A recent study published in Nature Microbiology has shed new light on how malaria parasites have extraordinary survival strategies and can persist in the human body for years without causing symptoms – much like we see with Lyme disease. Researchers from Weill Cornell Medicine, including senior author Dr. Kirk Deitsch, used single-cell RNA sequencing to uncover that Plasmodium falciparum can evade the immune system by silencing its var gene family, responsible for producing sticky surface proteins that normally make infected red blood cells visible to the host immune system.

📚 Citation: Wang J, Zou Z, Park H, et al. Plasmodium falciparum maintains long-term asymptomatic infection by silencing var gene expression. Nat Microbiol. 2025; https://doi.org/10.1038/s41564-025-01631-8

This discovery helps explain how individuals may unknowingly carry infectious parasites for years — and why some cases of transfusion-transmitted malaria have occurred long after the donor left an endemic area.

But what does this have to do with Lyme disease?

More than we think.

Lyme Disease and the Persister Hypothesis

In my Lyme disease practice, I’ve seen something similar. Patients diagnosed and treated for Lyme disease — sometimes years ago — return with persistent fatigue, joint pain, brain fog, or autonomic symptoms. Some relapse months after treatment. Others never fully recover.

For many, there is no clear test confirming ongoing infection. And yet their symptoms continue, often in patterns that relapse and remit. Their illness is real — but invisible.

This is where the persister hypothesis comes in. Like malaria, Borrelia burgdorferi, the bacterium that causes Lyme disease, may survive in low-metabolic, immune-evasive forms that standard testing and antibiotics fail to detect or eliminate.

Just as P. falciparum alters gene expression to escape the immune system, Borrelia can:

• Switch surface proteins (e.g., VlsE antigenic variation),

• Enter a dormant or slow-replicating state,

• Evade immune detection in poorly surveilled tissue compartments.

“Invisible” Doesn’t Mean “Gone”

In the malaria study, Dr. Deitsch likened the parasite’s strategy to a criminal who runs out of disguises — and then puts on an invisibility cloak. The immune system can’t see it, but the parasite is still there, quietly circulating at low levels.

In Lyme disease, we often lack a reliable biomarker for persistence. But the symptoms — relapsing fatigue, neurocognitive dysfunction, or migrating joint pain — often provide the clinical signal. Just like malaria, absence of detection doesn’t mean absence of infection.

Borrelia burgdorferi may persist by reducing its metabolic activity, altering surface antigen expression, and tolerating antibiotics rather than resisting them. These adaptations make it harder to identify and harder to treat.

When patients are told “the Lyme is gone,” but they continue to deteriorate, we need to ask better questions — and look more closely at the biology.

Implications for Lyme Disease Research and Treatment

What malaria research teaches us is that pathogens can evolve sophisticated ways to evade both immunity and medicine — and that detecting them requires innovation, not assumption.

This has several implications for Lyme:

• Persistent symptoms should not be dismissed without considering continued infection.

• Diagnostic innovation is urgently needed — perhaps including single-cell analysis.

• Treatment may require longer or combination antibiotic courses, individualized to the patient’s biology.

• We must acknowledge that persistent Lyme is biologically plausible — and for some patients, clinically likely.

A Call for Clinical Curiosity

If we accept that Plasmodium can linger invisibly for decades, why is it so hard to believe that Borrelia might do the same?

Lyme disease may not be malaria. But patients with relapsing symptoms — unexplained by autoimmunity or structural pathology — deserve the same scientific rigor that malaria researchers applied to uncover silent infections.

Sometimes, the infection isn’t over.
It’s just gone quiet.