Can the C6 Peptide Test Detect Borrelia miyamotoi?

The C6 peptide Lyme test may cross-react with Borrelia miyamotoi.
Negative Western blot results can complicate diagnosis.
Additional testing may be needed after tick exposure and fever.

A positive C6 Lyme disease test does not always confirm classic Lyme disease.

Researchers have found that the C6 peptide test may also react in patients infected with Borrelia miyamotoi, a relapsing fever Borrelia transmitted by the same ticks that spread Lyme disease.

This overlap may complicate diagnosis, particularly when patients have fever, fatigue, headaches, or persistent symptoms after a tick bite.

For a broader overview of Lyme-related symptoms and testing challenges, visit our Lyme Disease Symptoms Guide.

Researchers Studied C6 Reactivity in Borrelia miyamotoi

Koetsveld and colleagues examined C6 reactivity in mice infected with Borrelia miyamotoi and in 46 patients with PCR-confirmed Borrelia miyamotoi disease (BMD).

Their findings suggest that the C6 peptide test commonly used for Lyme disease may also react in patients with Borrelia miyamotoi infection.

The investigators found:

• 21 of 24 experimentally infected mice showed cross-reactivity to the C6 peptide
• 39 of 46 patients demonstrated a C6 antibody response
• More than 90% of convalescent samples in another study were C6-positive

Because Borrelia miyamotoi and Lyme disease occur in the same geographic regions, interpreting these results can become difficult.

Why a Positive C6 Test May Be Confusing

The C6 peptide assay is widely used in Lyme disease testing because it detects antibodies directed against a conserved region of the VlsE protein.

However, cross-reactive antibodies may also develop in Borrelia miyamotoi infection.

That means some patients may have:

• A positive C6 ELISA
• A negative Lyme immunoblot
• Persistent symptoms after a tick bite
• Fever or relapsing illness patterns

In these situations, relying solely on standard Lyme testing may overlook Borrelia miyamotoi disease.

Learn more about Lyme Disease Misdiagnosis.

When Additional Testing May Be Helpful

Koetsveld and colleagues proposed that patients with a positive C6 assay but negative Lyme immunoblot may require additional evaluation for Borrelia miyamotoi.

The authors specifically noted concern for patients presenting with fever several weeks after a tick bite.

Testing for the glycerophosphodiester phosphodiesterase (GlpQ) gene may help identify Borrelia miyamotoi infection because GlpQ is not present in Borrelia burgdorferi, the primary Lyme disease bacterium.

Diagnostic uncertainty may still persist because some patients could potentially have concurrent seronegative Lyme disease along with Borrelia miyamotoi.

In the study, 10 of the 39 patients reactive to the C6 peptide also demonstrated Lyme Western blot reactivity.

Symptoms May Overlap With Lyme Disease

Borrelia miyamotoi infection may resemble Lyme disease in some patients.

Symptoms can include:

• Fever
• Headaches
• Fatigue
• Body aches
• Chills
• Relapsing symptom patterns

Because the illness is less widely recognized, diagnosis may be delayed or missed entirely.

Learn more about Lyme Coinfections.

Diagnostic Challenges Continue to Evolve

As clinicians recognize more tick-borne infections beyond classic Lyme disease, diagnostic interpretation becomes increasingly complex.

Patients with persistent symptoms after tick exposure may require broader clinical consideration when standard Lyme testing does not fully explain the presentation.

Emerging infections such as Borrelia miyamotoi continue to challenge traditional testing algorithms.

Learn more about Doctors Face Challenges in Diagnosing Borrelia miyamotoi.

Frequently Asked Questions

What is the C6 peptide test?

The C6 peptide test is a Lyme disease antibody assay that detects immune responses to the VlsE protein of Borrelia burgdorferi.

Can Borrelia miyamotoi cause a positive C6 test?

Yes. Studies have shown that patients infected with Borrelia miyamotoi may develop cross-reactive antibodies that produce a positive C6 result.

Why might the Western blot be negative?

Because Borrelia miyamotoi differs from classic Lyme disease Borrelia, standard Lyme immunoblots may not detect the infection.

What is GlpQ testing?

GlpQ testing looks for antibodies or genetic markers associated with Borrelia miyamotoi, which lacks the VlsE protein found in Lyme disease Borrelia.

Can patients have both Lyme disease and Borrelia miyamotoi?

Possibly. Coinfection may occur because both infections are transmitted by the same tick species.

Clinical Takeaway

A positive C6 Lyme disease assay with a negative Western blot may not always represent classic Lyme disease alone.

Cross-reactivity with Borrelia miyamotoi may complicate interpretation, particularly in patients with fever, relapsing symptoms, or persistent illness after tick exposure.

Related Articles

Review treatment considerations in The Best Antibiotics to Treat Borrelia miyamotoi?.
Learn more about testing limitations in Blood Smear Not Reliable in Diagnosing Borrelia miyamotoi.
Learn more about delayed recognition in Delayed Lyme Disease Diagnosis.
Review prevention strategies in Prevention of Lyme Disease.
Learn more about persistent symptoms in Post-Treatment Lyme Disease Syndrome.

References

1. Koetsveld J, Platonov AE, Kuleshov K, et al. Borrelia miyamotoi infection leads to cross-reactive antibodies to the C6 peptide in mice and men. Clin Microbiol Infect. 2019;25(10):1304.e1-1304.e6.
2. Molloy PJ, Weeks KE, Todd B, Wormser GP. Seroreactivity to the C6 peptide in Borrelia miyamotoi infections occurring in the northeastern United States. Clin Infect Dis. 2018;66(9):1407-1410.

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Dr. Daniel Cameron, MD, MPH
Lyme disease clinician with over 30 years of experience and past president of ILADS.

Symptoms • Testing • Coinfections • Recovery • Pediatric • Prevention