How Does Borrelia Attach to Human Tissue?

Lyme bacteria interact directly with structures in human tissue
Surface proteins can help Borrelia attach to its surroundings
A 2025 study identified a new interaction involving collagen IV

Borrelia burgdorferi, the bacterium that causes Lyme disease, does not simply enter the body and float passively through the bloodstream. To establish infection, the organism must interact with the tissues and structures it encounters.

Researchers have identified several Borrelia surface proteins that can bind to components of the host. These proteins, often called adhesins, can help the bacterium interact with extracellular matrix proteins, cells, and blood vessels.

A 2025 study by Dutta and colleagues identified another potentially important interaction. The researchers found that a Borrelia burgdorferi enzyme called phosphomannose isomerase, or PMI, is present on the bacterial surface and can bind to collagen IV, an important component of basement membranes.¹

The finding adds another piece to the increasingly detailed picture of how Borrelia adapts when it moves from a tick into a mammalian host.

Why does Borrelia need to attach to human tissue?

After an infected tick transmits Borrelia burgdorferi, the bacteria initially encounter the skin. From there, the organism may disseminate and interact with a variety of host tissues.

Those environments contain an extracellular matrix: a network of proteins and other molecules that helps provide structure and support around cells.

Borrelia has evolved surface molecules that can interact with components of this matrix. These interactions may help the organism establish itself within the host and participate in the complex process of dissemination and tissue colonization.

Several Borrelia adhesins have already been studied. For example, BBK32 can interact with fibronectin and glycosaminoglycans, while decorin-binding proteins DbpA and DbpB interact with decorin.³

The 2025 research suggests that phosphomannose isomerase may add another mechanism to this list.

What is phosphomannose isomerase?

Phosphomannose isomerase is normally considered a metabolic enzyme. It participates in sugar metabolism by catalyzing the reversible conversion of mannose-6-phosphate and fructose-6-phosphate.¹

That would ordinarily suggest that PMI belongs inside the bacterial cell, where metabolic reactions occur.

But Dutta and colleagues found something unexpected.

In Borrelia burgdorferi, PMI was also localized on the surface of the bacterium. Even more interestingly, the surface-associated enzyme retained enzymatic activity and interacted with a host extracellular matrix protein: collagen IV.¹

What is a moonlighting protein?

A protein that performs a second function unrelated to its conventional role is sometimes described as a moonlighting protein.

Benach highlighted this concept in a 2025 mBio commentary discussing the Dutta findings. Some bacterial enzymes normally involved in metabolism can also appear on the bacterial surface, where they perform additional functions related to interactions with the host.²

PMI appears to fit this pattern in Borrelia burgdorferi.

Inside the bacterium, it functions as an enzyme involved in metabolism. On the bacterial surface, the same protein appears capable of interacting with collagen IV.

This second role may therefore contribute to the broader set of mechanisms Borrelia uses to interact with its host.

Why is collagen IV important?

Collagen IV is different from the collagen people commonly associate with tendons, ligaments, or other connective tissues.

It is a major structural component of basement membranes, specialized extracellular matrix structures that provide support beneath and around cells.

Collagen IV is present in skin and vascular basement membranes, making the interaction particularly interesting for a pathogen that initially enters through the skin and subsequently encounters host tissues and blood vessels.

In laboratory experiments, Dutta and colleagues compared BbPMI binding with several extracellular matrix molecules. The strongest interaction was observed with collagen IV. The researchers also demonstrated colocalization of Borrelia burgdorferi and collagen IV in experiments involving cultured human endothelial cells.¹

What did the 2025 study find?

The Dutta study went beyond simply showing that PMI could bind collagen IV.

The investigators found that BbPMI was present on the surface of intact Borrelia burgdorferi and remained enzymatically active there. Binding experiments indicated a specific interaction between BbPMI and collagen IV.¹

The researchers also explored whether interfering with PMI could affect the organism.

Several PMI inhibitors impaired the growth of diverse Borrelia burgdorferi strains in laboratory culture. In additional experiments, passive transfer of antibodies against BbPMI in ticks affected spirochete transmission to mice, while treating collagen IV-containing mouse skin with PMI inhibitors impaired infectivity.¹

Together, these experiments support a role for BbPMI in host-pathogen interactions during infection.

Does this mean PMI is a new Lyme disease treatment?

No. The study identifies a biological mechanism and a possible target for future investigation. It does not establish a new treatment for people with Lyme disease.

The inhibitor experiments were conducted in laboratory and animal models. A compound that interferes with a bacterial process in vitro or in an experimental model cannot automatically be assumed to be safe or effective as a treatment in humans.

The researchers described the PMI-collagen IV interaction as a potential opportunity for future therapeutic development.¹ That possibility requires substantially more research before it can be translated into clinical care.

Does this explain persistent Lyme disease symptoms?

The study was not designed to answer that question.

It provides evidence about how Borrelia burgdorferi interacts with host structures during the infectivity process. It does not demonstrate that PMI-collagen IV binding is responsible for persistent symptoms after treatment, nor does it establish how long this interaction occurs in human infection.

That distinction matters. Basic research into Borrelia biology can improve understanding of infection without necessarily explaining every clinical manifestation of Lyme disease.

The finding is most useful as evidence that the relationship between Borrelia and its host involves multiple molecular interactions rather than a single mechanism.

Why does this research matter?

Understanding Lyme disease requires understanding more than how a tick transmits the bacterium.

Once Borrelia burgdorferi enters a mammalian host, it must respond to a new environment, interact with extracellular matrix proteins and cells, encounter immune defenses, and potentially disseminate beyond the original site of inoculation.

Researchers have already identified several bacterial proteins involved in these processes. The discovery that a familiar metabolic enzyme may perform an additional function on the bacterial surface shows that some of the tools Borrelia uses may have more than one biological role.

The PMI finding therefore expands our understanding of how the Lyme disease bacterium interacts with host tissue while also identifying a mechanism that can be studied further.

Frequently Asked Questions

How does Borrelia attach to human tissue?

Borrelia burgdorferi produces surface proteins that can interact with cells and components of the extracellular matrix. Different proteins bind to different host structures, allowing the bacterium to participate in complex interactions with tissues during infection.

What does Borrelia bind to in the body?

Researchers have identified Borrelia proteins that interact with host molecules including fibronectin, decorin, glycosaminoglycans, and other extracellular matrix components. A 2025 study found that Borrelia burgdorferi phosphomannose isomerase can also bind collagen IV.

What is collagen IV?

Collagen IV is an important structural protein found in basement membranes. These specialized extracellular matrix structures are present in tissues including the skin and around blood vessels and other cells.

What is a moonlighting protein in Borrelia?

A moonlighting protein performs more than one biologically distinct function. In Borrelia burgdorferi, phosphomannose isomerase normally functions as a metabolic enzyme but has also been found on the bacterial surface, where it can interact with collagen IV.

Does the collagen IV discovery lead to a new Lyme disease treatment?

Not yet. Researchers found that interfering with PMI affected Borrelia in laboratory and animal experiments, making the protein an interesting research target. These findings do not establish that PMI inhibitors are safe or effective treatments for Lyme disease in people.

Clinical Takeaway

Borrelia burgdorferi uses multiple surface molecules to interact with the host environment. The 2025 discovery that phosphomannose isomerase can appear on the bacterial surface and bind collagen IV adds another potential mechanism to this process.

The work also illustrates why laboratory discoveries should be separated from clinical conclusions. The PMI-collagen IV interaction provides insight into Borrelia biology and may identify a target for future research, but it does not yet establish a new human treatment or explain persistent symptoms after Lyme disease.

Understanding how Borrelia attaches to host structures may ultimately help researchers better understand how the organism establishes infection and identify new ways to interrupt that process.

Related Articles

These articles explore how Borrelia adapts to different environments and interacts with the host during transmission and infection.

Why Is Borrelia burgdorferi So Difficult to Study?
Does a Tick Bite Change the Immune Response to Lyme Disease?
Why Can Borrelia Survive in Some Animals but Not Others?
Does the Patient Matter as Much as the Borrelia Strain?
How Can a Lyme Vaccine Work Inside the Tick?

References

1. Dutta S, Rana VS, Backstedt BT, et al. Borrelial phosphomannose isomerase as a cell surface localized protein that retains enzymatic activity and promotes host-pathogen interaction. mBio. 2025;16(3):e03609-24.
2. Benach JL. Moonlighting enzymes of Borrelia burgdorferi. mBio. 2025;16(5):e00279-25.
3. Antonara S, Ristow L, Coburn J. Adhesion mechanisms of Borrelia burgdorferi. Adv Exp Med Biol. 2011;715:35-49.

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