Can the Lyme Disease C6 Peptide Test Detect Borrelia miyamotoi?

The C6 peptide test is commonly used for Lyme disease.
Borrelia miyamotoi infection can also produce C6-reactive antibodies.
Additional testing may be needed to distinguish these tick-borne infections.

The C6 peptide ELISA is commonly used as part of Lyme disease antibody testing. Because the C6 peptide is derived from a conserved region of the VlsE protein, researchers have questioned whether antibodies produced during Borrelia miyamotoi infection may also react with this assay. Several studies suggest that C6 cross-reactivity is common in B. miyamotoi disease, although the test cannot distinguish Lyme disease from B. miyamotoi infection on its own.

Koetsveld and colleagues examined C6 reactivity in sera from both mice infected with Borrelia miyamotoi and from 46 patients with PCR-confirmed Borrelia miyamotoi disease (BMD). Their findings support the idea that the C6 peptide test used for Lyme disease may also identify antibody responses in patients with B. miyamotoi infection.

Can the Lyme disease C6 peptide test detect Borrelia miyamotoi?

The investigators found, “Cross-reactivity against the C6 peptide was confirmed in 21 out of 24 mice experimentally infected with B. miyamotoi.” A C6 antibody response was also present in 39 of the 46 PCR-confirmed patients.¹

Similarly, an earlier U.S. study found that “the C6 ELISA was also positive in the vast majority (>90%) of convalescent phase serum samples” obtained from patients with Borrelia miyamotoi disease.²

These findings suggest that a positive C6 peptide test does not necessarily indicate Lyme disease alone. A positive C6 result with a negative Lyme Western blot is one situation in which clinicians may consider additional testing for Borrelia miyamotoi.

Because B. miyamotoi is transmitted by the same Ixodes ticks that spread Lyme disease, clinicians should consider both infections when interpreting C6 test results. Because Lyme disease and Borrelia miyamotoi often occur in the same geographic regions and are transmitted by the same Ixodes ticks, distinguishing between the two infections may require additional laboratory testing.

Why can the Lyme disease C6 test react in Borrelia miyamotoi infection?

The C6 peptide detects antibodies directed against the VlsE protein used in Lyme disease testing. Although B. miyamotoi belongs to the relapsing fever group of Borrelia, it shares antigenic similarities with Lyme disease spirochetes that can result in antibody cross-reactivity. Recent reviews emphasize that this overlap can complicate interpretation of serologic testing and reinforce the importance of confirmatory laboratory evaluation when B. miyamotoi is suspected.

Because the C6 assay is not species-specific, it should be interpreted together with the patient’s symptoms, tick exposure, geographic risk, PCR testing when available, and additional serologic testing.

Koetsveld cautioned that because Borrelia miyamotoi disease and Lyme borreliosis occur in the same geographic regions, clinicians should use caution when relying solely on C6-reactivity testing.

“We propose that a positive C6 EIA with negative immunoblot, especially in patients with fever several weeks after a tick bite, warrants further testing for B. miyamotoi.”

Testing for antibodies to glycerophosphodiester phosphodiesterase (GlpQ), together with PCR when available, may help distinguish Borrelia miyamotoi from Lyme disease because GlpQ is present in relapsing fever borreliae but absent in Borrelia burgdorferi. Some laboratories report the result as a C6 ELISA or quantitative C6 antibody test, but the same limitations regarding cross-reactivity with Borrelia miyamotoi apply.

Koetsveld concluded, “Our results demonstrate that cross-reactive antibodies against the C6 peptide regularly occur in patients with Borrelia miyamotoi disease,” with as many as 90% (95% CI 68.3–98.8) of patients showing C6 reactivity in samples collected 10 to 19 days after symptom onset.

Editor’s note: It is also possible that some patients had concurrent Lyme disease that was not confirmed by standard two-tier testing. Because Borrelia miyamotoi and Borrelia burgdorferi are transmitted by the same Ixodes ticks, coinfection can occur. In this study, 10 of the 39 C6-reactive patients also had Western blot findings consistent with Lyme disease, highlighting the diagnostic complexity when these infections overlap.

Frequently Asked Questions

What is the Lyme disease C6 peptide test?

The C6 peptide ELISA is a blood test commonly used in Lyme disease antibody testing. It detects antibodies against the C6 region of the VlsE protein but does not identify which Borrelia species triggered the immune response.

Can the Lyme disease C6 test detect Borrelia miyamotoi?

Yes. Studies have shown that many patients with PCR-confirmed Borrelia miyamotoi disease develop antibodies that react with the Lyme disease C6 peptide test. However, the test cannot distinguish Lyme disease from B. miyamotoi infection.

Should a positive C6 test with a negative Western blot prompt additional testing?

It may. In patients with compatible symptoms, especially fever following a tick bite, researchers recommend considering additional evaluation for Borrelia miyamotoi, including PCR or GlpQ-based testing when available.

Can Lyme disease and Borrelia miyamotoi infection occur together?

Yes. Because both infections are transmitted by the same Ixodes ticks, coinfection is possible. Clinical findings and laboratory results should be interpreted together when evaluating patients from endemic regions.

Clinical Takeaway

A positive Lyme disease C6 peptide test may reflect either Lyme disease or Borrelia miyamotoi infection because antibodies to both organisms can react with the assay.

When a patient has compatible symptoms, especially fever after a tick bite, a positive C6 test with a negative Lyme immunoblot should prompt consideration of Borrelia miyamotoi and appropriate confirmatory testing rather than being dismissed as a false-positive result.

Related Articles

Learn more about the diagnosis and testing of Borrelia miyamotoi and Lyme disease:

How accurate are Lyme disease tests?
The best antibiotics to treat Borrelia miyamotoi?
Doctors face challenges in diagnosing Borrelia miyamotoi
Blood smear not reliable in diagnosing Borrelia miyamotoi

“`

---

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