However, sometimes the elimination of the causative pathogen is not enough, and the sequelae of the bacterial virulence can be detrimental. For instance, severe infections due to S. pyogenes require aggressive antibiotic treatment and supportive measures in patients with symptoms of shock. As S. pyogenes continues to be highly susceptible to penicillin and other
-lactam antibiotics, penicillin remains the drug of choice for uncomplicated S. pyogenes infections. However, overall response to treatment with penicillin for severe infections has decreased and is associated with high morbidity and mortality. A better understanding of the effect of antibiotics on the release and production of bacterial endotoxin, exotoxins, and other virulence factors may lead to identification of more effective treatment strategies for virulent pathogens.
(Enlarge Image)
Description of the pathogenesis of virulent gram-negative and gram-positive infections and the potential for antimicrobial therapy to exacerbate the release of bacterial virulence factors, leading to increased tissue injury. IL = interleukin; TNF = tumor necrosis factor; LPS = lipopolysaccharide.
A number of bacterial surface constituents and secreted products contribute to the severity of infections. Enzymes such as hemolysins, streptolysins, nucleases, proteases, lipases, and hyaluronidase convert host tissues into nutrients for bacterial growth. Surface proteins also help bacteria evade the immune system by preventing opsonization and phagocytosis by the polymorphonuclear leukocytes. In addition, some bacteria produce exotoxins, also known as superantigens, which are potent inducers of the host immune system. These virulent factors, and not the organism itself, enhance the pathogenesis of infections such as severe food poisoning, toxic shock syndrome, scalded skin syndrome, and necrotizing fasciitis.
Gram-negative bacteria can induce septic shock and the release of cytokines such as tumor necrosis factor (TNF)-
, interleukin (IL)-1
, and IL-6 via the release of the cell wall lipopolysaccharide or endotoxin. The release of cytokines instigates systemic inflammation that can lead to hemodynamic instabilities and multiorgan failure. In addition, some gram-negative bacteria, such as E. coli and P. aeruginosa, can release exotoxins that can further stimulate the immune system, leading to life-threatening infections such as hemorrhagic diarrhea.
The M proteins and the streptococcal pyrogenic exotoxins (SPEs) A, B, and C have long been known to play an important role in the pathogenesis of severe group A streptococcal infections. The M proteins protect the bacteria from phagocytosis, allowing for bacterial survival, and are responsible for production of SPEs. The SPEs A, B, and C are responsible for the rash, strawberry tongue, and desquamation of skin associated with scarlet fever, and the invasion of soft tissues and toxic shock associated with necrotizing fasciitis and streptococcal toxic shock syndrome. Streptococcal pyrogenic exotoxin A has frequently been isolated from S. pyogenes strains responsible for severe streptococcal infections. Animal studies of invasive group A streptococcal infections have revealed a direct relationship between increases in circulating SPE A and systemic inflammation (increases in IL-6). Streptococcal pyrogenic exotoxin B is an extracellular cysteine protease that can be associated with inflammation, shock, and tissue destruction. Streptococcal pyrogenic exotoxin B is produced by all S. pyogenes strains, some producing significantly more (as much as 150 mg/L) than others.
The exotoxins produced by S. aureus include toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxins, and the exfoliative toxins. Toxic shock syndrome toxin-1 is the superantigen associated with staphylococcal toxic shock syndrome and scalded skin syndrome. Like other superantigens, its immunologic properties consist of the ability to activate T lymphocytes, leading to cytokine production and development of shock. Staphylococcal toxic shock syndrome is a relatively rare yet highly fatal syndrome commonly associated with vaginal, wound, and postsurgical infections; however, the effect of TSST-1 may be more widespread. For example, TSST-1 has been found in the kidneys of infants who died from sudden infant death syndrome, and strains of S. aureus that produce TSST-1 have been isolated in more than half of patients with Kawasaki syndrome. Toxic shock syndrome toxin-1 has also been shown to enhance the lethality of endotoxin in rabbits up to 100,000-fold. Alpha-toxin, which is encoded by the hla gene, also is a major virulence factor of S. aureus, responsible for cytolytic, hemolytic, and dermonecrotic effects associated with severe infections. In addition, S. aureus can contain protein A, which is similar to protein M in S. pyogenes and can yield resistance to phagocytosis by polymorphonuclear leukocytes.
Morbidity and mortality due to certain bacterial pathogens have not declined despite the availability of effective antimicrobial treatments. Staphylococcus aureus and Streptococcus pyogenes cause a number of serious infections, such as necrotizing fasciitis and toxic shock syndrome, which are associated with the release of bacterial toxins. Animal studies have demonstrated clindamycin, a protein synthesis inhibitor, to be more effective in treating these severe infections than other more susceptible antimicrobial treatments. Linezolid, another protein synthesis inhibitor, also has shown efficacy in in vitro studies. Human trials to validate the effects of antibiotic therapies on bacterial virulence have not been performed. Future animal and human studies are needed to help elucidate the immunomodulatory mechanisms of protein synthesis inhibitors in order to optimize antimicrobial treatment and decrease the morbidity and mortality associated with severe bacterial infections.
Despite the availability of effective antibacterial therapies, morbidity and mortality due to certain bacterial pathogens have not declined. Sepsis due to virulent gram-negative bacteria such as Pseudomonas aeruginosa and Escherichia coli is responsible for approximately 50% of cases of septicemia in the United States. Gram-positive organisms, most notably Staphylococcus aureus, are often the culprit in a number of serious infections, such as pneumonia, bacteremia, scalded skin syndrome, and toxic shock syndrome. Streptococcal toxic shock syndrome and necrotizing fasciitis due to Streptococcus pyogenes (group A streptococcus) increasingly have been reported in the community.
Current approaches to antimicrobial therapy for most infections revolve around the ability of an antibiotic regimen to eradicate the offending organism rapidly. At the onset of infection, bacteria rapidly replicate and release various bacterial virulence factors that can directly cause tissue damage. In addition, these bacterial toxins stimulate the immune system, leading to cytokine release and further tissue injury, making bacterial eradication imperative (Figure 1). However, sometimes the elimination of the causative pathogen is not enough, and the sequelae of the bacterial virulence can be detrimental. For instance, severe infections due to S. pyogenes require aggressive antibiotic treatment and supportive measures in patients with symptoms of shock. As S. pyogenes continues to be highly susceptible to penicillin and other
-lactam antibiotics, penicillin remains the drug of choice for uncomplicated S. pyogenes infections. However, overall response to treatment with penicillin for severe infections has decreased and is associated with high morbidity and mortality. A better understanding of the effect of antibiotics on the release and production of bacterial endotoxin, exotoxins, and other virulence factors may lead to identification of more effective treatment strategies for virulent pathogens.
(Enlarge Image)
Description of the pathogenesis of virulent gram-negative and gram-positive infections and the potential for antimicrobial therapy to exacerbate the release of bacterial virulence factors, leading to increased tissue injury. IL = interleukin; TNF = tumor necrosis factor; LPS = lipopolysaccharide.
A number of bacterial surface constituents and secreted products contribute to the severity of infections. Enzymes such as hemolysins, streptolysins, nucleases, proteases, lipases, and hyaluronidase convert host tissues into nutrients for bacterial growth. Surface proteins also help bacteria evade the immune system by preventing opsonization and phagocytosis by the polymorphonuclear leukocytes. In addition, some bacteria produce exotoxins, also known as superantigens, which are potent inducers of the host immune system. These virulent factors, and not the organism itself, enhance the pathogenesis of infections such as severe food poisoning, toxic shock syndrome, scalded skin syndrome, and necrotizing fasciitis.
Gram-negative bacteria can induce septic shock and the release of cytokines such as tumor necrosis factor (TNF)-
, interleukin (IL)-1
, and IL-6 via the release of the cell wall lipopolysaccharide or endotoxin. The release of cytokines instigates systemic inflammation that can lead to hemodynamic instabilities and multiorgan failure. In addition, some gram-negative bacteria, such as E. coli and P. aeruginosa, can release exotoxins that can further stimulate the immune system, leading to life-threatening infections such as hemorrhagic diarrhea.
The M proteins and the streptococcal pyrogenic exotoxins (SPEs) A, B, and C have long been known to play an important role in the pathogenesis of severe group A streptococcal infections. The M proteins protect the bacteria from phagocytosis, allowing for bacterial survival, and are responsible for production of SPEs. The SPEs A, B, and C are responsible for the rash, strawberry tongue, and desquamation of skin associated with scarlet fever, and the invasion of soft tissues and toxic shock associated with necrotizing fasciitis and streptococcal toxic shock syndrome. Streptococcal pyrogenic exotoxin A has frequently been isolated from S. pyogenes strains responsible for severe streptococcal infections. Animal studies of invasive group A streptococcal infections have revealed a direct relationship between increases in circulating SPE A and systemic inflammation (increases in IL-6). Streptococcal pyrogenic exotoxin B is an extracellular cysteine protease that can be associated with inflammation, shock, and tissue destruction. Streptococcal pyrogenic exotoxin B is produced by all S. pyogenes strains, some producing significantly more (as much as 150 mg/L) than others.
The exotoxins produced by S. aureus include toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxins, and the exfoliative toxins. Toxic shock syndrome toxin-1 is the superantigen associated with staphylococcal toxic shock syndrome and scalded skin syndrome. Like other superantigens, its immunologic properties consist of the ability to activate T lymphocytes, leading to cytokine production and development of shock. Staphylococcal toxic shock syndrome is a relatively rare yet highly fatal syndrome commonly associated with vaginal, wound, and postsurgical infections; however, the effect of TSST-1 may be more widespread. For example, TSST-1 has been found in the kidneys of infants who died from sudden infant death syndrome, and strains of S. aureus that produce TSST-1 have been isolated in more than half of patients with Kawasaki syndrome. Toxic shock syndrome toxin-1 has also been shown to enhance the lethality of endotoxin in rabbits up to 100,000-fold. Alpha-toxin, which is encoded by the hla gene, also is a major virulence factor of S. aureus, responsible for cytolytic, hemolytic, and dermonecrotic effects associated with severe infections. In addition, S. aureus can contain protein A, which is similar to protein M in S. pyogenes and can yield resistance to phagocytosis by polymorphonuclear leukocytes.
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