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Antibodies to the conserved region of the M protein and a streptococcal superantigen cooperatively resolve toxic shock-like syndrome in HLA-humanized mice.

ABSTRACT: Invasive streptococcal disease (ISD) and toxic shock syndrome (STSS) result in over 160,000 deaths each year. We modelled these in HLA-transgenic mice infected with a clinically lethal isolate expressing Streptococcal pyrogenic exotoxin (Spe) C and demonstrate that both SpeC and streptococcal M protein, acting cooperatively, are required for disease. Vaccination with a conserved M protein peptide, J8, protects against STSS by causing a dramatic reduction in bacterial burden associated with the absence of SpeC and inflammatory cytokines in the blood. Furthermore, passive immunotherapy with antibodies to J8 quickly resolves established disease by clearing the infection and ablating the inflammatory activity of the M protein, which is further enhanced by addition of SpeC antibodies. Analysis of 77 recent isolates of Streptococcus pyogenes causing ISD, demonstrated that anti-J8 antibodies theoretically recognize at least 73, providing strong support for using antibodies to J8, with or without antibodies to SpeC, as a therapeutic approach.

SUBMITTER: Pandey M

PROVIDER: S-EPMC6726444 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Antibodies to the conserved region of the M protein and a streptococcal superantigen cooperatively resolve toxic shock-like syndrome in HLA-humanized mice.

Pandey Manisha M Calcutt Ainslie A Ozberk Victoria V Chen Zhenjun Z Croxen Matthew M Powell Jessica J Langshaw Emma E Mills Jamie-Lee JL Jen Freda E-C FE McCluskey James J Robson Jenny J Tyrrell Gregory J GJ Good Michael F MF

Science advances 20190904 9

Invasive streptococcal disease (ISD) and toxic shock syndrome (STSS) result in over 160,000 deaths each year. We modelled these in HLA-transgenic mice infected with a clinically lethal isolate expressing Streptococcal pyrogenic exotoxin (Spe) C and demonstrate that both SpeC and streptococcal M protein, acting cooperatively, are required for disease. Vaccination with a conserved M protein peptide, J8, protects against STSS by causing a dramatic reduction in bacterial burden associated with the a ...[more]

PMID: 31517054

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Project description:BackgroundStreptococcus suis serotype 2 (S. suis 2, SS2) is a major zoonotic pathogen that causes only sporadic cases of meningitis and sepsis in humans. Most if not all cases of Streptococcal toxic shock syndrome (STSS) that have been well-documented to date were associated with the non-SS2 group A streptococcus (GAS). However, a recent large-scale outbreak of SS2 in Sichuan Province, China, appeared to be caused by more invasive deep-tissue infection with STSS, characterized by acute high fever, vascular collapse, hypotension, shock, and multiple organ failure.Methods and findingsWe investigated this outbreak of SS2 infections in both human and pigs, which took place from July to August, 2005, through clinical observation and laboratory experiments. Clinical and pathological characterization of the human patients revealed the hallmarks of typical STSS, which to date had only been associated with GAS infection. Retrospectively, we found that this outbreak was very similar to an earlier outbreak in Jiangsu Province, China, in 1998. We isolated and analyzed 37 bacterial strains from human specimens and eight from pig specimens of the recent outbreak, as well as three human isolates and two pig isolates from the 1998 outbreak we had kept in our laboratory. The bacterial isolates were examined using light microscopy observation, pig infection experiments, multiplex-PCR assay, as well as restriction fragment length polymorphisms (RFLP) and multiple sequence alignment analyses. Multiple lines of evidence confirmed that highly virulent strains of SS2 were the causative agents of both outbreaks.ConclusionsWe report, to our knowledge for the first time, two outbreaks of STSS caused by SS2, a non-GAS streptococcus. The 2005 outbreak was associated with 38 deaths out of 204 documented human cases; the 1998 outbreak with 14 deaths out of 25 reported human cases. Most of the fatal cases were characterized by STSS; some of them by meningitis or severe septicemia. The molecular mechanisms underlying these human STSS outbreaks in human beings remain unclear and an objective for further study.

Project description:Toxic shock syndrome (TSS) caused by the superantigen exotoxins of Staphylococcus aureus and Streptococcus pyogenes is characterized by robust T cell activation, profound elevation in systemic levels of multiple cytokines, including interferon-? (IFN-?), followed by multiple organ dysfunction and often death. As IFN-? possesses pro- as well as anti-inflammatory properties, we delineated its role in the pathogenesis of TSS. Antibody-mediated in vivo neutralization of IFN-? or targeted disruption of IFN-? gene conferred significant protection from lethal TSS in HLA-DR3 transgenic mice. Following systemic high dose SEB challenge, whereas the HLA-DR3.IFN-?(+/+) mice became sick and succumbed to TSS, HLA-DR3.IFN-?(-/-) mice appeared healthy and were significantly protected from SEB-induced lethality. SEB-induced systemic cytokine storm was significantly blunted in HLA-DR3.IFN-?(-/-) transgenic mice. Serum concentrations of several cytokines (IL-4, IL-10, IL-12p40 and IL-17) and chemokines (KC, rantes, eotaxin and MCP-1) were significantly lower in HLA-DR3.IFN-?(-/-) transgenic mice. However, SEB-induced T cell expansion in the spleens was unaffected and expansion of SEB-reactive TCR V?8(+) CD4(+) and CD8(+) T cells was even more pronounced in HLA-DR3.IFN-?(-/-) transgenic mice when compared to HLA-DR3.IFN-?(+/+) mice. A systematic histopathological examination of several vital organs revealed that both HLA-DR3.IFN-?(+/+) and HLA-DR3.IFN-?(-/-) transgenic mice displayed comparable severe inflammatory changes in lungs, and liver during TSS. Remarkably, whereas the small intestines from HLA-DR3.IFN-?(+/+) transgenic mice displayed significant pathological changes during TSS, the architecture of small intestines in HLA-DR3.IFN-?(-/-) transgenic mice was preserved. In concordance with these histopathological changes, the gut permeability to macromolecules was dramatically increased in HLA-DR3.IFN-?(+/+) but not HLA-DR3.IFN-?(-/-) mice during TSS. Overall, IFN-? seemed to play a lethal role in the immunopathogenesis of TSS by inflicting fatal small bowel pathology. Our study thus identifies the important role for IFN-? in TSS.

Dataset Information

Antibodies to the conserved region of the M protein and a streptococcal superantigen cooperatively resolve toxic shock-like syndrome in HLA-humanized mice.

Publications

Antibodies to the conserved region of the M protein and a streptococcal superantigen cooperatively resolve toxic shock-like syndrome in HLA-humanized mice.

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