In the world of infectious disease, few organisms are as stubborn as Mycobacterium tuberculosis. This pathogen, responsible for tuberculosis (TB), is notorious for surviving silently in the human body for months, years—even decades. During this time, it causes no obvious symptoms. It evades detection. And it waits for the right moment to reactivate.¹

We call this latent TB, and it’s widely accepted in medicine and microbiology. But here’s what’s often overlooked:

What if TB isn’t the only one that hides?

What if Lyme disease can do something similar?

The TB Analogy: Persistence Isn’t a Mystery

Latent TB happens when the bacteria enter a low-metabolic, non-replicating state. They’re not dead. They’re just quiet—slowed down, hidden, and hard to kill. That’s why TB treatment lasts 6 to 12 months and uses multiple drugs.² Even then, relapses can happen.

Clinicians who treat TB know this well: just because symptoms resolve doesn’t mean the bacteria are gone.

So why are we so quick to assume that Lyme disease is “cured” after a 2–4 week course of antibiotics?

Lyme Disease and the Persister Hypothesis

Most patients with early Lyme disease—especially those with the classic bull’s-eye rash—do well with short-term antibiotics.

But others don’t.

They go on to develop fatigue, pain, brain fog, sensory issues, and mood changes. Some improve briefly, only to relapse months later. When this happens, patients are often told they have Post-Treatment Lyme Disease Syndrome (PTLDS)—a diagnosis that assumes the infection is gone and the symptoms are just fallout.

But what if the infection isn’t gone?

That’s the idea behind the persister hypothesis in Lyme disease: that Borrelia burgdorferi can survive treatment by entering slow-growing, antibiotic-tolerant forms—just like TB.

The Science Behind Lyme Persistence

In laboratory studies, Borrelia has shown several survival strategies that may help explain chronic illness³:

• Persister cells: forms that replicate slowly or not at all, allowing them to tolerate antibiotics.

• Antigenic variation: the ability to change surface proteins to escape immune recognition.

• Sequestration in immune-privileged sites: including joints, connective tissue, and the nervous system.

Animal models—including mice, dogs, and primates—have demonstrated that Borrelia DNA, and in some cases viable organisms, can be found in tissues after treatment.⁴ ⁵ These findings raise the possibility that symptoms may reflect ongoing infection—not just residual inflammation.

What About Biofilms?

Some researchers have suggested that Borrelia burgdorferi may form biofilm-like aggregates in vitro—structured bacterial communities that are more resistant to antibiotics.⁶

In other infections (e.g., urinary catheters or chronic sinusitis), biofilms are well-established as contributors to treatment failure. However, the role of biofilms in human Lyme disease remains unconfirmed. While lab-based studies show that Borrelia can produce protective matrices in artificial settings, direct evidence of clinically relevant biofilms in human tissues is still lacking.

Still, if biofilm-like structures are part of Borrelia’s survival strategy, they could help explain why some infections persist despite appropriate treatment.

The Debris Hypothesis — And Why It May Be Misleading

Some researchers argue that persistent symptoms may be due to bacterial debris—fragments of DNA or peptidoglycan that continue to stimulate the immune system after the infection has been cleared.

This idea is often used to explain symptoms in so-called PTLDS.

But just as in TB, the presence of lingering bacterial material doesn’t necessarily mean the infection is gone. In Lyme arthritis, for example, Borrelia peptidoglycan has been found in joint fluid—raising questions about whether it’s inert, or part of an ongoing process⁷.

In TB, persisters can’t always be cultured—but they’re still alive. We may be seeing something similar in Lyme disease.

Why This Matters Clinically

In TB, we don’t tell patients they’re fine because their symptoms outlast treatment. We reevaluate. We retreat if needed. We don’t dismiss symptoms as psychological.

Lyme patients deserve the same respect.

If a patient improves with additional or combination therapy—as many do⁸—it suggests there’s more going on than immune memory or anxiety.

What This Means for Research and Treatment

• Duration matters: A short course of doxycycline may not be sufficient—especially in late, neurologic, or cardiac cases.

• Combination therapy may be necessary: Like TB, Lyme may require multi-drug regimens to fully address the infection.

• Clinical judgment is key: Negative tests don’t always mean resolution. Symptoms may be the clearest sign of persistence.

• Persistent symptoms may be treatable: And we should stop assuming they’re emotional.

TB and Lyme: A Shared Lesson

We’ve known for decades that TB can lie dormant, evade the immune system, and flare again after treatment. That’s why we treat it aggressively and monitor long after therapy ends.

Borrelia burgdorferi may not behave exactly the same way—but the clinical lesson is familiar.

If a Lyme patient remains ill, we should stop assuming they’re cured.

Because sometimes, the bacteria haven’t been beaten.

They’ve just gone quiet.

References

1. Barry CE et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol. 2009;7(12):845–855.

2. World Health Organization. Guidelines for treatment of drug-susceptible tuberculosis and patient care. 2017.

3. Feng J, Auwaerter PG, Zhang Y. Drug Combinations against Borrelia persisters. Antibiotics (Basel). 2015;4(3):397–412.

4. Embers ME et al. Persistence of Borrelia burgdorferi in Rhesus Macaques following antibiotic treatment of disseminated infection. PLoS One. 2012;7(1):e29914.

5. Hodzic E et al. Resurgence of Borrelia burgdorferi after antibiotic treatment in mice. Antimicrob Agents Chemother. 2008;52(5):1728–1736.

6. Sapi E et al. Borrelia burgdorferi forms biofilm-like colonies in vitro. PLoS One. 2012;7(10):e48277.

7. Jutras BL et al. Borrelia burgdorferi peptidoglycan is a persistent antigen in patients with Lyme arthritis. Proc Natl Acad Sci USA. 2019;116(27):13498–13507.

8. Cameron DJ. Consequences of treatment delay in Lyme disease: a systematic review. Diagn Microbiol Infect Dis. 2021;99(3):115273.