An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections

The role of host genetic factors in conferring predisposition or protection in infectious diseases has become evident. Infection with group A streptococci causes a wide spectrum of disease ranging from pharyngitis to streptococcal toxic shock syndrome. The release of inflammatory cytokines triggered by streptococcal superantigens has a pivotal role in invasive streptococcal disease. However, individuals infected with the same strain can develop very different manifestations. We report here that the immunogenetics of the host influence the outcome of invasive streptococcal infection, and demonstrate the underlying mechanism for these genetic associations. Specific human leukocyte antigen class II haplotypes conferred strong protection from severe systemic disease, whereas others increased the risk of severe disease. Patients with the DRB1*1501/DQB1*0602 haplotype mounted significantly reduced responses and were less likely to develop severe systemic disease (P < 0.0001). We propose that human leukocyte antigen class II allelic variation contributes to differences in severity of invasive streptococcal infections through their ability to regulate cytokine responses triggered by streptococcal superantigens.     

Invasive infection caused Streptococcus group A and streptococcal toxic shock syndrome

Modern data on the etiology and pathogenesis of invasive streptococcal infection and the syndrome of streptococcal toxic shock are presented. In the course of the last 10-15 years essential changes in the system of interaction of group A streptococci and the macroorganism have been noted. The growth of morbidity in severe invasive forms of streptococcal infection with different clinical manifestations, including the syndrome of toxic shock, is observed. Most often this disease develops in elderly people, making up a group of risk, but sometimes affects healthy young people. Different pathogenicity factors of streptococci, capable of inducing the development of infection, are analyzed. Special attention is given to superantigens: pyrogenic toxins and M-protein. The suggestion that the development of the disease is seemingly linked with the state of specific protective immunity is substantiated. In spite of achievements in the field of the microbiology and immunology of group A streptococci, the causes of the appearance and development of invasive streptococcal infection have not yet been determined.     

The classification of streptococci and human streptococcal diseases

The modern nomenclature, phenotypic, medical, ecological and phylogenetic classification of streptococci and different classification of streptococcal human diseases are presented. All phylogenetic groups of streptococci have been shown to contain species causing diseases in man. The most medically significant groups are the phylogenetic groups Pyogenes and Mitis. Directions of the improvement of the classification of streptococci and streptococcal human diseases on the basis of modern concepts on the taxonomy of streptococci, the biological properties and ecology of the infective agents, as well as the genesis and clinical picture of diseases induced by them, have been determined.     

Genetic regulation of host responses to group A streptococcus in mice.

The group A streptococci (GAS, Streptococcus pyogenes) are important human pathogens which can cause a variety of diseases, ranging from mild infections to very severe invasive diseases. In recent years, evidence has been accumulated that host genetic factors have a major influence on the outcome of streptococcal infections. Variability in the degree of susceptibility of different inbred mouse strains to infection with GAS has demonstrated that the host genetic background largely determines the susceptibility of mice to this pathogen. This information is particularly useful for studying the immune mechanisms underlying disease susceptibility in mice, and provides an entry point for the identification of host defence loci. This paper reviews the recent advances in the characterisation of pathogenic mechanisms associated with the development of GAS-induced septic shock in the mouse model and outlines the current knowledge regarding the genetic control of immune responses to Group A streptococcus in mice.     

Streptococcal L forms and phage. A clinical-epidemiologic study

This study showed that streptococcal L forms could not be isolated from children who were either carriers of group A streptococci or had disease due to this pathogen. It was possible to induce L colony formation in 15 strains of group A. Streptococcal bacteriophages were demonstrated in 20% of group A streptococci isolated from school children who were carriers, but did not have clinical evidence of streptococcal disease, and from 44.9% of children whose physicians considered they had acute streptococcal upper respiratory infections. Lysogeny (bacteriophage) was demonstrated more frequently during 1969-70 when carrier rates were high and from children who had manifest streptococcal disease, suggesting a possible positive relationship between lysogeny, high carrier rates, and infection in the children studied. Lysogeny and erythrogenic toxin production by group A streptococci occurred simultaneously in approximately half of the strains of group A streptococci tested, suggesting that lysogeny is not a sine qua non for erythrogenic toxin production.     

Receptors for polysaccharides of group A streptococci on human thymic lymphocytes. Stimulation of their expression by action of adenosine, theophylline and supernatant of thymocytes

It was established by indirect immunofluorescence that thymic lymphocytes bear receptors for polysaccharide of group A streptococci (Rps). The ability of thymic lymphocytes to express Rps depends on the cAMP concentration in the cell, because the treatment of thymocytes with adenosine and theophylline increases the number of cells with Rps (Tps cells). Supernatant of thymic lymphocytes is also capable of stimulating expression of Rps. Because the A-polysaccharide has common antigenic determinant with thymus epithelium antigen it can be assumed that A-polysaccharide links with the thymocytes via receptor for this epithelial antigen. This assumption needs a detailed study in view of the hypothesis about the important role of cross-reactive antigens of group A streptococci in generating autoimmune process during rheumatic fever and other streptococcal diseases. It should also be noted that Rps may be a useful marker for identification and studying the changes of Tps subpopulation in the thymus and peripheral lymphoid organs of patient with different streptococcal diseases.     

Genetic bases and medical relevance of capsular polysaccharide biosynthesis in pathogenic streptococci

Many streptococci are human and/or animal pathogens and the frequent cause of life-threatening diseases. Among various streptococcal virulence factors, capsular polysaccharides (CPs) are recognized as essential to prevent phagocytosis by macrophages and neutrophils. In the last decade, an impressive advance on the knowledge of the genetic bases underlying capsule formation has been achieved. The capsular gene cluster driving the formation of the CP of Streptococcus pyogenes and other hyaluronate-producing streptococci, represents one of the simplest cases of gene organization to synthesize a capsule. A more complex situation has been found in Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus suis, and other streptococci. On the whole, there exists a direct relationship between the structural and chemical complexity of the repeating unit of the polysaccharide and the number of genes found in the corresponding capsular locus. Streptococcal vaccines, either polysaccharide or conjugate, are currently being tested in clinical trials to overcome the rise of worldwide antibiotic resistance, although, for different reasons, none of these vaccines are expected to provide the required full coverage in a near future. This concern has prompted to explore alternative possibilities with an improved therapeutic potential against streptococcal diseases.     

The dynamics of detecting group-A streptococci in an infectious disease clinic]

The study revealed that the isolation rate of group A streptococci in scarlet fever patients at the time of hospitalization did not exceed 68%. The isolation rate of these streptococci was greatly influenced by antibacterial therapy carried out before hospitalization. Under clinical conditions with intensive penicillin therapy group A streptococci were eliminated from the larynx on days 3-4. In 13% of children repeated streptococcal infection was observed 0.5-3 months after discharge from hospital.     

β-溶血型链球菌与银屑病发病、发生及发展的研究现状

银屑病的发病与链球菌感染的相关性近年来得到人们的密切关注.银屑病是一类由T细胞介导的自身免疫性疾病,链球菌抗原可在易感人群中诱发或加重银屑病并使银屑病慢性持续存在.从β-溶血型链球菌诱发银屑病相关的细胞壁、细胞膜、CpG DNA序列及其他相关蛋白的自身抗原及β-溶血型链球菌通过活化T细胞、抗原抗体反应途径、通过作用机体的基因改变遗传易感性诱发银屑病的可能作用途径几方面,阐述β-溶血型链球菌与银屑病发病、发生及发展的研究现状.     

CONTROL OF STREPTOCOCCAL THROAT INFECTIONS IN SCHOOLS—A Cooperative Program Followed in Orange County

Attempts to identify streptococcal throat infections on clinical evidence alone do not provide an adequate or reliable index of the prevalence of these infections in the community.Epidemiologic information on streptococcal throat infections based on bacteriological identification permits a more accurate assessment of the situation and more logical and more effective control measures.Recent refinements in laboratory procedures have provided a simple, reliable and relatively inexpensive method for the identification of Group A beta hemolytic streptococci by public health or clinical laboratories.In Orange County a program for the identification of streptococcal throat infections by cooperative action of the medical profession, the health department and the school authorities greatly aided in control of the disease. A voluntary health agency (heart association) made an important contribution toward the success of the control program.     

Control of streptococcal throat infections in schools; a cooperative program followed in Orange County

Attempts to identify streptococcal throat infections on clinical evidence alone do not provide an adequate or reliable index of the prevalence of these infections in the community. Epidemiologic information on streptococcal throat infections based on bacteriological identification permits a more accurate assessment of the situation and more logical and more effective control measures. Recent refinements in laboratory procedures have provided a simple, reliable and relatively inexpensive method for the identification of Group A beta hemolytic streptococci by public health or clinical laboratories. In Orange County a program for the identification of streptococcal throat infections by cooperative action of the medical profession, the health department and the school authorities greatly aided in control of the disease. A voluntary health agency (heart association) made an important contribution toward the success of the control program.     

Prevalence of IgA receptors in clinical isolates of Streptococcus pyogenes and Streptococcus agalactiae; Serologic distinction between the receptors by blocking antibodies

Abstract Group A and B streptococci ( Streptococcus pyogenes and Streptococcus agalactiae ) are the only known bacterial pathogens expressing IgA Fc-receptors. However, the IgA binding proteins of the two species have been found genetically unrelated. In the present investigation the binding of human IgA among clinical isolates of group A and group B streptococci was studied and the respective IgA-binding epitopes were compared serologically. Surface binding of radiolabelled, monoclonal human IgA1 occurred in 38% of 115 unselected group A streptococcal isolates. Comparing four predominant T-types, IgA-binding was found in 77% and 85%, respectively, of types T4 and T28 strains but only in 5% and 25%, respectively, of T1 and T12 strains. In group B streptococci, 70% of 58 type Ib strains but only 2% of 399 strains of other serotypes bound IgA. Using rabbit immune sera raised to the two streptococcal species it was found that strains exhibiting IgA Fc-receptors often induced antibodies blocking the binding of IgA to bacteria. Furthermore, the blocking shown by an individual serum was restricted to the streptococcal group used for immunization showing that also the IgA-binding epitopes in group A and B streptococci are conformationally distinct. Though infections with serotypes often binding IgA, compared to other types, are not known to differ, it is assumed that the non-immune binding of IgA might favour mucosal colonization of the organisms.     

Streptococcus Adherence and Colonization

Summary: Streptococci readily colonize mucosal tissues in the nasopharynx; the respiratory, gastrointestinal, and genitourinary tracts; and the skin. Each ecological niche presents a series of challenges to successful colonization with which streptococci have to contend. Some species exist in equilibrium with their host, neither stimulating nor submitting to immune defenses mounted against them. Most are either opportunistic or true pathogens responsible for diseases such as pharyngitis, tooth decay, necrotizing fasciitis, infective endocarditis, and meningitis. Part of the success of streptococci as colonizers is attributable to the spectrum of proteins expressed on their surfaces. Adhesins enable interactions with salivary, serum, and extracellular matrix components; host cells; and other microbes. This is the essential first step to colonization, the development of complex communities, and possible invasion of host tissues. The majority of streptococcal adhesins are anchored to the cell wall via a C-terminal LPxTz motif. Other proteins may be surface anchored through N-terminal lipid modifications, while the mechanism of cell wall associations for others remains unclear. Collectively, these surface-bound proteins provide Streptococcus species with a “coat of many colors,” enabling multiple intimate contacts and interplays between the bacterial cell and the host. In vitro and in vivo studies have demonstrated direct roles for many streptococcal adhesins as colonization or virulence factors, making them attractive targets for therapeutic and preventive strategies against streptococcal infections. There is, therefore, much focus on applying increasingly advanced molecular techniques to determine the precise structures and functions of these proteins, and their regulatory pathways, so that more targeted approaches can be developed.     

Biochemical and biological properties of the binding of human fibrinogen to M protein in group A streptococci.

Fibrinogen is known to bind to group A streptococci and precipitate with extracts containing streptococcal M protein. We have previously shown that the binding of fibrinogen to M-positive streptococci prevents opsonization by complement and protects that organism from phagocytosis in nonimmune blood. In the present study, we used 3H-labeled fibrinogen, a highly purified peptide fragment of type 24 M protein (pep M24), and anti-pep M sera to show that fibrinogen binds to M-positive streptococci with high affinity (dissociation constants, 1 to 5 nM); occupation of the high-affinity binding sites suffices to protect the organism from phagocytosis; proteolytic treatments that remove M protein from streptococcal cells abolish binding; binding is competitively inhibited by anti-pep M sera; pep M24 precipitates fibrinogen; and binding to type 24 cells is inhibited by pep M24. We conclude that M protein is the cell surface structure principally responsible for binding fibrinogen on the surface of M-positive streptococci and that this binding contributes to the known antiopsonic property of M proteins.     

The Crystal Structure of the Streptococcal Collagen-like Protein 2 Globular Domain from Invasive M3-type Group A Streptococcus Shows Significant Similarity to Immunomodulatory HIV Protein gp41

The arsenal of virulence factors deployed by streptococci includes streptococcal collagen-like (Scl) proteins. These proteins, which are characterized by a globular domain and a collagen-like domain, play key roles in host adhesion, host immune defense evasion, and biofilm formation. In this work, we demonstrate that the Scl2.3 protein is expressed on the surface of invasive M3-type strain MGAS315 of Streptococcus pyogenes. We report the crystal structure of Scl2.3 globular domain, the first of any Scl. This structure shows a novel fold among collagen trimerization domains of either bacterial or human origin. Despite there being low sequence identity, we observed that Scl2.3 globular domain structurally resembles the gp41 subunit of the envelope glycoprotein from human immunodeficiency virus type 1, an essential subunit for viral fusion to human T cells. We combined crystallographic data with modeling and molecular dynamics techniques to gather information on the entire lollipop-like Scl2.3 structure. Molecular dynamics data evidence a high flexibility of Scl2.3 with remarkable interdomain motions that are likely instrumental to the protein biological function in mediating adhesive or immune-modulatory functions in host-pathogen interactions. Altogether, our results provide molecular tools for the understanding of Scl-mediated streptococcal pathogenesis and important structural insights for the future design of small molecular inhibitors of streptococcal invasion.     

Phase changes in the population of group A streptococci and their influence on the course of the epidemic process of tonsillitis

This work presents the data on the complex evaluation of the population of group A streptococci, studied at each of four phases (reservation, epidemic transformation, epidemic spread, reservational transformation) of the course of the epidemic process of streptococcal infection of the respiratory tracts (tonsillitis) in an organized group of adults. The characterization of the phases of the infective agent in accordance with the level of the carrier state, the size of streptococcal foci and the virulence of streptococci is given. Thus, the study shows that the heterogeneity of group A streptococci with respect to their virulence reaches its maximum level at the phases of reservation and epidemic spread and its minimum level at the phases of epidemic and reservational transformation. The size of streptococcal foci in carriers and the virulence of streptococci isolated from them are the inter-related unidirectional signs of the population of the infective agent and, at the same time, the main factors responsible for the phase character of the epidemic process and the morbidity level in tonsillitis.     

Is plasminogen deployed as a Streptococcus pyogenes virulence factor?

Streptococcus pyogenes (group A streptococcus) causes human skin and throat infections as well as highly invasive diseases including necrotizing fasciitis. Group A streptococcal infections and invasive disease have made a resurgence in developed countries during the past two decades. S. pyogenes use multiple pathways for the acquisition and activation of human plasminogen, securing potent proteolytic activity on the bacterial cell surface. Recent experimental evidence using a humanized transgenic mouse model suggests a crucial role for human plasminogen in the dissemination of S. pyogenes in vivo.     

Streptococcus fryi sp. nov., a novel species with Lancefield group M antigens

The taxonomic characteristics of β-hemolytic streptococcal strains that reacted with Lancefield group M antisera were investigated. Group M streptococci have not been proposed as a species to date. Four strains of the group M streptococci isolated from dog were located within the pyogenic group of the genus Streptococcus on 16S rRNA gene-based phylogenetic analysis; the group M strains were located a short distance away from all other members of the group. The homology values of 16S rRNA gene sequences between group M strains and all other streptococci were<95.6%. Group M strains exhibited low levels of DNA-DNA homology to other streptococcal species. Some biochemical traits, such as β-galactosidase activity and acid production from glycogen, could distinguish these group M strains from other closely related species. Thus, these strains are proposed to constitute a new species -Streptococcus fryi sp. nov. The type strain is PAGU 653(T) (=NCTC 10235(T)=JCM 16387(T)).     

Isolation of non-type-specific protein antigens of Streptococcus group B

Hydrochloride extracts obtained from group B streptococcal strains of different serotypes have proved to be the source of type-nonspecific protein antigens, precipitated with ethanol and studied by gel chromatography and spectrophotometric scanning in ultraviolet rays. Thus, 2 or 3 antigens, one of them found to be common for streptococci of groups A, B and G, as well as the admixture of group-specific polysaccharide, have been detected. In extracts obtained from group B streptococcal strains of different serotypes a common protein antigen, specific only for group B, has been detected. The suitability of gel chromatography with the use Toyopearl gel HW-55F for the preparative isolation of the specific fraction of protein type-nonspecific antigen with a view to the subsequent study of immune response to group B streptococci has been shown.