COVID, Lyme Disease, and Shared Inflammatory Pathways We Can’t Ignore

While none of us enjoy hearing the newest, slightly-longer-than-four-letter curse word—COVID—research into the pathophysiology of both acute and chronic COVID illness has provided an unexpected benefit: it has helped us better understand Lyme disease.

Clinical experience in both adult and pediatric functional medicine clinics confirms what the research is now revealing, COVID and Lyme disease activate many of the same inflammatory pathways. In some patients, COVID infection, or even COVID vaccination, has been followed by a relapse of previously dormant Lyme disease.

At first glance, this overlap can feel discouraging. But when we understand the shared mechanisms driving these conditions, we are no longer left guessing. Instead, we gain clarity—and with it, a more effective treatment strategy.

In this essay, I’ll explain:

• How COVID and Lyme overlap at the immune and inflammatory level

• Why COVID can sometimes reactivate Lyme disease

• How we begin to distinguish post-COVID inflammation from Lyme relapse

• Why understanding the mechanism matters more than the label
  

SARS-CoV-2 and ACE2: A Key Difference That Starts the Cascade

SARS-CoV-2—the virus responsible for acute COVID-19 and post-COVID syndrome—shares an impressive number of inflammatory pathways with Lyme disease. However, one of its most distinctive mechanisms deserves attention first.

SARS-CoV-2 enters cells by binding to ACE2 (angiotensin-converting enzyme 2). Under normal circumstances, ACE2 helps regulate blood pressure, inflammation, and vascular health by converting angiotensin II into angiotensin 1-7.

When the virus hijacks ACE2 for cell entry, less ACE2 is available to perform its normal regulatory role. The result is an accumulation of angiotensin II, which significantly contributes not only to lung dysfunction, but also to systemic inflammation and multi-organ involvement.

The Cytokine Cascade: Where COVID and Lyme Strongly Overlap

Beyond the ACE2 mechanism, the inflammatory cascade triggered by SARS-CoV-2 closely mirrors that seen in tick-borne infections such as Lyme disease. While acute COVID tends to trigger a more intense initial inflammatory response, chronic Lyme disease and post-COVID syndrome share striking similarities in cytokine patterns and immune dysregulation.

Common elevations include:

• Transforming Growth Factor-beta (TGF-β)

• Matrix metalloproteinases, contributing to tissue damage

• p38 MAPK pathway activation

• Elevated interleukins including IL-1β, IL-4, IL-6, and IL-10

These same pathways have long been recognized in chronic Lyme disease and other biotoxin-related illnesses, including mold toxicity.

Angiotensin II, p38 MAPK, and the Inflammatory Domino Effect

When ACE2 activity is reduced, angiotensin II accumulates. This excess angiotensin II activates the p38 MAPK pathway, which in turn drives increases in:

• IL-6

• TNF-alpha

• IL-1β

These cytokines play a central role in both acute COVID symptoms and the lingering manifestations of post-COVID syndrome. IL-6, in particular, serves as a key driver of fever and systemic inflammation. It stimulates multiple immune pathways—activating CD4 and CD8 T-cells, B-cells, and additional cytokine production, while simultaneously suppressing regulatory T-cells that normally help keep inflammation in check.

TGF-Beta: A Quiet Driver of Chronic Symptoms

Elevated TGF-β acts as a powerful amplifier of chronic illness. When persistently high, it can:

• Disrupt deep, restorative sleep

• Slow muscle regeneration

• Decrease bone density

• Suppress red blood cell production

• Lower natural killer cell activity

• Increase oxidative stress and free radical damage

• Promote fibrosis and abnormal blood vessel growth

• Contribute to viral reactivation, including EBV
  

These effects help explain why patients with chronic Lyme or post-COVID syndrome often feel stuck in a cycle of fatigue, poor recovery, and immune dysfunction.

IL-6, TNF-Alpha, and IL-1β in Long COVID

The combination of IL-6, TNF-alpha, and IL-1β appears to drive many of the hallmark symptoms of long COVID.

• TNF-alpha amplifies inflammation and heightens sensitivity to environmental stressors.

• IL-1β, while helpful in acute infections, becomes problematic when chronically elevated—contributing to autoimmune activation and tissue damage.

• IL-6 sustains immune activation while suppressing immune regulation.
  

These same cytokines are deeply familiar to clinicians treating chronic Lyme disease.

Galectin-3: An Overlooked but Critical Link

One of the most intriguing shared mechanisms between Lyme and post-COVID illness involves Galectin-3, a molecule that normally helps regulate inflammation. The SARS-CoV-2 spike protein closely resembles Galectin-3. Research has shown that higher Galectin-3 levels correlate with increased disease severity in acute COVID, including ICU admission and mortality.

At a recent conference, Dr. Hinchey discussed evidence supporting the use of modified citrus pectin to help interrupt Galectin-3-driven inflammation. Her presentation explored both mechanisms of action and supporting research, offering insight into how chronic inflammatory cycles may be broken.

Why COVID Can Reactivate Dormant Lyme Disease

Given the shared inflammatory pathways, it is not surprising that COVID infection—or vaccination—can trigger a relapse of Lyme disease that had previously been in remission.

While the exact mechanisms are still being studied, several theories exist:

• COVID-related inflammation and micro-clotting may create tissue damage that provides a favorable environment for Borrelia activity

• Immune imbalance between Th1 and Th2 pathways may weaken immune surveillance

• Shared cytokine elevations may allow dormant infections to re-emerge
  

Because Lyme and post-COVID alter nearly identical cytokines, with the exception of tick-specific factors, the symptom overlap is substantial.

Shared Symptoms, Subtle Differences

Both conditions can cause:

• Fatigue

• Brain fog

• Headaches

• Sleep disturbances

• Dizziness

• Sweats

• Palpitations

• Generalized pain

Even routine laboratory findings may overlap, including false-positive ANA, rheumatoid factor, antiphospholipid antibodies, and imaging changes.

The most consistent differences:

• COVID tends to cause less migratory musculoskeletal pain

• Lyme disease is less likely to cause loss of smell or significant shortness of breath
  

How Functional Medicine Approaches the Overlap

When a patient with Lyme disease in remission reports worsening symptoms after COVID, the first step is not guessing, it is reducing inflammatory burden.

Initial support often includes:

• Glutathione

• Vitamin C

• Resveratrol

• Quercetin

• Curcumin

• Specialized pro-resolving mediators (SPMs)
  

If inflammation improves but Lyme-specific symptoms—such as migratory pain—persist, we then return to addressing active Lyme infection. In some cases, additional lab markers such as CD57 and C4a may help differentiate Lyme reactivation from post-COVID inflammation, though clinical response remains the most valuable guide.

Recovery Is Possible—Even After a Setback

Many patients who previously recovered from Lyme are surprised by how smoothly they move through COVID. Others need a secondary recovery phase to regain their health after COVID temporarily sets them back. Our goal is always the same: to help patients return to healthier, more abundant lives, even when multiple inflammatory insults overlap.

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Medical Disclaimer: These essays are for educational purposes only.We assume no responsibility for your choice to implement something from these essays. Even if you are a patient of our clinic, you should consult with us before adding therapies.If you are not one of our patients, talk with your health care provider before trying any of these therapies.

Bibliography

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