Many pathogenic bacteria produce extracellular DNase, but the benefit of this enzymatic activity is not understood. For example, all strains of the human bacterial pathogen group A Streptococcus (GAS) produce at least one extracellular DNase, and most strains make several distinct enzymes. Despite six decades of study, it is not known whether production of DNase by GAS enhances virulence. To test the hypothesis that extracellular DNase is required for normal progression of GAS infection, we generated seven isogenic mutant strains in which the three chromosomal- and prophage-encoded DNases made by a contemporary serotype M1 GAS strain were inactivated. Compared to the wild-type parental strain, the isogenic triple-mutant strain was significantly less virulent in two mouse models of invasive infection. The triple-mutant strain was cleared from the skin injection site significantly faster than the wild-type strain. Preferential clearance of the mutant strain was related to the differential extracellular killing of the mutant and wild-type strains, possibly through degradation of neutrophil extracellular traps, innate immune structures composed of chromatin and granule proteins. The triple-mutant strain was also significantly compromised in its ability to cause experimental pharyngeal disease in cynomolgus macaques. Comparative analysis of the seven DNase mutant strains strongly suggested that the prophage-encoded SdaD2 enzyme is the major DNase that contributes to virulence in this clone. We conclude that extracellular DNase activity made by GAS contributes to disease progression, thereby resolving a long-standing question in bacterial pathogenesis research.

Extracellular deoxyribonuclease made by group A Streptococcus assists pathogenesis by enhancing evasion of the innate immune response

By means of the immunofluorescent staining technique, antisera to a wide variety of serological types of Group A and A variant streptococci were found to contain an antibody which reacted with mammalian striated muscle, both skeletal and cardiac, as well as with smooth muscle in the endocardium and in the media of arterioles. Similar heart-reactive antibodies were not present in antisera to most other groups of hemolytic streptococci and to other Gram-positive cocci. Chemical and serological studies clearly pointed to the cell (protoplast) membrane of the Group A streptococcus as the locus of the antigenic determinant of this heart-reactive antibody. In addition, preliminary studies suggested that the reaction between this streptococcal antibody and cardiac tissue represented an immunological relationship between the sarcolemma, the membrane of a mammalian muscle cell and the cell membrane of a bacterium, the hemolytic streptococcus.

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An immunological relationship between the group. A streptococcus and mammalian muscle.

CONTENTS INTRODUCTION 265 Related Terminology 266 Range of Coverage 268 LYSOGENY 268 Inducibility of Lysogeni¢ Bacteria 272 Elimination of Prophages from Lysogenic Bacteria: "Curing". 274 Variations in the Patterns of Lysogeny 275 THE PHAGE CARRIER STATE, PSEUDOLYSOGENY 276 Condition 1: Phage Infection Limited by Available Receptors on Bacterial Cell .... 277 Condition 2: Loss of Receptors Due to the Action of Virolysin (Endolysin) ....... 278 Condition 3: The Accumulation of Mutant ~’* in a Population of Bac (~) ........ 279 MODEL PHAGE CONVERSIONS 280 Bacteriophages ~ls and e~ and the Conversion of O-Antigens in Salmonella anatum 280 Corynebacteriophages and Diphtherial Toxin 284

Persisting Bacteriophage Infections, Lysogeny, and Phage Conversions

Antibody levels to streptococcal Group A and A-variant carbohydrates were determined using a radioactive immune precipitation technique on patients with rheumatic fever, with and without valvular disease, on patients with post-streptococcal acute glomerulonephritis, and on age-matched controls. During the acute phase of the above illness, the means of the antibody levels to both carbohydrate antigens were equally elevated and were significantly higher than the normal controls. When Group A antibody levels were determined on sera obtained at intervals of 5–12 months and 1–5 yr after the acute illness) it was found that the antibody levels declined within the normal range at the 5–12 month interval in patients with glomerulonephritis as well as in patients with rheumatic fever in whom no valvular involvement had complicated the disease, i.e., patients with pure Sydenham's chorea. However, in patients with rheumatic valvulitis, who had been on penicillin prophylaxis after the last acute episode, the A antibody level showed little decline from the level obtained during the acute illness. The elevated antibody level in patients with rheumatic valvulitis, including patients with Sydenham's chorea with valvulitis, persisted for periods of at least 1 yr and up to 20 yr after the last acute attack. The pattern of the decline of the antibody levels to the A-variant carbohydrate as well as of the antibody titers to the other streptococcal antigens tested, ASO and anti-DNase B, was similar in all patients studied regardless of the presence of valvular disease. These findings suggest that prolonged persistence of the Group A antibody is a phenomenon peculiar to patients with rheumatic valvular disease. Whether this persistence is involved in the pathogenesis or is an outcome of the valvular disease remains to be determined.

https://rupress.org/jem/article-pdf/128/5/1081/1392250/1081.pdf

Persistence of streptococcal group a antibody in patients with rheumatic valvular disease

Streptococcus pyogenes secretes many proteins that influence host-pathogen interactions. Despite their importance, relatively little is known about the regulation of these proteins. The rgg gene (also known as ropB) is required for the expression of streptococcal erythrogenic toxin B (SPE B), an extracellular cysteine protease that contributes to virulence. Proteomics was used to determine if rgg regulates the expression of additional exoproteins. Exponential- and stationary-phase culture supernatant proteins made by S. pyogenes NZ131 rgg and NZ131 speB were separated by two-dimensional electrophoresis. Differences were identified in supernatant proteins from both exponential- and stationary-phase cultures, although considerably more differences were detected among stationary-phase supernatant proteins. Forty-two proteins were identified by peptide fingerprinting with matrix-assisted laser desorption mass spectrometry. Mitogenic factor, DNA entry nuclease (open reading frame [ORF 226]), and ORF 953, which has no known function, were more abundant in the culture supernatants of the rgg mutant compared to the speB mutant. ClpB, lysozyme, and autolysin were detected in the culture supernatant of the speB mutant but not the rgg mutant. To determine if Rgg affected protein expression at the transcriptional level, real-time (TaqMan) reverse transcription (RT)-PCR was used to quantitate Rgg-regulated transcripts from NZ131 wild-type and speB and rgg mutant strains. The results obtained with RT-PCR correlated with the proteomic data. We conclude that Rgg regulates the transcription of several genes expressed primarily during the stationary phase of growth.

R E O Williams

Papers

The Streptococcus, Rheumatic Fever and Glomerulonephritis