Important Read.

Bay Area Lyme Foundation, a leading sponsor of Lyme disease research in the U.S., has announced a study finding a new mechanism of immune evasion used by Borrelia burgdorferi (Bb), the bacterium that causes Lyme disease.

This study is the first to identify the specific Borrelia protein that acts as a “don’t eat me” signal to the body’s immune system in people with Lyme disease.

This offers insight into how the bacteria may persist in Lyme patients and introduces an entirely new research direction toward potential future treatments.

The research was conducted at Stanford University and University of California San Francisco and funded in part by Bay Area Lyme Foundation. This groundbreaking data posted on bioRxiv on April 30, 2024, is expected to be published in a peer-review journal in the future.

Evading the immune system

“One of the big mysteries of Lyme disease has been how Borrelia is able to evade and survive the immune system – and this study helps answer that question. We’ve unlocked a critical door to understanding how this bacteria, and possibly other pathogens, manage to trick the immune system to evade clearance,” said lead author Michal Tal, PhD, principal scientist, Massachusetts Institute of Technology.

Tal is a Bay Area Lyme Foundation 2018 Emerging Leader Award winner who has received additional funding from the organization for this project.

In this study, researchers found that P66, a known Borrelia surface protein and one of the IgG Western Blot testing “bands” used for diagnosis, can inhibit an important portion of the immune response.

“Patients need both a robust immune response and antibiotics to eradicate an infection – antibiotics alone are not usually sufficient. Addressing the mechanisms of immune evasion could help patients more efficiently eradicate the infection,” said Wendy Adams, research grant director, Bay Area Lyme Foundation, who also notes that persistent Lyme disease impacts more than two million Americans today.

The “don’t eat me” signal

Harmful bacteria entering the body are usually targeted by macrophages—immune cells which look for invaders to engulf and eliminate. However, this study shows that P66 is a bacterial “don’t eat me” signal encouraging the macrophage to ignore the bacteria by binding to a receptor on the macrophages’ surface called SIRP-alpha.

This type of “don’t eat me” signal is a known mechanism in cancer and more recently, atherosclerosis. Specifically, the human “don’t eat me” signal protein CD47 binds the SIRP-alpha receptor on macrophages to signal that the cell shouldn’t be destroyed. Drugs that prevent CD47 from binding SIRP-alpha have been tested in clinical trials for the treatment of some cancers.

One of the study’s senior authors Irving Weissman, MD, professor and director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University and a Bay Area Lyme Foundation scientific advisory board member, explains that this study is a discovery of how an established protein can protect the bacteria with which it has co-evolved. These exciting and field-generating observations will have broad-reaching implications.

Dr. Weissman is renowned for his pioneering work in identifying “don’t eat me” proteins and his lab discovered all four known mammalian “don’t eat me proteins”: CD47, CD24, PDL1 and B2M. He is also the founder of companies which have developed or are developing therapeutics that target these mechanisms in cancer and atherosclerosis.

Unleashing the immune system

Researchers hope that blocking P66 activity, like blocking CD47’s activity in cancer, could help unleash the immune system in recognizing and fighting Borrelia bacteria.

“This work could extend beyond the Borrelia genus. Further investigation into whether other bacteria have “don’t eat me” signal protein mimics is crucial for understanding bacterial interactions with the immune system,” said second author Paige Hansen, Tal Research Group Researcher, Massachusetts Institute of Technology.

Click here for the full text of the study.

For more information about the mechanism of persistent infection, please see this review article in mBio.

SOURCE: Bay Area Lyme Foundation

Melinda

Important Read.

By Nancy Dougherty

The immune response in Lyme disease has been described as dysregulated or maladjusted.

This is supported in part by the fact that many individuals who clearly have Lyme disease do not make a detectable immune (antibody) response to Borrelia burgdorferi (Bb), the tick-borne pathogen that drives the disease.

Research at the Johns Hopkins University School of Medicine may provide insights into why this occurs.

Dendritic cells (DCs) are a broad class of immune cells that reside at strategic sentinel sites in the body, including the skin and GI tract.

Dendritic cells stand watch for pathogens

DCs constantly monitor their environment by gobbling up the fluid that surrounds them to sense when pathogens arrive on the scene. When they detect a pathogen, DCs stop capturing material and move to the closest lymph node.

There, DCs interact with T lymphocytes (T cells) to activate and drive pathogen-specific T cells to help initiate a strong immune response to clear the pathogen and resolve the infection.

When everything is working right, activated dendritic cells provide three signals to T cells (signals 1, 2 & 3) that synergize to generate a strong T cell activation.

In a 2023 Johns Hopkins study, using proteomic and genomics-based approaches,  researchers found that DCs exposed to Borrelia burgdorferi were fully capable of generating signal 1 but signals 2 & 3 were abnormal. In fact, the features discovered overlapped with what is found in a tumor microenvironment, a site where immune responses are known to be suppressed and dysregulated.

A lead author of the publication, Mark Soloski, PhD, Professor Emeritus, Johns Hopkins University School of Medicine, divulges, “It has been known for some time that Borrelia burgdorferi is highly capable of evading the immune response, and this disruption of dendritic cell activation signaling is likely another clever way that Borrelia mutes the immune response.”

He adds, “Further study is needed to better understand the precise nature of the dendritic cell driven T cell responses in patients with Lyme disease.”

There are immediate implications, however.

Clearly, antibody-based diagnostic tests (the current standard) are going to miss those who are not making a normal antibody response due to Borrelia burgdorferi’s immune response disrupting behavior.

The need for direct testing

The need for effective direct diagnostic tests that identify Bb DNA or proteins directly has never been more obvious. Misdiagnosis and delayed diagnosis are indeed a common Lyme disease occurrence. Resulting treatment delays lead to worse prognoses, including potentially disabling chronic illness.

Fifty years after the discovery of Bb as the causative agent of Lyme disease, there are still no FDA-approved direct diagnostic tests for Lyme disease or treatments for persistent Lyme disease. These need to be developed, validated, and become broadly available.

Given that dendritic cells play such a key early role in immune response initiation, the novel features identified in Borrelia burgdorferi exposed cells may suggest new therapeutic targets that could help generate stronger, more robust immune responses in Lyme disease that could result in enhanced bacterial clearance and disease resolution. Immune modulators are effective therapeutic targets in cancer and could be promising therapeutic approaches for Lyme disease as well.

Nancy Dougherty is an education and communications consultant for the Johns Hopkins Lyme Disease Research Center. 

Melinda

As of May 29, the Kansas Department of Health and Environment (KDHE) has received over 200 laboratory reports of tick-borne diseases.

Additionally, KDHE has received several reports of tick bites and complaints of high numbers of ticks, which indicates that tick activity and density are increasing and are occurring earlier in the season this year.

Numerous tick-borne diseases caused by bacteria are present in Kansas.

These include ehrlichiosis, Rocky Mountain spotted fever and other spotted fever group rickettsioses (SFGR), and tularemia. Two rare tick-borne viruses, Heartland virus and Bourbon virus, have also been identified in Kansas in both humans and ticks.

All of these tick-borne diseases are transmitted by the lone star tick, the most abundant tick in Kansas. Lone star ticks can be found widely throughout at least the eastern two-thirds of the state in a variety of habitats and are aggressive human biters.

This year alone, KDHE has investigated several tick-borne disease cases with severe health outcomes, including hospitalizations due to Rocky Mountain spotted fever and tularemia, and a fatal case of Bourbon virus.

“Vector-borne diseases, both those that are transmitted by ticks and those transmitted by mosquitoes are extremely active this year,” Dr. Erin Petro, KDHE State Public Health Veterinarian, said.

“I really encourage people to take the risk of vector-borne diseases seriously and take personal protective measures for themselves and their pets to reduce their chance of acquiring an illness from a tick or mosquito bite. We’re also seeing emerging tick-associated conditions, like alpha-gal syndrome, which can have lifelong consequences for those affected, which is why bite prevention is so important.”

SOURCE: Kansas Department of Health and Environment

Melinda

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