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Immunization with a streptococcal multiple-epitope recombinant protein protects mice against invasive group A streptococcal infection.

ABSTRACT: Streptococcus pyogenes (group A Streptococcus; GAS) causes clinical diseases, including pharyngitis, scarlet fever, impetigo, necrotizing fasciitis and streptococcal toxic shock syndrome. A number of group A streptococcus vaccine candidates have been developed, but only one 26-valent recombinant M protein vaccine has entered clinical trials. Differing from the design of a 26-valent recombinant M protein vaccine, we provide here a vaccination using the polyvalence epitope recombinant FSBM protein (rFSBM), which contains four different epitopes, including the fibronectin-binding repeats domain of streptococcal fibronectin binding protein Sfb1, the C-terminal immunogenic segment of streptolysin S, the C3-binding motif of streptococcal pyrogenic exotoxin B, and the C-terminal conserved segment of M protein. Vaccination with the rFSBM protein successfully prevented mortality and skin lesions caused by several emm strains of GAS infection. Anti-FSBM antibodies collected from the rFSBM-immunized mice were able to opsonize at least six emm strains and can neutralize the hemolytic activity of streptolysin S. Furthermore, the internalization of GAS into nonphagocytic cells is also reduced by anti-FSBM serum. These findings suggest that rFSBM can be applied as a vaccine candidate to prevent different emm strains of GAS infection.

SUBMITTER: Kuo CF

PROVIDER: S-EPMC5371370 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Immunization with a streptococcal multiple-epitope recombinant protein protects mice against invasive group A streptococcal infection.

Kuo Chih-Feng CF Tsao Nina N Hsieh I-Chen IC Lin Yee-Shin YS Wu Jiunn-Jong JJ Hung Yu-Ting YT

PloS one 20170329 3

Streptococcus pyogenes (group A Streptococcus; GAS) causes clinical diseases, including pharyngitis, scarlet fever, impetigo, necrotizing fasciitis and streptococcal toxic shock syndrome. A number of group A streptococcus vaccine candidates have been developed, but only one 26-valent recombinant M protein vaccine has entered clinical trials. Differing from the design of a 26-valent recombinant M protein vaccine, we provide here a vaccination using the polyvalence epitope recombinant FSBM protein ...[more]

PMID: 28355251

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Project description:Streptococcal secreted esterase (Sse) is a platelet-activating factor acetylhydrolase that is critical for Group A Streptococcus (GAS) skin invasion and innate immune evasion. There are two Sse variant complexes that share >98% identity within each complex but display about 37% variation between the complexes in amino acid sequences. Sse immunization protects mice against lethal infection and skin invasion in subcutaneous infection with the hypervirulent CovRS mutant strain, MGAS5005. However, it is not known whether Sse immunization provides significant protection against infection of GAS with functional CovRS and whether immunization with Sse of one variant complex provides protection against infection of GAS that produces Sse of another variant complex. This study was designed to address these questions. Mice were immunized with recombinant Sse of M1 GAS (SseM1) and challenged with MGAS5005 (serotype M1, CovS mutant, and Sse of variant complex I), MGAS315 (M3, CovS mutant, and Sse of variant complex I), MGAS2221 (M1, wild-type CovRS, and Sse of variant complex I), and MGAS6180 (M28, wild-type CovRS, and Sse of variant complex II). SseM1 immunization significantly increased survival rates of mice in subcutaneous MGAS5005 and intraperitoneal MGAS6180 challenges and showed consistently higher or longer survival in the other challenges. Immunized mice had smaller skin lesion and higher neutrophil responses in subcutaneous infections and lower GAS burdens in spleen, liver, and kidney in most of the challenge experiments than control mice. SseM1 immunization enhanced proinflammatory responses. These data suggest that Sse immunization has a broad benefit against GAS infections that can vary in extent from strain to strain and that the benefit may be due to the immunization-enhanced proinflammatory responses. In particular, immunization with SseM1 can provide protection against M28 GAS infection even though its Sse and SseM1 have significant variations.

Project description:IntroductionRecent studies have shown that histones, the chief protein component of chromatin, are released into the extracellular space during sepsis, trauma, and ischemia-reperfusion injury, and act as major mediators of the death of an organism. This study was designed to elucidate the cellular and molecular basis of histone-induced lethality and to assess the protective effects of recombinant thrombomodulin (rTM). rTM has been approved for the treatment of disseminated intravascular coagulation (DIC) in Japan, and is currently undergoing a phase III clinical trial in the United States.MethodsHistone H3 levels in plasma of healthy volunteers and patients with sepsis and DIC were measured using enzyme-linked immunosorbent assay. Male C57BL/6 mice were injected intravenously with purified histones, and pathological examinations were performed. The protective effects of rTM against histone toxicity were analyzed both in vitro and in mice.ResultsHistone H3 was not detectable in plasma of healthy volunteers, but significant levels were observed in patients with sepsis and DIC. These levels were higher in non-survivors than in survivors. Extracellular histones triggered platelet aggregation, leading to thrombotic occlusion of pulmonary capillaries and subsequent right-sided heart failure in mice. These mice displayed symptoms of DIC, including thrombocytopenia, prolonged prothrombin time, decreased fibrinogen, fibrin deposition in capillaries, and bleeding. Platelet depletion protected mice from histone-induced death in the first 30 minutes, suggesting that vessel occlusion by platelet-rich thrombi might be responsible for death during the early phase. Furthermore, rTM bound to extracellular histones, suppressed histone-induced platelet aggregation, thrombotic occlusion of pulmonary capillaries, and dilatation of the right ventricle, and rescued mice from lethal thromboembolism.ConclusionsExtracellular histones cause massive thromboembolism associated with consumptive coagulopathy, which is diagnostically indistinguishable from DIC. rTM binds to histones and neutralizes the prothrombotic action of histones. This may contribute to the effectiveness of rTM against DIC.

Dataset Information

Immunization with a streptococcal multiple-epitope recombinant protein protects mice against invasive group A streptococcal infection.

Publications

Immunization with a streptococcal multiple-epitope recombinant protein protects mice against invasive group A streptococcal infection.

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