Trends in Molecular Medicine
Research FocusUncovering the mysteries of invasive streptococcal diseases
Introduction
Group A streptococci (GAS) are responsible for a wide variety of human diseases that range from uncomplicated pharyngitis and skin infections to severe and even life-threatening manifestations, such as necrotising fasciitis and toxic-shock-like syndrome. The recent resurgence of invasive group A streptococcal diseases, even in industrialised countries, has labelled GAS as flesh-eating bacteria [1]. The initial encounter of GAS with the host takes place at the epithelial surfaces, either in the pharynx or tonsils or in the skin. How this extracellular pathogen breaks the cellular and tissue barriers to gain access into the vascular system and cause invasive disease has been a topic of intensive investigation during the last few years [2]. Many bacterial and host components have been speculated to have a role in this process [3]. The bottlenecks in this area of research are the human specificity of GAS and the genetic diversity of these organisms. Sun et al. [4] used a transgenic mouse expressing human plasminogen to show the crucial role of this proenzyme in invasive disease of humans. A second paper, from Aziz et al. [5], provides new insights into how SpeB, a cysteine protease, can change the expression of selected virulence factors, ensuring that the correct repertoire is expressed during discrete infection processes. A third paper, by Beres et al. [6], describes the genome-wide molecular dissection of certain GAS strains to understand the molecular events underlying epidemics of GAS invasive infections. The understanding of invasive mechanisms is a prerequisite for the development of novel strategies to control and combat GAS invasive diseases.
Section snippets
Human plasminogen and bacterial streptokinase
The ability of GAS to cause invasive disease requires the invasion of host tissue and circumvention of the host immune defence. The proteolytic digestion of host proteins facilitates certain types of infection. The broad proteolytic activity of plasmin and the high concentration of plasminogen in mammals make the plasminogen system an attractive target for GAS to exploit [7]. It has been hypothesised that the interaction between host plasminogen and streptokinase, which is secreted by GAS,
Other proteolytic enzymes involved in virulence
Our new understanding of the specific interaction between plasminogen and streptokinase is just one of several new advances that illuminate the mystery of invasive disease progression in GAS. Studies into the activity of the bacterially derived proteolytic enzyme SpeB is increasing our understanding of how this bacterium controls the expression of virulence factors which are crucial at different stages of infection. The regulation of these factors at the level of transcription can occur through
GAS virulence and prophage acquisition
A major impediment to our understanding of the genetic factors involved in GAS infection and epidemiology has been the observation that individual GAS serotypes (or M-types) are differentially but not absolutely associated with different streptococcal diseases. For example, M3 is an isolate that is over-represented in invasive disease cases compared with other M-types [17]. Some GAS M-types also appear to increase and decrease in disease-causing frequency in epidemic-like waves. To further
Concluding remarks
The study of Sun et al. [4] and Beres et al. [6] have introduced cutting-edge technologies in mouse genetics and bacterial genomics to understand complex streptococcal diseases. The use of a humanised mouse to investigate the plasminogen–streptokinase interaction and new investigations of SpeB activity [5] are providing crucial insights into the importance of proteases in the virulence of Streptococcus pyogenes. Such research is leading to the development of complex models of streptococcal
Acknowledgement
David J. McMillan is a recipient of Alexander von Humboldt fellowship.
References (22)
- et al.
Streptococcal invasion
Curr. Opin. Microbiol.
(1999) Molecular co-operation between protein PAM and streptokinase for plasmin acquisition by Streptococcus pyogenes
J. Biol. Chem.
(1998)Protein GRAB of Streptococcus pyogenes regulates proteolysis at the bacterial surface by binding α2-macroglobulin
J. Biol. Chem.
(1999)Effect of a bacterial pheromone peptide on host chemokine degradation in group A streptococcal necrotising soft-tissue infections
Lancet
(2004)- et al.
Streptococcal infections of skin and soft tissues
N. Engl. J. Med.
(1996) - et al.
Extracellular matrix interaction with Gram positive bacteria
(1999) Plasminogen is a critical host pathogenicity factor for group A streptococcal infection
Science
(2004)Invasive M1T1 group A Streptococcus undergoes a phase-shift in vivo to prevent proteolytic degradation of multiple virulence factors by SpeB
Mol. Microbiol.
(2004)Genome-wide molecular dissection of serotype M3 group A Streptococcus strains causing two epidemics of invasive infections
Proc. Natl. Acad. Sci. U. S. A.
(2004)Coevolutionary patterns in plasminogen activation
Proc. Natl. Acad. Sci. U. S. A.
(2003)
Plasminogen enhances virulence of group A streptococci by streptokinase-dependent and streptokinase-independent mechanisms
J. Infect. Dis.
Cited by (20)
Structure, dynamics and immunogenicity of a catalytically inactive CXC chemokine-degrading protease SpyCEP from Streptococcus pyogenes
2020, Computational and Structural Biotechnology JournalCitation Excerpt :The global disease burden attributed to S. pyogenes infection is estimated to be over 600 million cases annually, of which 18 million cases can be attributed to severe S. pyogenes infection, with approximately 1.8 million new cases, and over 517,000 deaths reported annually [2,3]. S. pyogenes expresses an array of virulence factors to evade or inactivate the innate immune response [4]. Neutrophil recruitment and activation, mediated by the ELR+ group of chemokines and vital for bacterial clearance, is impaired in lethal soft-tissue S. pyogenes infections [5,6].
Streptococcal Diseases
2016, International Encyclopedia of Public HealthInfection of human keratinocytes by Streptococcus dysgalactiae subspecies dysgalactiae isolated from milk of the bovine udder
2016, Microbes and InfectionCitation Excerpt :For comparative purposes, adherence and internalization of the SDSD isolate that caused ascending upper limb cellulitis (SDSD GCS-Si) [3], an invasive human isolate S. pyogenes GAP58 collected from the blood of a patient, and a S. pyogenes GAP8 human isolate from the oropharynx of an asymptomatic carrier [14] were also assessed. Primary keratinocytes were selected due to the common colonization of non-intact skin by S. pyogenes [17] and the ascending upper limb cellulitis caused by SDSD GCS-Si. Fig. 1 shows that there is 1 internalized/adhered VSD5 cell per 10 keratinocytes.
Cannabis use among children and adolescents: Impacts and consequences
2014, Bulletin de l'Academie Nationale de MedecineGroup A streptococcus activates type I interferon production and MyD88-dependent signaling without involvement of TLR2, TLR4, and TLR9
2008, Journal of Biological ChemistryStreptococcal diseases
2008, International Encyclopedia of Public Health