Bacterial Quorum-Sensing Peptides as Immune Modulators Present in Systemic Circulation

Quorum-sensing peptides (QSPs) are bacterial peptides traditionally considered only as inter-bacterial communication molecules. Recently, their involvement in microbiome–host interactions influencing host diseases such as cancer and sarcopenia were explored. However, it is still unknown to what extent these peptides have the potential to modulate the immune system. In this proof-of-concept study, we screened 89 QSPs for their potential to induce IL-6 and TNFα in murine splenocytes and J774 macrophages. Confirmatory experiments on the positive screening-hits were conducted using murine splenocytes and human PBMCs of different ages. Finally, to investigate the biological relevance of immunomodulatory QSPs, we analysed plasma in a human cohort for the presence of the immunomodulatory QSP Q010. To do this, we used a newly developed UHPLC-MS/MS method. Our findings indicated that specific QSPs activate immune cells in vitro, with Q007, Q010, Q017 and Q212 being the top four screening hits. Q007 and Q010 were affirmed in subsequent confirmatory experiments using murine splenocytes and human PBMCs. Finally, Q010 was detected in human plasma, demonstrating for the first time the presence of an immunomodulatory QSP in human circulation. In conclusion, our data are the first evidence indicating the potential of biologically relevant quorum-sensing peptides to modulate the immune system.

[1]  M. De Mey,et al.  The bacterial quorum sensing peptide iAM373 is a novel inducer of sarcopenia , 2022, Clinical and translational medicine.

[2]  D. Laukens,et al.  The quorum sensing peptide EntF* promotes colorectal cancer metastasis in mice: a new factor in the host-microbiome interaction , 2022, BMC Biology.

[3]  C. Carter A "Gut Feeling" to Create a 10th Hallmark of Aging. , 2021, The journals of gerontology. Series A, Biological sciences and medical sciences.

[4]  Kelly B. Menees,et al.  Sex- and age‐dependent alterations of splenic immune cell profile and NK cell phenotypes and function in C57BL/6J mice , 2021, Immunity & ageing : I & A.

[5]  Elham Mousavinezhad Sarasia,et al.  A Global Review on Short Peptides: Frontiers and Perspectives , 2021, Molecules.

[6]  Christel Claes,et al.  PapRIV, a BV-2 microglial cell activating quorum sensing peptide , 2020, Scientific Reports.

[7]  P. Wilson,et al.  Association of Statin Use With All-Cause and Cardiovascular Mortality in US Veterans 75 Years and Older. , 2020, JAMA.

[8]  M. Pencina,et al.  Overlap Weighting: A Propensity Score Method That Mimics Attributes of a Randomized Clinical Trial. , 2020, JAMA.

[9]  A. Cruz-Jentoft,et al.  Biomarkers of sarcopenia in very old patients with hip fracture , 2020, Journal of cachexia, sarcopenia and muscle.

[10]  N. Debunne,et al.  A LC-MS compatible anti-adsorption diluent for peptide analysis. , 2019, Analytical chemistry.

[11]  N. Van Den Noortgate,et al.  Quorum sensing molecules as a novel microbial factor impacting muscle cells. , 2019, Biochimica et biophysica acta. Molecular basis of disease.

[12]  B. Bhushan,et al.  Role of microbes, metabolites and effector compounds in host–microbiota interaction: a pharmacological outlook , 2019, Environmental Chemistry Letters.

[13]  S. Snyder,et al.  A Connective Tissue Mast-Cell-Specific Receptor Detects Bacterial Quorum-Sensing Molecules and Mediates Antibacterial Immunity. , 2019, Cell host & microbe.

[14]  Toshio Tanaka,et al.  Targeting Interleukin-6 Signaling in Clinic. , 2019, Immunity.

[15]  S. Ponnazhagan,et al.  Characterization of immune cell subtypes in three commonly used mouse strains reveals gender and strain-specific variations , 2018, Laboratory Investigation.

[16]  J. Nielandt,et al.  Disbiome database: linking the microbiome to disease , 2018, BMC Microbiology.

[17]  K. Audenaert,et al.  Screening of quorum sensing peptides for biological effects in neuronal cells , 2018, Peptides.

[18]  Evelien Wynendaele,et al.  Peptides as Quorum Sensing Molecules: Measurement Techniques and Obtained Levels In vitro and In vivo , 2017, Front. Neurosci..

[19]  J. Latcham,et al.  Does age matter? The impact of rodent age on study outcomes , 2016, Laboratory animals.

[20]  K. Peremans,et al.  Quorum Sensing Peptides Selectively Penetrate the Blood-Brain Barrier , 2015, PloS one.

[21]  Evelien Wynendaele,et al.  Exploring the chemical space of quorum sensing peptides , 2015, Biopolymers.

[22]  K. Peremans,et al.  Crosstalk between the microbiome and cancer cells by quorum sensing peptides , 2015, Peptides.

[23]  James A. Nathan,et al.  Muscle wasting in disease: molecular mechanisms and promising therapies , 2014, Nature Reviews Drug Discovery.

[24]  B. Spiegeleer,et al.  Human skin kinetics of cyclic depsipeptide mycotoxins , 2014 .

[25]  M. Uyttendaele,et al.  Diversity of Bacillus cereus group strains is reflected in their broad range of pathogenicity and diverse ecological lifestyles. , 2013, FEMS microbiology ecology.

[26]  Evelien Wynendaele,et al.  Quorumpeps database: chemical space, microbial origin and functionality of quorum sensing peptides , 2012, Nucleic Acids Res..

[27]  R. Grenha,et al.  Structural basis for the activation mechanism of the PlcR virulence regulator by the quorum-sensing signal peptide PapR , 2012, Proceedings of the National Academy of Sciences.

[28]  Michael Prummer,et al.  Hypothesis Testing in High-Throughput Screening for Drug Discovery , 2012, Journal of biomolecular screening.

[29]  M. Otto Staphylococcus colonization of the skin and antimicrobial peptides. , 2010, Expert review of dermatology.

[30]  S. Arold,et al.  Molecular basis for group-specific activation of the virulence regulator PlcR by PapR heptapeptides , 2008, Nucleic acids research.

[31]  N. Filipov,et al.  Differential effects of age on circulating and splenic leukocyte populations in C57BL/6 and BALB/c male mice , 2008, Immunity & Ageing.

[32]  P. Artursson,et al.  Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers , 2007, Nature Protocols.

[33]  A. Bitler,et al.  RNAIII inhibiting peptide (RIP), a global inhibitor of Staphylococcus aureus pathogenesis: structure and function analysis , 2001, Peptides.

[34]  T. Muir,et al.  Activation and Inhibition of the Staphylococcal AGR System , 2000 .

[35]  F. Santolaria,et al.  Cytokine levels (IL-6 and IFN-gamma), acute phase response and nutritional status as prognostic factors in lung cancer. , 1999, Cytokine.

[36]  S. Akira,et al.  Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF) , 1990, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[37]  W. Marasco,et al.  Characterization of a class of nonformylated Enterococcus faecalis-derived neutrophil chemotactic peptides: the sex pheromones. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[38]  T. Hugli,et al.  Characterization of the human neutrophil response to sex pheromones from Streptococcus faecalis. , 1989, The American journal of pathology.

[39]  E. Suchman,et al.  The American Soldier: Adjustment During Army Life. , 1949 .