First-in-Human Study of MANP: A Novel ANP (Atrial Natriuretic Peptide) Analog in Human Hypertension
Studies Zoom In On Clues To Why Lyme Disease Persists And Which Antibiotic To Prescribe
It starts with the ticks. These bugs infect people with the bacteria that cause Lyme disease, microbes that are complicated to study, difficult to detect when they cause illness, and challenging to treat so they don't linger in the human body.
Understanding that bacterium, Borrelia burgdorferi, requires basic research before creating diagnostics or vaccines, slow progress that is frustrating for people affected by the chronic fatigue and brain fog of long-term Lyme illness or the joint pain of Lyme arthritis. There is even scientific debate about whether the bacteria and infection persist after antibiotic treatment.
"It's just fundamentally different from basically all other disease-causing agents," Brandon Jutras, an associate professor in microbiology-immunology in the Feinberg School of Medicine at Northwestern University, told STAT. He is the senior author of two new research papers published Wednesday in Science Translational Medicine.
In both studies, the scientists used mouse models to explore unique chemical components that persist in the roughly 15% of people who don't recover from Lyme infections and go on to develop a syndrome similar to other infection-associated illnesses, including long Covid. One study tracked antigens among the bacterial remnants that travel to the liver, and the other study screened more than 500 approved antibiotics to find one that may be safer and more effective at a lower dose than standard-of-care doxycycline.
Together, they may offer better recognition and potentially lead to alternative treatment choices for the nearly 1,200 people in the United States who develop Lyme disease every day.
The first paper studied a mouse model of Lyme disease to trace where part of the bacteria's cell wall travels. As the bacteria grow, they spit out peptidoglycan, a component of the cell wall that acts like a large molecular bag. These remnants can still cause inflammation if injected into healthy mice. When it accumulates in the liver and persists for weeks, it can be a continuous source of antigens, which the immune system sees and attacks. In previous research, the authors discovered that people with post-infectious Lyme arthritis also had that bacterial peptidoglycan cell wall floating in the synovial fluid of their inflamed joints. And consistent with other facts about this bacteria, their peptidoglycans are chemically different, too. "We found that the unusual chemical features of the Borrelia burgdorferi peptidoglycan is what makes it able to persist," Jutras said. "It looks like the liver is acting as a sink for these unusual pieces of peptidoglycan." And back to those ticks: The scientists can't say for certain, but they suspect a sugar carried by ticks may penetrate the cell walls shed by the bacteria in ways that trap them in the liver, keeping the immune system on high alert. Those antigens from the discarded cell walls that remain may trigger post-treatment Lyme disease, which has similarities to long Covid and other infection-associated illnesses. The peptidoglycan fragments appeared in the mouse livers even after less severe Lyme illness, but to a lesser degree. Amy Proal, a microbiologist who is chief scientific officer at the nonprofit PolyBio Research Foundation and scientific director of the Cohen Center for Recovery from Complex Chronic Illness at Mount Sinai, told STAT studies need to go beyond the persistent antigens in the peptidoglycan cell walls and to search for the bacteria themselves. She was not involved in Wednesday's Science Translation Medicine studies. "When we find persistent antigen in patients with long Covid, we interpret our findings differently than this team. I think that's a key thing to consider," she said. "It is helpful, I guess, to know that peptidoglycan can persist a little bit longer than we thought or something. But to be most comprehensive and fully understand what can happen in people who get Borrelia and get chronic symptoms, there'd have to be some work after this to actually look for Borrelia, including in the tissue of the patients who have symptoms after Lyme disease." Proal said it's possible the antigens are being actively produced by bacteria lingering in hidden reservoirs, as is the case with the SARS-CoV-2 virus in long Covid. In response, Jutras said purified peptidoglycan, alone, persists in mice, asserting that this work suggests that Lyme can persist without the bacteria still present, because of the peptidoglycan's unusual features. Medicine struggles to define chronic Lyme. Long Covid has only made it harder"Peptidoglycan can be detected in human patients after oral and/or IV antibiotics. We have previously attempted to detect bacterial DNA from B. Burgdorferi in the exact same patient samples tested in manuscript and were unable to do so," he told STAT in an email. "Now, it is possible that Borrelia is still present in these human patients, but at levels that are undetectable even by quantitative PCR. That said, virtually undetectable levels of B. Burgdorferi (DNA), if present, cannot explain the considerable concentrations of peptidoglycan we have measured in these samples."
The second paper addressed drawbacks in standard antibiotic treatment for Lyme infections. Doxycycline is the go-to medication, but it can't be given to children under age 8. Because it is a broad-spectrum antibiotic, it harms helpful members of the human microbiome while killing the bacteria that cause Lyme disease.
The scientists used a sophisticated screening process tied to Borrelia's properties to yield piperacillin as the best choice, a member of the penicillin family that could be used at a lower dose and with fewer off-target effects. The study's rationale was that an approved antibiotic might already be out there, just not yet found for this purpose.
"With respect to pipericillin and the antibiotic therapy, we already know that it's safe in humans, but what we don't know is whether it works to treat Lyme disease in humans," Jutras said. "The obvious next step is a human clinical trial, but those are very expensive and they require federal support."
Piperacillin hasn't drawn much interest from the private sector because it's a generic antibiotic.
"I think the field is making incredible strides in all facets of treatment, diagnosis, and in prevention. It's desperately needed, given the rapid and continual expansion and increase in the number of cases and geographically speaking, where those cases are occurring," he said. "So further supporting the research and the field in general, I think, is paramount and something that is very much in question these days."
STAT's coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies. Our financial supporters are not involved in any decisions about our journalism.
The Skin Mark That Signals You've Caught Life-long Virus That Spikes In Spring – As Health Chiefs Issue Fresh Warning
THINK spring and the health hazard that likely jumps to the forefront of your mind is hay fever.
And while this time of the year can signal pollen bombs aplenty, health chiefs have warned of another, more serious risk - a virus that left untreated can lead to lifelong, debilitating symptoms.
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Singer Justin Bieber revealed he'd been diagnosed with the disease back in 2020Credit: Getty
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Supermodel Bella Hadid has experienced flare ups linked to the virus over the yearsCredit: GettyThe UK Health Security Agency (UKHSA) has urged people to "protect themselves" from tick-borne infections like Lyme disease this spring.
Several well-known celebs have fallen victim to the bacterial infection, including, Justin Bieber, Bella Hadid, Avril Lavigne, and Shania Twain.
And it's not just US stars that have been hit - in the UK, comedian Miranda Hart revealed she'd been left bedbound and struggling for years after a Lyme disease diagnosis.
The UKHSA warns ticks "hang out" in grassy, wooded areas and are most active in the months April to July, when we spend the most time outside.
While not all ticks in England carry the bacteria that causes Lyme disease, the infection can trigger a wide range of symptoms, from joint pain to memory problems, if it's not treated quickly.
Earlier this month the UKHSA said on X, formerly Twitter: "During the spring time everyone wants to enjoy the sunshine and fresh air in the great outdoors, but don't forget that ticks often hang out in grassy, wooded areas too.
"Stay safe, #BeTickAware, and learn simple ways to protect yourself."
It also issued guidance detailing what to do if you're bitten by a tick.
It states:
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Ticks 'hang out' in grassy, wooded areas and are most active in the months April to JulyCredit: Getty
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The Lyme disease rash is often described as having a similar appearance to a bullseye on a dartboardCredit: GettyMost people are unaware about the threat of ticks to their long term well being, said bite prevention expert and CEO of Incognito, Howard Carter.
But getting a correct diagnosis for Lyme disease is critical as it needs treating early with antibiotics.
Lyme disease that goes untreated for months or years may be harder to treat this way.
If this is the case, it's still worth speaking to your doctor, as they may be able to help refer you for support and other services that can be helpful.
Howard said: "It can become a chronic and debilitating illness if left untreated.
"So regardless of your destination, home or aboard; make sure that you consider the risks of ticks before you pack your bags."
Justin Bieber: 'I had a rough couple of years'
IN January 2020, Justin Bieber publicly revealed he'd been diagnosed with Lyme disease and that it had been a "rough couple of years" leading up to his diagnosis.
He wrote on Instagram at the time people had suggested he looked like he was "on meth", but "they failed to realise I've been recently diagnosed with Lyme disease, not only that but had a serious case of chronic mono which affected my skin, brain function, energy and overall health".
The singer's experience with the disease was detailed in his documentary series Seasons on YouTube.
The series includes footage of him using a hyperbaric oxygen chamber and receiving IV infusions at a doctor's office, as well as interviews with his psychiatrist and the doctor who diagnosed and treated him for Lyme disease.
Bieber recently indicated he's "back and better than ever".
Many people with early symptoms of Lyme disease develop a circular red skin rash around a tick bite.
Most rashes appear within the first four weeks and usually last for several weeks.
However, this rash can appear up to three months after being bitten by a tick, warned Howard.
He explained: "The rash is circular in nature and is often described as having a similar appearance to a bullseye on a dartboard or target board."
Sometimes the rash might not appear...
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Flu-like symptoms can also appear with a Lyme disease infectionCredit: GettyThe bullseye rash appears in about 70-80 per cent of Lyme disease cases.
While it's a common symptom, it's important to remember that not everyone with Lyme disease will develop the rash.
Bella Hadid: 'A tooth infection caused my Lyme disease to flare up'
IN 2023, Bella Hadid took to social media to share she'd been through more than 100 days of "Lyme, chronic disease, co-infection treatment" after "almost 15 years of invisible suffering".
The supermodel, who was diagnosed with the condition in 2012, posted images of her undergoing unspecified medical procedures.
It was on TikTok that she revealed a tooth infection caused a reoccurrence of her Lyme disease.
The flare up occurred nearly one year after she had a root canal surgery for a problem tooth.
She wrote: "Please listen to your bodies my friends please!!! Thismade my Lyme flare up, which means the Lyme is attacking the places that are suffering ie tooth, jaw, gut, brain, spine, bones etc oh, and the entire nervous system."
While Hadid admitted she wasn't worried because "Lyme flare-ups happen all the time", she shared her jaw was "radiating" with pain.
"Some days it's okay! And some days are difficult," she added.
Other signs that can appear, either instead of or as well as a rash, include flu-like symptoms, such as a fever, headaches, muscles aches and neck pain.
Dr Deborah Lee, of Dr Fox Online Pharmacy, said weeks or months after becoming infected with Lyme disease a person may have neurological symptoms, cardiovascular issues, and eye problems.
She said: "Neurological symptoms include Bell's palsy (facial paralysis) and/or meningitis associated with neck stiffness.
"Cardiovascular problems include heart inflammation leading to myocarditis, pericarditis and abnormal heart rhythms. These cause chest pain, palpitations, dizziness and feeling unwell.
"And eye problems, such as conjunctivitis, uveitis and optic neuritis, resulting in a gritty feeling or painful eye or eyes, and blurred vision."
Months after a Lyme disease infection, tingling in the arms and legs, difficulty concentrating and poor short-term memory may occur.
Miranda Hart: 'I was basically bedbound and housebound'
IN October last year, Miranda Hart revealed her struggle with chronic fatigue after being diagnosed with Lyme disease.
In her book, I Haven't Been Entirely Honest With You, Hart provided a frank account of the past 10 years, including the challenges posed by her ill health.
She told BBC Radio 4's Today programme: "I was basically bedbound and housebound.
"There'd be times where I'd look at a glass of water, and think, I don't know how to pick that up.
"All anyone wants is to be heard, accepted, loved and seen...And when you're not - particularly in a medical situation - it's the worst."
Dr Lee added: "Lyme disease can also cause anxiety, depression and behavioural problems.
"It also affects large joints such as the knee. 60 per cent of those with untreated Lyme disease going on to develop arthritis, with joint pain, redness, swelling and tenderness of affected joints."
Areas of the UK to be extra alert
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Some areas of the UK are known to harbour infected ticks more than others - including the New ForestCredit: GETTYThere are areas of the UK known to harbour infected ticks, according to Dr Sanjay Mehta, GP at The London General Practice.
He advised: "These areas include the Lake District, the New Forest, the North York Moors,and the Scottish Highlands."
If you do see ticks on your skin, you don't necessarily get transmission for up to four hours, adds Dr Mehta, so if you can remove them that's ideal.
He added: "If you are going to any of these areas, there are also a few simple things you can do to limit the risk.
"Try to keep to paths in grassy, wooded areas, and keep away from long grass and vegetation.
"It sounds obvious, but shower on your return - often ticks fall off - and check yourself for them too.
"Wear insect repellent, long T-shirts, and long trousers if possible."
How to prevent tick bites - and remove the bugs
There are a few things you can do to lessen your likelihood of tick bites.
Firstly, try and cover as much of your skin as possible while walking outdoors and tuck your trousers into your socks.
You should also be using insect repellent containing DEET on your clothes and skin, and wearing light coloured clothing so you can spot a tick easily.
Also stick to paths where possible when you're out walking.
How can I remove a tick safely?
To remove a tick safely:
The chance of getting ill is low. You do not need to do anything else unless you notice a rash or become unwell.
If either of these happen, make sure to see a GP so you can get treatment as soon a possible.
Post-treatment Lyme Disease Syndrome May Be Driven By Remnants Of Infection
Symptoms that persist long after Lyme disease is treated are not uncommon -- a 2022 study found that 14% of patients who were diagnosed and treated early with antibiotic therapy would still develop Post Treatment Lyme Disease (PTLD). Yet doctors puzzle over the condition's causes and how to help their patients through symptoms ranging from severe fatigue and cognitive challenges to body pain and arthritis.
Now, Northwestern University scientists believe they know what causes the treated infection to mimic chronic illness: the body may be responding to remnants of the Borrelia burgdorferi (the bacteria that causes Lyme) cell wall, which breaks down during treatment yet lingers in the liver. This matches one theory behind the underlying causes of long COVID-19 in that persisting viral molecules may encourage a strong, albeit unnecessary, immune response, said bacteriologist Brandon L. Jutras.
"Lyme and long COVID-19 are clearly vastly different diseases, but it's possible that they share a more general mechanism of inappropriate inflammation caused by remnants of a previous infection," said Jutras, who led the research. "The maladaptive response is a product of an infection, but perhaps not necessarily an active one in all cases."
Peptidoglycan is a structural feature of virtually all bacterial cells and a common target of antibiotics, including penicillin. The research, to be published April 23 in the journal Science Translational Medicine, tracked the biodistribution of peptidoglycan from different bacteria, in real time, and found that all cell wall material is rapidly shed, but Lyme disease's peptidoglycan persists for weeks to months.
Lyme arthritis is one of the more common long-term impacts of exposure to Lyme. If a patient has a swollen knee, for instance, it is full of synovial fluid, a natural lubricant found in joints. Jutras said his team looked at the fluid in humans and found that pieces of the peptidoglycan were omnipresent weeks to months after treatment.
"In the context of Lyme arthritis, if you give patients anti-inflammatory, disease-modifying antirheumatic drugs, they get better," Jutras said. "Some of these very same patients do not get better after oral and IV antibiotics, which implies there is something unique about how patients respond at a genetic level."
Jutras, who joined Northwestern faculty last summer, is an associate professor of microbiology-immunology at Northwestern University Feinberg School of Medicine and a member of the Center for Human Immunobiology at Northwestern. He has been studying Lyme disease for more than 15 years, beginning in graduate school, and was previously an associate professor at Virginia Tech University.
"Peptidoglycan is kind of like a structural skeleton in virtually all bacteria, acting as a big protective bag for the bacterium," Jutras said. "Penicillin and amoxicillin and dozens of other drugs target peptidoglycan synthesis because it's a molecule that is specific to bacteria, it has similar structural features across the kingdom, and it's essential."
Lyme's peptidoglycan, however, is structurally unique, and this difference may be behind its persistence in humans. Instead of looking the same as with other bacteria, the Lyme peptidoglycan is fundamentally distinct, which is facilitated in part by sucking up sugars from its tick vector. Upon bacterial cell death -- by antibiotics or the immune system -- surviving molecules tend to relocate to the liver, which can't process the modified peptidoglycan.
Without this modification, it seems likely that the peptidoglycan would clear right away, as in other infections.
"The unusual chemical properties of Borrelia peptidoglycan promote persistence, but it's the individual patient response to the molecule that likely impacts the overall clinical outcome," Jutras said. "Some patients will have a more robust or stronger immune response, which could result in a worse disease outcome, while the immune system of others may largely ignore the molecule. So, in essence, it's not about whether the molecule is there or not, it's more about how an individual responds to it."
Jutras hopes the groundbreaking findings will lead to development of more accurate tests, possibly for PTLD patients, and refined treatment options when antibiotics have failed. To effectively stymie PTLD, instead of neutralizing an infection that may no longer exist, efforts are underway to neutralize the inflammatory molecule, including weaponizing monoclonal antibodies to target peptidoglycan for destruction.
The research was supported by the National Institutes of Allergy and Infectious Diseases (R21AI159800, R01AI173256, R01AI178711), the Steven & Alexandra Cohen Foundation, the Department of Defense (TB220039), the Global Lyme Alliance and the Bay Area Lyme Foundation.
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