Scientists Detect “Ghost” Proteins That Could Explain Long COVID

Scientists have uncovered viral protein fragments lingering in the blood of long COVID patients, potentially offering the first measurable biomarker for the condition.

These hidden traces suggest the virus may persist in the body long after infection, raising new questions about lingering reservoirs and how they might drive chronic symptoms.

Discovery of a Potential Long COVID Biomarker

Scientists at the Translational Genomics Research Institute (TGen), part of City of Hope, along with colleagues at the Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, have discovered what may be a biomarker for long COVID.

If other research groups can validate these findings, this marker could become the first measurable tool for diagnosing long COVID. At present, doctors rely solely on patient-reported symptoms that appear weeks or months after infection with SARS-CoV-2 to make a diagnosis.

“If a patient arrives in clinic and they relate the persistence of typical signs and symptoms of long COVID, 12 weeks or more after COVID -19 infection, I give them a presumptive diagnosis, but I don’t have any blood tests or biomarkers to confirm this diagnosis,” said William Stringer, M.D., a Lundquist Institute investigator and senior author on the study.

Tracking the Virus Through Tiny Cellular Packages

The findings, published in the journal Infection, describe the presence of SARS-CoV-2 protein fragments inside extracellular vesicles (EVs). EVs are small, naturally produced particles that allow cells to transfer proteins, metabolites, and other biological materials. For the study, the team analyzed 56 blood samples taken from 14 patients who participated in a 12-week aerobic exercise program as part of a clinical trial led by Stringer.

Within these samples, the researchers identified 65 unique protein fragments from SARS-CoV-2. These fragments originated from the virus’s Pp1ab protein, an RNA Replicase enzyme critical for viral replication and the production of new viral particles. Importantly, this protein is unique to SARS-CoV-2 and does not exist in healthy human cells, noted Asghar Abbasi, Ph.D., the study’s first author and investigator at the Lundquist Institute.

Evidence of Lingering Viral Reservoirs

Significantly, the researchers found that these viral peptides were demonstrated in each subject, but not each blood draw, in the EVs of Long COVID patients and were not detected in a separate control group of pre-pandemic EV samples.

These findings add to growing evidence that suggests that SARS-CoV-2 may persist in certain body tissues long after the initial infection. Some groups hypothesize these lingering viral reservoirs could play a role in Long COVID. How the virus reaches tissues without its usual entry points—such as the brain—remains an open question, and may be related to EV particles.

“We thought that maybe if the virus is circulating or moving in the body, we should try to see if EVs are carrying those viral fragments,” Abbasi explained.

This idea became part of an ongoing clinical trial led by Drs. Abbasi and Stringer, which was already studying EVs to see if they are linked to changes in immune function related to exercise and post-exertional malaise, a common symptom in these patients.

Questions About Timing and Triggers

“While promising, the molecular signal of the viral peptides within the study samples was observed to be subtle and not consistently detected at every blood collection time point,” said Patrick Pirrotte, Ph.D., associate professor at TGen, director of the Integrated Mass Spectrometry Shared Resource at TGen and City of Hope, and co-senior author of the study. “There’s still a lot to unpack that we don’t know at this point.”

For instance, he added, the researchers don’t know if the exercise itself drives the expression of viral programs intracellularly, and then those viral programs result in proteins that are going to be shed, or if there is a permanent reservoir in those cells, and it’s just a matter of detecting it at a certain time point. Although the identified peptides originated from one of the virus’ largest proteins, the researchers did not detect other comparably large proteins indicative of active viral replication. It’s possible that the peptides contained in the EVs are just molecular “trash” leftover after the formation of new viral proteins.

“We haven’t run [our tests] on people without long COVID symptoms who are currently, or who were, infected with COVID,” said Stringer. “This raises the question: is this just continuing to take out the trash from the COVID infected cell or is this really ongoing replication someplace? I think that’s the mechanistic issue that needs to be resolved in future studies.”

Reference: “Possible long COVID biomarker: identification of SARC-CoV-2 related protein(s) in Serum Extracellular Vesicles” by Asghar Abbasi, Ritin Sharma, Nathaniel Hansen, Patrick Pirrotte and William W. Stringer, 21 July 2025, Infection.
DOI: 10.1007/s15010-025-02612-x

The Pulmonary Education and Research Foundation (PERF) and the UCLA David Geffen School of Medicine (DGSoM)-Ventura County Community Foundation (VCCF) funded this research.

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