EGFR transactivation contributes to neuroinflammation in Streptococcus suis meningitis
Related Experiment Video
Updated: Mar 13, 2026
Intracranial Subarachnoidal Route of Infection for Investigating Roles of Streptococcus suis Biofilms in Meningitis in a Mouse Infection Model
Published on: July 1, 2018
Xiao-Pei Yang1,2, Ji-Yang Fu1,2, Rui-Cheng Yang1,2
1State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
Background:
Streptococcus suis serotype 2 (SS2) is an important zoonotic bacterial pathogen in both humans and animals, which can cause high morbidity and mortality. Meningitis is one of the major clinical manifestations of SS2 infection. However, the specific process of SS2 meningitis and its molecular mechanisms remain unclear. Epidermal growth factor receptor (EGFR) has been reported to initiate transduction of intracellular signals and regulate host inflammatory responses. Whether and how EGFR contributes to the development of S. suis meningitis are currently unknown.
Methods:
The tyrosine phosphorylation of cellular proteins, the transactivation of EGFR, as well as its dimerization, and the associated signal transduction pathways were investigated by immunoprecipitation and western blotting. Real-time quantitative PCR was used to investigate the transcriptional level of the ErbB family members, EGFR-related ligands, cytokines, and chemokines. The secretion of cytokines and chemokines in the serum and brain were detected by Q-Plex™ Chemiluminescent ELISA.
Results:
We found an important role of EGFR in SS2 strain SC19-induced meningitis. SC19 increasingly adhered to human brain microvascular endothelial cells (hBMEC) and caused inflammatory lesions in the brain tissues, with significant induction and secretion of proinflammatory cytokines and chemokines in the serum and brains. SC19 infection of hBMEC induced tyrosine phosphorylation of cellular EGFR in a ligand-dependent manner involving the EGF-like ligand HB-EGF, amphiregulin (AREG), and epiregulin (EREG) and led to heterodimerization of EGFR/ErbB3. The EGFR transactivation did not participate in SS2 strain SC19 adhesion of hBMEC, as well as in bacterial colonization in vivo. However, its transactivation contributed to the bacterial-induced neuroinflammation, via triggering the MAPK-ERK1/2 and NF-κB signaling pathways in hBMEC that promote the production of proinflammatory cytokines and chemokines.
Conclusions:
We investigated for the first time the tyrosine phosphorylation of cellular proteins in response to SS2 strain SC19 infection of hBMEC and demonstrated the contribution of EGFR to SS2-induced neuroinflammation. These observations propose a novel mechanism involving EGFR in SS2-mediated inflammatory responses in the brain, and therefore, EGFR might be an important host target for further investigation and prevention of neuroinflammation caused by SS2 strains.
Insights
Streptococcus suis serotype 2 (SS2) causes meningitis by activating the epidermal growth factor receptor (EGFR). This activation promotes neuroinflammation through specific signaling pathways, highlighting EGFR as a potential therapeutic target.
Area of Science:
- Neuroscience
- Infectious Diseases
- Cell Biology
Background:
- Streptococcus suis serotype 2 (SS2) is a zoonotic pathogen causing significant morbidity and mortality, with meningitis being a key clinical manifestation.
- The precise molecular mechanisms underlying SS2 meningitis remain largely unelucidated.
- The role of Epidermal Growth Factor Receptor (EGFR) in initiating intracellular signals and regulating inflammatory responses suggests a potential involvement in SS2 pathogenesis.
Purpose of the Study:
- To investigate the role of EGFR in SS2-induced meningitis.
- To elucidate the molecular mechanisms by which SS2 interacts with host cells, specifically focusing on EGFR signaling.
- To determine if EGFR activation contributes to the neuroinflammatory processes associated with SS2 infection.
Main Methods:
- Immunoprecipitation and western blotting were employed to analyze protein tyrosine phosphorylation, EGFR transactivation, dimerization, and associated signaling pathways.
- Quantitative PCR was utilized to assess the transcriptional levels of ErbB family members, EGFR ligands, cytokines, and chemokines.
- Cytokine and chemokine secretion in serum and brain tissues was quantified using Q-Plex™ Chemiluminescent ELISA.
Main Results:
- SS2 strain SC19 adhered to human brain microvascular endothelial cells (hBMEC) and induced brain inflammatory lesions with elevated proinflammatory cytokines and chemokines.
- SC19 infection triggered EGFR tyrosine phosphorylation in hBMEC in a ligand-dependent manner, involving HB-EGF, amphiregulin (AREG), and epiregulin (EREG), leading to EGFR/ErbB3 heterodimerization.
- EGFR transactivation was not essential for bacterial adhesion or colonization but was crucial for SS2-induced neuroinflammation by activating MAPK-ERK1/2 and NF-κB pathways, subsequently promoting cytokine and chemokine production.
Conclusions:
- This study demonstrates a significant role for EGFR in SS2-induced meningitis, specifically in promoting neuroinflammation.
- A novel mechanism involving EGFR-mediated inflammatory responses in the brain during SS2 infection is proposed.
- EGFR emerges as a potential host-targeted therapeutic candidate for preventing or treating SS2-related neuroinflammation.
