PMID- 38408992
OWN - NLM
STAT- MEDLINE
DCOM- 20240228
LR  - 20240229
IS  - 1423-0127 (Electronic)
IS  - 1021-7770 (Print)
IS  - 1021-7770 (Linking)
VI  - 31
IP  - 1
DP  - 2024 Feb 27
TI  - Reduced interleukin-18 secretion by human monocytic cells in response to 
      infections with hyper-virulent Streptococcus pyogenes.
PG  - 26
LID - 10.1186/s12929-024-01014-9 [doi]
LID - 26
AB  - BACKGROUND: Streptococcus pyogenes (group A streptococcus, GAS) causes a variety 
      of diseases ranging from mild superficial infections of the throat and skin to 
      severe invasive infections, such as necrotizing soft tissue infections (NSTIs). 
      Tissue passage of GAS often results in mutations within the genes encoding for 
      control of virulence (Cov)R/S two component system leading to a hyper-virulent 
      phenotype. Dendritic cells (DCs) are innate immune sentinels specialized in 
      antigen uptake and subsequent T cell priming. This study aimed to analyze 
      cytokine release by DCs and other cells of monocytic origin in response to 
      wild-type and natural covR/S mutant infections. METHODS: Human primary 
      monocyte-derived (mo)DCs were used. DC maturation and release of pro-inflammatory 
      cytokines in response to infections with wild-type and covR/S mutants were 
      assessed via flow cytometry. Global proteome changes were assessed via mass 
      spectrometry. As a proof-of-principle, cytokine release by human primary 
      monocytes and macrophages was determined. RESULTS: In vitro infections of moDCs 
      and other monocytic cells with natural GAS covR/S mutants resulted in reduced 
      secretion of IL-8 and IL-18 as compared to wild-type infections. In contrast, 
      moDC maturation remained unaffected. Inhibition of caspase-8 restored secretion 
      of both molecules. Knock-out of streptolysin O in GAS strain with unaffected 
      CovR/S even further elevated the IL-18 secretion by moDCs. Of 67 fully sequenced 
      NSTI GAS isolates, 28 harbored mutations resulting in dysfunctional CovR/S. 
      However, analyses of plasma IL-8 and IL-18 levels did not correlate with presence 
      or absence of such mutations. CONCLUSIONS: Our data demonstrate that strains, 
      which harbor covR/S mutations, interfere with IL-18 and IL-8 responses in 
      monocytic cells by utilizing the caspase-8 axis. Future experiments aim to 
      identify the underlying mechanism and consequences for NSTI patients.
CI  - (c) 2024. The Author(s).
FAU - Tolken, Lea A
AU  - Tolken LA
AD  - Department of Molecular Genetics and Infection Biology, University of Greifswald, 
      Greifswald, Germany.
FAU - Paulikat, Antje D
AU  - Paulikat AD
AD  - Department of Molecular Genetics and Infection Biology, University of Greifswald, 
      Greifswald, Germany.
FAU - Jachmann, Lana H
AU  - Jachmann LH
AD  - Department of Molecular Genetics and Infection Biology, University of Greifswald, 
      Greifswald, Germany.
FAU - Reder, Alexander
AU  - Reder A
AD  - Department of Functional Genomics, University Medicine Greifswald, Greifswald, 
      Germany.
FAU - Salazar, Manuela Gesell
AU  - Salazar MG
AD  - Department of Functional Genomics, University Medicine Greifswald, Greifswald, 
      Germany.
FAU - Medina, Laura M Palma
AU  - Medina LMP
AD  - Center for Infectious Medicine, Karolinska Institutet, Karolinska University 
      Hospital, Huddinge, Sweden.
FAU - Michalik, Stephan
AU  - Michalik S
AD  - Department of Functional Genomics, University Medicine Greifswald, Greifswald, 
      Germany.
FAU - Volker, Uwe
AU  - Volker U
AD  - Department of Functional Genomics, University Medicine Greifswald, Greifswald, 
      Germany.
FAU - Svensson, Mattias
AU  - Svensson M
AD  - Center for Infectious Medicine, Karolinska Institutet, Karolinska University 
      Hospital, Huddinge, Sweden.
FAU - Norrby-Teglund, Anna
AU  - Norrby-Teglund A
AD  - Center for Infectious Medicine, Karolinska Institutet, Karolinska University 
      Hospital, Huddinge, Sweden.
FAU - Hoff, Katharina J
AU  - Hoff KJ
AD  - Institute of Mathematics and Computer Science, University of Greifswald, 
      Greifswald, Germany.
FAU - Lammers, Michael
AU  - Lammers M
AD  - Department of Synthetic and Structural Biochemistry, Institute of Biochemistry, 
      University of Greifswald, Greifswald, Germany.
FAU - Siemens, Nikolai
AU  - Siemens N
AUID- ORCID: 0000-0003-0657-3822
AD  - Department of Molecular Genetics and Infection Biology, University of Greifswald, 
      Greifswald, Germany. nikolai.siemens@uni-greifswald.de.
LA  - eng
GR  - 492903360/Deutsche Forschungsgemeinschaft/
GR  - 503880638/Deutsche Forschungsgemeinschaft/
GR  - 305340/European Union Seventh Framework Programme/
GR  - 90456/VINNOVA/
PT  - Journal Article
DEP - 20240227
PL  - England
TA  - J Biomed Sci
JT  - Journal of biomedical science
JID - 9421567
RN  - 0 (Bacterial Proteins)
RN  - EC 3.4.22.- (Caspase 8)
RN  - 0 (Cytokines)
RN  - 0 (Interleukin-18)
RN  - 0 (Interleukin-8)
RN  - 0 (IL18 protein, human)
SB  - IM
MH  - Humans
MH  - Bacterial Proteins/genetics/metabolism
MH  - Caspase 8
MH  - Cytokines/genetics
MH  - Interleukin-18/genetics
MH  - Interleukin-8
MH  - *Monocytes/metabolism
MH  - *Streptococcus pyogenes/genetics
PMC - PMC10898077
OTO - NOTNLM
OT  - CovR/S
OT  - Dendritic cells
OT  - Interleukin-18
OT  - Necrotizing soft tissue infection
OT  - Streptococcus pyogenes
COIS- All authors declare no competing interests.
EDAT- 2024/02/27 00:42
MHDA- 2024/02/28 06:43
PMCR- 2024/02/27
CRDT- 2024/02/26 23:37
PHST- 2023/12/12 00:00 [received]
PHST- 2024/02/20 00:00 [accepted]
PHST- 2024/02/28 06:43 [medline]
PHST- 2024/02/27 00:42 [pubmed]
PHST- 2024/02/26 23:37 [entrez]
PHST- 2024/02/27 00:00 [pmc-release]
AID - 10.1186/s12929-024-01014-9 [pii]
AID - 1014 [pii]
AID - 10.1186/s12929-024-01014-9 [doi]
PST - epublish
SO  - J Biomed Sci. 2024 Feb 27;31(1):26. doi: 10.1186/s12929-024-01014-9.