The Reemergence of Severe Group A Streptococcal Disease: an Evolutionary Perspective

Low, Donald E.; McGeer, Allison; Schwartz, Benjamin

doi:10.1128/9781555816940.ch7

Cited by 21 publications

(10 citation statements)

References 236 publications

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“…GAS invasive disease may be complicated by the development of STSS, which increases mortality rates; 23 to 81% of STSS patients die within 7 days postinfection (7,(80)(81)(82). There has been a notable global increase in the percentage of invasive GAS infections that are severe since the late 1980s (19,20,83,84). A 2005 WHO study estimated that at least 663,000 cases of invasive GAS disease occur each year, resulting in 163,000 deaths (5).…”

Section: Burden Of Invasive Diseasementioning

confidence: 99%

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

et al. 2014

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SUMMARY Streptococcus pyogenes , also known as group A Streptococcus (GAS), causes mild human infections such as pharyngitis and impetigo and serious infections such as necrotizing fasciitis and streptococcal toxic shock syndrome. Furthermore, repeated GAS infections may trigger autoimmune diseases, including acute poststreptococcal glomerulonephritis, acute rheumatic fever, and rheumatic heart disease. Combined, these diseases account for over half a million deaths per year globally. Genomic and molecular analyses have now characterized a large number of GAS virulence determinants, many of which exhibit overlap and redundancy in the processes of adhesion and colonization, innate immune resistance, and the capacity to facilitate tissue barrier degradation and spread within the human host. This improved understanding of the contribution of individual virulence determinants to the disease process has led to the formulation of models of GAS disease progression, which may lead to better treatment and intervention strategies. While GAS remains sensitive to all penicillins and cephalosporins, rising resistance to other antibiotics used in disease treatment is an increasing worldwide concern. Several GAS vaccine formulations that elicit protective immunity in animal models have shown promise in nonhuman primate and early-stage human trials. The development of a safe and efficacious commercial human vaccine for the prophylaxis of GAS disease remains a high priority.

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Section: Burden Of Invasive Diseasementioning

confidence: 99%

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

et al. 2014

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“…The emergence of virulent strains of GAS bacteria in the early 1980s coincided with a remarkable resurgence of severe and often deadly forms of invasive infections associated with STSS and NSTIs (5,6,12,13). One particular strain that emerged during that time is the clonal M1T1 strain that disseminated globally and continues to be one of the most prevalently isolated strains from patients with invasive and/or noninvasive GAS infections (12,(14)(15)(16)(17).…”

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confidence: 99%

“…treptococcus pyogenes or group A streptococci (GAS) are the causative agents of a multitude of human diseases ranging from nonsevere strep throat, pharyngitis, and impetigo to lifethreatening necrotizing soft tissue infections (NSTIs) and streptococcal toxic shock syndrome (STSS) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). The multifaceted nature of invasive GAS infections requires several modes of pathogenic adaptation to evade host immune defenses to successfully colonize and survive in host niches.…”

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confidence: 99%

Host Genetic Variations and Sex Differences Potentiate Predisposition, Severity, and Outcomes of Group A Streptococcus-Mediated Necrotizing Soft Tissue Infections

et al. 2016

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bHost genetic variations play an important role in several pathogenic diseases, and we previously provided strong evidence that these genetic variations contribute significantly to differences in susceptibility and clinical outcomes of invasive group A Streptococcus (GAS) patients, including sepsis and necrotizing soft tissue infections (NSTIs). The goal of the present study was to investigate how genetic variations and sex differences among four commonly used mouse strains contribute to variation in severity, manifestations, and outcomes of NSTIs. DBA/2J mice were more susceptible to NSTIs than C57BL/6J, BALB/c, and CD-1 mice, as exhibited by significantly greater bacteremia, excessive dissemination to the spleen, and significantly higher mortality. Differences in the sex of the mice also contributed to differences in disease severity and outcomes: DBA/2J female mice were relatively resistant compared to their male counterparts. However, DBA/2J mice exhibited minimal weight loss and developed smaller lesions than did the aforementioned strains. Moreover, at 48 h after infection, compared with C57BL/6J mice, DBA/2J mice had increased bacteremia, excessive dissemination to the spleen, and excessive concentrations of inflammatory cytokines and chemokines. These results indicate that variations in the host genetic context as well as sex play a dominant role in determining the severity of and susceptibility to GAS NSTIs. Streptococcus pyogenes or group A streptococci (GAS) are the causative agents of a multitude of human diseases ranging from nonsevere strep throat, pharyngitis, and impetigo to lifethreatening necrotizing soft tissue infections (NSTIs) and streptococcal toxic shock syndrome (STSS) (1-12). The multifaceted nature of invasive GAS infections requires several modes of pathogenic adaptation to evade host immune defenses to successfully colonize and survive in host niches. In addition to the plethora of pathogenic factors contributing to disease severity, variations in the host genetic context play an equally important role in manipulating disease severity, manifestations, and outcomes.The emergence of virulent strains of GAS bacteria in the early 1980s coincided with a remarkable resurgence of severe and often deadly forms of invasive infections associated with STSS and NSTIs (5,6,12,13). One particular strain that emerged during that time is the clonal M1T1 strain that disseminated globally and continues to be one of the most prevalently isolated strains from patients with invasive and/or noninvasive GAS infections (12,(14)(15)(16)(17). This strain produces many secreted and surface-bound virulence factors; most of them are adapted to evade human host defense mechanisms (12, 18). However, previous studies from our laboratory characterized indistinguishable, invasive M1T1 isolates from patients with starkly different disease severity and outcomes (19). These findings underscored the contribution of host factors to the stark differences in severity and outcomes of invasive GAS infections.Indeed, ensuing ...

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“…Occasionally, however, these bacteria are transformed to the point where they become highly pathogenic and invasive, gaining access to normally sterile sites within the infected host, including blood, muscle, deep tissues, and lungs, and causing severe, life-threatening complications associated with severe and often deadly diseases (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Two of the severe but least common life-threatening infections are necrotizing fasciitis (NF) and streptococcal toxic shock syndrome (STSS) (11,12).…”

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confidence: 99%

Metal-Mediated Modulation of Streptococcal Cysteine Protease Activity and Its Biological Implications

et al. 2014

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dStreptococcal cysteine protease (SpeB), the major secreted protease produced by group A streptococcus (GAS), cleaves both host and bacterial proteins and contributes importantly to the pathogenesis of invasive GAS infections. Modulation of SpeB expression and/or its activity during invasive GAS infections has been shown to affect bacterial virulence and infection severity. Expression of SpeB is regulated by the GAS CovR-CovS two-component regulatory system, and we demonstrated that bacteria with mutations in the CovR-CovS two-component regulatory system are selected for during localized GAS infections and that these bacteria lack SpeB expression and exhibit a hypervirulent phenotype. Additionally, in a separate study, we showed that expression of SpeB can also be modulated by human transferrin-and/or lactoferrin-mediated iron chelation. Accordingly, the goal of this study was to investigate the possible roles of iron and other metals in modulating SpeB expression and/or activity in a manner that would potentiate bacterial virulence. Here, we report that the divalent metals zinc and copper inhibit SpeB activity at the posttranslational level. Utilizing online metal-binding site prediction servers, we identified two putative metal-binding sites in SpeB, one of which involves the catalytic-dyad residues 47 Cys and 195 His. Based on our findings, we propose that zinc and/or copper availability in the bacterial microenvironment can modulate the proteolytic activity of SpeB in a manner that preserves the integrity of several other virulence factors essential for bacterial survival and dissemination within the host and thereby may exacerbate the severity of invasive GAS infections.

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The Reemergence of Severe Group A Streptococcal Disease: an Evolutionary Perspective

Cited by 21 publications

References 236 publications

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

Host Genetic Variations and Sex Differences Potentiate Predisposition, Severity, and Outcomes of Group A Streptococcus-Mediated Necrotizing Soft Tissue Infections

Metal-Mediated Modulation of Streptococcal Cysteine Protease Activity and Its Biological Implications

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