Brain Inflammation: Finding Evidence for TMPRSS2, Encephalitis, and Meningitis

Introduction

Encephalitis and meningitis are serious neurological conditions characterized by inflammation—encephalitis involves the brain tissue itself, while meningitis affects the protective membranes surrounding the brain and spinal cord (the meninges). When both the brain and meninges are inflamed, the condition is referred to as meningoencephalitis.

Key Differences

Meningitis: Inflammation of the meninges, often caused by bacterial infections but also viral or fungal agents.
Encephalitis: Inflammation of brain tissue, most commonly due to viral infections, though bacterial and autoimmune causes also exist.

Cerebrospinal Fluid (CSF) and Brain Swelling

While encephalitis is not the most common cause of cerebrospinal fluid (CSF) obstruction, it can lead to brain edema (swelling), particularly around the ventricles. This swelling may compress the ventricular system or subarachnoid spaces, restricting CSF flow and potentially resulting in elevated intracranial pressure.

Emerging Research: TMPRSS2 in Viral Encephalitis

Recent studies have explored the role of TMPRSS2 (transmembrane serine protease 2) in facilitating viral entry into host cells. This protein has been implicated in infections caused by SARS-CoV-2 and Herpes Simplex Virus (HSV)—both of which can lead to encephalitis.

Understanding the involvement of TMPRSS2 in brain inflammation is crucial for improving diagnostic accuracy and developing targeted treatments for viral encephalitis and possibly meningitis.

Investigative Techniques

To examine the role of TMPRSS2 in encephalitis and meningitis, researchers use a range of biochemical, molecular, and neuroimaging techniques. These include:

Immunohistochemistry to detect TMPRSS2 expression in brain tissues
PCR and Western blotting to assess gene and protein levels
Animal models to study disease progression and TMPRSS2 involvement
MRI and CT scans to visualize brain inflammation and structural changes

These approaches help clarify TMPRSS2’s function in neuroinflammation and guide the development of potential therapeutic interventions.

1. Cerebrospinal Fluid (CSF) Analysis

Why CSF?

Since encephalitis and meningitis involve brain inflammation, cerebrospinal fluid (CSF) is an essential diagnostic tool for detecting biomarkers of infection, inflammation, and viral/bacterial presence.

Tests to Detect TMPRSS2 & Related Markers in CSF:

Western Blotting – Detects TMPRSS2 protein and its fragments in CSF. This method was used in the study investigating TMPRSS2 in SARS-CoV-2-related encephalitis.
ELISA (Enzyme-Linked Immunosorbent Assay) – Measures TMPRSS2, ACE2, and other inflammatory markers in CSF.
PCR (Polymerase Chain Reaction) – Identifies viral or bacterial DNA/RNA in CSF, including Herpes Simplex Virus (HSV) for encephalitis and Neisseria meningitidis for bacterial meningitis.

2. Brain Tissue & Cellular Studies

Why?

To determine how TMPRSS2 is expressed in the brain during encephalitis or meningitis, researchers analyze brain tissue samples from biopsies or post-mortem studies.

Methods:

Immunohistochemistry (IHC) – Stains TMPRSS2 in brain tissue to visualize its expression in neurons, glial cells, and endothelial cells.
RT-qPCR (Real-Time Quantitative PCR) – Measures TMPRSS2 mRNA levels in brain tissue, helping quantify gene expression changes during infection.
Single-Cell RNA Sequencing – Identifies which specific brain cells express TMPRSS2 and how its expression changes during infection.

3. Blood Biomarker Testing

Why?

Some inflammatory and viral markers that are present in CSF can also be detected in the blood, providing a less invasive way to study brain inflammation.

Tests:

Serum TMPRSS2 Levels – If CSF collection is not feasible, blood samples can provide indirect evidence of TMPRSS2’s involvement in infection.
Cytokine Panel (IL-6, TNF-α, IFN-γ, etc.) – Measures inflammation-related proteins in blood, which can indicate viral encephalitis or bacterial meningitis.

4. Imaging for Encephalitis & Meningitis Diagnosis

Why?

To confirm brain inflammation and rule out other potential causes such as stroke or tumors.

Techniques:

MRI (Magnetic Resonance Imaging) – Identifies inflammation, brain swelling, or damage commonly seen in encephalitis and meningitis.
CT Scan (Computed Tomography) – Used in emergency settings to detect brain swelling, hemorrhage, or structural abnormalities.

5. In Vitro (Lab) Studies on TMPRSS2 & Brain Infections

Why?

To test how TMPRSS2 influences viral or bacterial infection in brain cells, researchers use laboratory-based models.

Approaches:

Human Brain Cell Cultures – Neurons or glial cells are infected with HSV or SARS-CoV-2 to determine if TMPRSS2 enhances viral entry.
CRISPR Knockout Studies – TMPRSS2 genes are removed from cells to examine whether its absence reduces infection severity.

6. Animal Models for Studying TMPRSS2 in Brain Infections

Why?

Animal models help researchers observe how TMPRSS2 contributes to brain infections in a living system.

Models Used:

Mouse Models of Encephalitis & Meningitis – Mice lacking TMPRSS2 (genetically modified) can help determine whether the protein is essential for viral or bacterial infection in the brain.
CSF & Brain Analysis in Infected Mice – Using the same CSF and tissue methods mentioned above to compare results between infected and healthy mice.

7. Clinical Studies & Autopsy Reports

Why?

Post-mortem analysis and clinical case studies help determine TMPRSS2’s role in human cases of encephalitis and meningitis.

Research Approaches:

CSF & Blood Testing in Hospitalized Patients – Helps identify biomarkers of TMPRSS2, ACE2, and inflammation in living patients.
Brain Tissue Analysis from Autopsy Cases – Compares TMPRSS2 levels in SARS-CoV-2-related encephalitis, HSV encephalitis, and bacterial meningitis.

Key Findings: TMPRSS2, ACE2, and Brain Inflammation

1. ACE2 in CSF & SARS-CoV-2 Brain Entry

ACE2, the primary entry receptor for SARS-CoV-2, was detected in different forms: full-length and cleaved fragments (80 kDa and 85 kDa).
In SARS-CoV-2 encephalitis (CoV-Enceph) patients:
- Increased full-length ACE2 and the 80 kDa fragment were found.
- The 85 kDa fragment was absent, unlike in non-COVID encephalitis cases.
Interpretation: This suggests that SARS-CoV-2 alters ACE2 cleavage, potentially aiding viral penetration into the brain.

2. TMPRSS2 in CSF & Brain Inflammation

TMPRSS2 is critical for viral activation (including SARS-CoV-2 & HSV).
In non-COVID encephalitis patients: TMPRSS2 levels were increased in CSF.
In SARS-CoV-2 encephalitis patients: TMPRSS2 levels remained unchanged, similar to healthy controls.
Interpretation: TMPRSS2 may be more linked to general brain inflammation rather than SARS-CoV-2 specifically.

Relevance to HSV Encephalitis & Meningitis

HSV encephalitis is a leading cause of viral brain inflammation and also relies on TMPRSS2 for entry into host cells.
Meningitis affects the brain’s protective membranes and might exhibit a different pattern of TMPRSS2 and ACE2 changes than encephalitis.
In non-COVID encephalitis (which may include HSV cases), TMPRSS2 was significantly elevated, suggesting a role in general viral neuroinflammation.

Future Research & Clinical Applications for TMPRSS2 in Brain Infections

Future Research Directions

1. TMPRSS2 in Viral vs. Bacterial Brain Infections

Why? While TMPRSS2 is known to aid viral infections, its role in bacterial meningitis remains unclear.
Approach: Compare TMPRSS2 levels in viral encephalitis (HSV, SARS-CoV-2) vs. bacterial meningitis (N. meningitidis, S. pneumoniae) using CSF, blood, and brain tissue.

2. TMPRSS2-Dependent vs. Independent Brain Infections

Why? Not all infections rely on TMPRSS2 for entry.
Approach: Use CRISPR gene editing to remove TMPRSS2 in brain cells and assess viral infectivity (HSV, SARS-CoV-2, Influenza, West Nile Virus).

3. TMPRSS2 Variants & Genetic Susceptibility to Encephalitis

Why? Genetic differences in TMPRSS2 may influence infection severity.
Approach: Study TMPRSS2 mutations in severe vs. mild encephalitis cases and analyze ethnic variations affecting susceptibility.

4. TMPRSS2 Inhibitors as Potential Treatments

Why? Blocking TMPRSS2 could reduce viral entry and inflammation.
Approach: Test TMPRSS2 inhibitors (camostat, nafamostat) in animal models and explore drug repurposing for encephalitis.

5. TMPRSS2 & ACE2 Crosstalk in Brain Infections

Why? TMPRSS2 regulates ACE2, a key receptor for SARS-CoV-2, potentially influencing brain inflammation.
Approach: Compare ACE2 vs. TMPRSS2 levels in different encephalitis cases and test whether ACE inhibitors alter outcomes.

Clinical Applications

1. TMPRSS2-Based Diagnostic Tests

Why? Changes in TMPRSS2 levels could serve as biomarkers for encephalitis.
Application: Develop CSF & blood tests (ELISA, PCR) to detect TMPRSS2-related infections early.

2. Personalized Treatment for Encephalitis

Why? TMPRSS2 levels might predict disease severity & treatment response.
Application: Identify high-risk patients and tailor antiviral therapies accordingly.

3. TMPRSS2 Inhibitor Trials for Brain Infections

Why? TMPRSS2 inhibitors have been studied for COVID-19, but not for brain infections.
Application: Conduct clinical trials to test TMPRSS2 inhibitors in HSV encephalitis or COVID-19 neurological complications.

4. TMPRSS2’s Role in Neuroprotection

Why? If linked to neuroinflammation, modulating TMPRSS2 could prevent long-term brain damage.
Application: Investigate whether TMPRSS2 suppression prevents cognitive decline in post-encephalitis patients.

5. Preventive Screening for At-Risk Populations

Why? High TMPRSS2 expression may indicate increased infection risk.
Application: Develop genetic screening tools and explore TMPRSS2-blocking therapies for at-risk individuals.

Final Thoughts

Could brain inflammation meet the SOFA score for sepsis criteria?

TMPRSS2 research holds huge potential for better diagnostics, targeted treatments, and preventive strategies. Future efforts should:
Clarify TMPRSS2’s role in bacterial vs. viral brain infections
Test TMPRSS2 inhibitors for neuroprotection & viral suppression
Identify biomarkers for early encephalitis detection
Develop personalized medicine approaches based on TMPRSS2 levels

Finding Clinical Trials

European Union Clinical Trials Register – Check TMPRSS2-related trials in Europe.
PubMed – Search for recent studies on TMPRSS2 in neurological infections.

Finding Research Collaborations

Universities & Medical Centers – Institutions like Harvard, Oxford, or NIH often conduct TMPRSS2 research.
Biotech & Pharma Companies – Companies like Apeiron Biologics and Takeda are working on TMPRSS2 inhibitors.
Professional Networks – Use LinkedIn, ResearchGate, or Google Scholar to connect with experts in neurology and infectious diseases.

Conclusion

To test for TMPRSS2’s role in encephalitis and meningitis, the most effective approach involves CSF analysis, brain imaging, and molecular testing. Further research using cell cultures, animal models, and autopsy samples can clarify how TMPRSS2 contributes to brain infections.

Understanding these mechanisms can improve diagnostic tools and lead to targeted treatments for encephalitis, meningitis, and other neurological complications of viral infections like SARS-CoV-2 and HSV.

Reference:

Herpes Simplex Virus and Its Impact on the Brain: Understanding HHV-6 Encephalitis
https://swaresearch.blogspot.com/2025/05/herpes-simplex-virus-and-its-impact-on.html

Detection of toxoplasma tachyzoites in the cerebrospinal fluid of a COVID-19 positive SLE patient: a case study https://link.springer.com/article/10.1186/s12879-025-10630-1