Extracellular vesicles from methicillin resistant Staphylococcus aureus stimulate proinflammatory cytokine production and trigger IgE-mediated hypersensitivity

Emerg Microbes Infect. 2021 Dec;10(1):2000-2009. doi: 10.1080/22221751.2021.1991239.


Extracellular vesicles (EVs) released from bacteria are enclosed particles carrying biological active molecules. They have been shown to play a role in bacterial communications and delivery of virulence factors to the host cells. Staphylococcus aureus is an opportunistic pathogen causing a variety of infections ranging from impetigo to septicaemia. The EVs released from S. aureus have a high potential to be used for vaccine development against S. aureus infections. However, it is important to clearly understand the impact of SaEVs on the host's immune response. Our study demonstrated that purified EVs from a clinical isolated methicillin-resistant S. aureus (SaEVs) significantly stimulated proinflammatory cytokine production in mouse immune cells and induced host cell death. An impairment of cytokine production in the Toll-like receptor (TLR)-silenced macrophages suggested that SaEVs stimulate proinflammatory response via TLRs 2, 4 and 9. In mouse infection model, the results demonstrated that SaEV immunization did not provide protective effect. In contrast, all SaEV-immunized mice died within Day 1 after methicillin-resistant S. aureus (MRSA) infection. After MRSA infection for 3 h, the production of IL-6, TNF-α and IL-17 in the spleen of SaEV-immunized mice was significantly higher than that of control mice. On Day 5 after the second immunization, total IgE in the serum was significantly enhanced, and a high titre of Th2-related cytokines was remarkably induced after ex vivo stimulation of the spleen cells with SaEVs. These results suggested that MRSA-derived EVs act as an immunostimulant that induces inflammatory response and IgE-mediated hypersensitivity after MRSA infection.

Keywords: IgE-mediated hypersensitivity; Staphylococcus aureus; inflammatory stimulation; membrane vesicles; methicillin resistance.

MeSH terms

  • Animals
  • Cytokines / genetics
  • Cytokines / immunology*
  • Extracellular Vesicles / genetics
  • Extracellular Vesicles / immunology*
  • Female
  • Humans
  • Hypersensitivity, Immediate / etiology*
  • Hypersensitivity, Immediate / genetics
  • Hypersensitivity, Immediate / immunology*
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Macrophages / immunology
  • Methicillin-Resistant Staphylococcus aureus / genetics
  • Methicillin-Resistant Staphylococcus aureus / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Staphylococcal Infections / complications*
  • Staphylococcal Infections / immunology
  • Staphylococcal Infections / microbiology
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / immunology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology


  • Cytokines
  • Interleukin-17
  • Interleukin-6
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha

Grant support

This study was supported by the Japan Society for the Promotion of Science [grant number 17K08819] and a grant from the 35th Karoji Memorial Fund for Medical Research in Hirosaki University [grant A to Asano K., 2016].