Abstract
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.
Highlights
Streptococcus pyogenes called Group A Streptococcus (GAS), can produce an arsenal of extracellular secreted proteins to evade the innate immune system (Walker et al, 2014; Hynes and Sloan, 2016; Liu and Lei, 2018; Happonen et al, 2019)
The streptococcal esterase secreted esterase (Sse) hydrolyzes plateletactivating factor to impede neutrophil recruitment and facilitate innate immune evasion (Liu et al, 2007, 2012, 2013, 2015,Zhu et al, 2009)
Sse of M1 GAS (SseM1) immunization induced a high level of antibody production, which was almost saturated at day 28
Summary
Streptococcus pyogenes called Group A Streptococcus (GAS), can produce an arsenal of extracellular secreted proteins to evade the innate immune system (Walker et al, 2014; Hynes and Sloan, 2016; Liu and Lei, 2018; Happonen et al, 2019). The proteins within each complex share >98% identity in amino acid sequence and there is 63% sequence identity between the complexes These observations raise two important questions regarding the immunogenicity of Sse. First, does Sse immunization provide significant protection against infection of GAS with functional CovRS? Does immunization with Sse of one Sse variant complex provide protection against infection of GAS that produces Sse of another variant complex? We prepared recombinant Sse protein derived from the M1 strain MGAS5005, SseM1, and characterized its capacity to provide protective immunity against MGAS2221, MGAS315, and MGAS6180 infection. SseM1 immunization protects mice against MGAS5005 and MGAS315 in subcutaneous infection route, while it protects mice against MGAS5005, MGAS315, MGAS2221, and MGAS6180 in intraperitoneal infection route
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