Category: Diseases, Syndromes and Conditions

Categories : Diseases, Syndromes and Conditions Immune SystemTags :

Pseudomonas Aeruginosa Locks out Immune Cells

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Pseudomonas
Scanning Electron Micrograph of Pseudomonas aeruginosa. Credit: CDC/Janice Carr

Pseudomonas aeruginosa bacteria are a common menace in hospital wards, causing life-threatening infections, and are often resistant to antibiotics. Researchers have discovered a mechanism that likely contributes to the severity of P. aeruginosa infections, which could also be a target for future treatments. The results were recently appeared in the journal EMBO Reports.

Many bacterial species use sugar-binding molecules called lectins to attach to and invade host cells. Lectins can also influence the immune response to bacterial infections. However, these functions have hardly been researched so far. A research consortium led by Prof Dr Winfried Römer at the University of Freiburg and Prof Dr Christopher G. Mueller at the CNRS/University of Strasbourg has investigated the effect of the lectin LecB from P. aeruginosa on the immune system. It found that isolated LecB can render immune cells ineffective: The cells are then no longer able to migrate through the body and trigger an immune response. The administration of a substance directed against LecB prevented this effect and led to the immune cells being able to move unhindered again.

LecB blockades immune cells

As soon as they perceive an infection, cells of the innate immune system migrate to a nearby lymph node, where they activate T and B cells, triggering a targeted immune response. LecB, according to the current study, prevents this migration. “We assume that LecB not only acts on the immune cells themselves in this process, but also has an unexpected effect on the cells lining the inside of the blood and lymph vessels,” Römer explains. “When LecB binds to these cells, it triggers extensive changes in them.” Indeed, the researchers observed that important structural molecules were relocated to the interior of the cells and degraded. At the same time, the cell skeleton became more rigid. “The cell layer thus becomes an impenetrable barrier for the immune cells,” Römer said.

An effective agent against LecB

Can this effect be prevented? To find out, the researchers tested a specific LecB inhibitor that resembles the sugar building blocks to which LecB otherwise binds. “The inhibitor prevented the changes in the cells, and T-cell activation was possible again,” Mueller said. The inhibitor was developed by Prof Dr Alexander Titz, who conducts research at the Helmholtz Institute for Pharmaceutical Research Saarland and Saarland University.

Further studies are needed to determine how clinically relevant the inhibition of the immune system by LecB is to the spread of P. aeruginosa infection and whether the LecB inhibitor has potential for therapeutic application. “The current results provide further evidence that lectins are a useful target for the development of new therapies, especially for antibiotic-resistant pathogens such as P. aeruginosa,” the authors conclude.

Source: University of Freiburg

Categories : Diseases, Syndromes and ConditionsTags :

Tackling the Challenges of Lysosomal Storage Diseases Diagnosis and Treatment

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Source: NCI

A disease is defined as ’rare’ when it affects fewer than 1 in 2000 people,1 and there are currently more than 7000 known rare diseases (lysosomal storage diseases), affecting more than 300 million people worldwide.1-2 Most (70–80%) lysosomal storage diseases are genetic and inherited, while some may be acquired, and 70% are exclusively paediatric in onset.2

Patients with lysosomal storage diseases present unique challenges to healthcare professionals (HCPs), including diagnostic delays and a lack of information, expertise, and treatment options for many lysosomal storage diseases. Appropriate referrals to specialists, timely diagnosis and treatment, coordinated cross-functional care, and assisting patients in obtaining the proper support are vital roles for HCPs in enhancing quality of life for lysosomal storage disease patients and their families.3,4

Monique Nel, Medical Advisor – Rare Diseases at Sanofi, says: “We understand that HCPs may face difficulties when it comes to the diagnosis of a lysosomal storage disease, and that a coordinated approach to diagnosis and care for people living with lysosomal storage diseases is needed. Lysosomal storage diseases deserve the same amount of time, resources and dedication to finding effective treatments and therapies as any other condition. This is a mission that Sanofi strives to uphold every day, to help HCPs to improve diagnosis, especially as we are starting to see more patients diagnosed with lysosomal storage diseases in both the public and private sectors.”

“Sanofi is focused on education around innovative treatment and research efforts that improve real-world outcomes, investing in education and research to better manage and understand these conditions, and identifying areas requiring more attention,” says Nel.

In the 10 years of its existence, patient advocacy group Rare Diseases SA has made great strides in advocacy for lysosomal storage disease patients. Founder and CEO, Kelly du Plessis, says: “We need to acknowledge that local doctors and healthcare practitioners may have limited knowledge and experience of lysosomal storage diseases. What we would like to see is that they are upskilled on the following three aspects: knowing that lysosomal storage diseases exist, knowing the impact that these have on the patient, and knowing where to refer a patient who they think may have a rare condition. If we can tick these three boxes, great strides will have been made for the diagnostic odyssey that patients with lysosomal storage diseases go through.”

Says du Plessis: “Most importantly, we need a lysosomal storage disease policy to be recognised and enforced in SA, and we need National Treasury to assign a budget to treat these patients so that once an official diagnosis is made, they can receive immediate care. There is also a need for mechanisms to escalate product registration where there are no existing products or alternatives available for lysosomal storage disease patients.”

Partnerships with various stakeholders are paramount in terms of bringing innovative medicines and access to treatment to lysosomal storage disease patients. Says Nel: “For more than 40 years, Sanofi has been a pioneer in science and innovation, rallying its people and resources to help improve the lives of those living with lysosomal storage diseases. Through its commitment to faster diagnoses, innovative treatments, sustainable access and integrated support along the patient journey, Sanofi strives to enable more fulfilling futures.”

Sanofi continues to build on its scientific understanding and strives to develop more therapies with the potential to improve the lives of those living with lysosomal storage diseases and beyond.5 Says Nel: “Sanofi’s lysosomal storage disease patient registries represent one of the largest collections of real-world data for lysosomal storage diseases amassed over the past 30 years. It has a presence in 65 countries, with more than 920 participating sites and over 18,000 patients enrolled. These registries help researchers to publish the latest information on real-world outcomes, showcasing innovative treatments and ongoing research for people living with lysosomal storage diseases.”

Sanofi also has a Rare Humanitarian Programme, which has been running for 32 years and provides humanitarian support to people living with lysosomal storage diseases.Says Nel: “This isan integral part of Sanofi’s mission to develop sustainable healthcare systems, increase access, and improve standards of care for lysosomal storage diseases worldwide. Over 1,000 people in over 70 countries are currently receiving access to free therapy.6

“By building meaningful connections with all stakeholders through various platforms, we continuously strive to transform the practice of medicine, sharing experiences and breaking down barriers,” says Nel.

A useful resource for HCPs and patients is the list of lysosomal storage diseases maintained by the Genetic and Rare Diseases Information Center (GARD) of the US National Institutes of Health.7           

References

1.   NIH. Genetic and Rare Disease Information Center. FAQs About Rare Diseases. Available at: https://rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases. Accessed January 2022.

2.   Nguengang Wakap S, Lambert DM, Olry A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 2020;28:165–173.

https://doi.org/10.1038/s41431-019-0508-0.

3.    Elliott E, Zurynski Y. Rare diseases are a ‘common’ problem for clinicians. Aust Fam Physician. 2015 Sep;44(9):630. http://www.ncbi.nlm.nih.gov/pubmed/26488039.

4.    Dudding-Byth T. A powerful team: the family physician advocating for patients with a rare disease. Aust Fam Physician. 2015 Sep;44(9):634. http://www.ncbi.nlm.nih.gov/pubmed/26488040. NIH.

5.   Sanofi Your Health webpage. Rare Disease. https://www.sanofi.com/en/your-health/specialty-care/rare-diseases. Accessed February 2023.

6.   Sanofi. The Sanofi Genzyme Rare Humanitarian Program turns 30. Available at: https://www.sanofi.com/en/about-us/our-stories/the-sanofi-genzyme-rare-humanitarian-program-turns-30. Accessed February 2023.

7.   Genetic and Rare Disease Information Center. Browse by disease. Available at: https://rarediseases.info.nih.gov/diseases. Accessed February 2023.

Categories : Diseases, Syndromes and Conditions Immune SystemTags :

How the Body Responds to Life-threatening Disease from HSV-1

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Source: National Cancer Institute on Unsplash

Analysing an infant’s genome has allowed scientists to find a new way genetics influences the body’s antiviral response by studying a life-threatening disease caused by a common virus: herpes simplex virus 1 (HSV-1). The findings, published in Science Immunology, hold potential as a genetic marker doctors could use to gauge a child’s risk of herpes encephalitis, although such mutations are generally very rare in the population.

The researchers analysed genetic data from a patient with immunodeficiency and hospitalised at nine months old with herpes encephalitis, a rare but life-threatening brain inflammation after HSV-1 infection. They identified novel mutations in the gene GTF3A, and found that these mutations impair the innate immune response.

Many people are infected in childhood with the HSV-1 virus but the vast majority don’t suffer from encephalitis. The most common symptom of HSV-1 is oral cold sores, but many people show no signs at all. HSV-1 is more threatening to children and adults who are immunodeficient, whose immune system cannot control the virus well.

“Genetic and mechanistic analyses of uncommon viral diseases like herpes encephalitis are quite rare. In fact, the causes underlying severe herpes encephalitis are often unknown,” says Michaela Gack, PhD, FRIC’s scientific director. “This information provides us with invaluable insight into the fundamental molecular processes that govern our immune response and opens up opportunities for future research on severe disease outcomes.”

The Ghent research team led by Filomeen Haerynck, MD, PhD, reached out to Dr Gack’s team after finding the mutations in the gene. Dr Gack’s lab studies interactions between the human immune system and viruses on a molecular level.

The GTF3A mutations shape how cells respond to viral activity through the genetic makeup of a protein called TFIIIA. TFIIIA plays a role in helping a human enzyme produce certain types of RNA that can determine specific functions inside cells. Some RNAs can elicit an anti-herpes viral immune response.

Dr Gack’s team tested cells that have the mutations, and found that because of defects in certain immunostimulatory RNAs, the cells were more susceptible to HSV-1 infection and lost the ability to control the HSV-1 virus.

The affected gene is part of the body’s defence system that produces interferons to combat viruses. Interferons are crucial to the human immune response and for suppressing virus infection and spread.

This new genetic pathway could be helpful in understanding the immune response to other viruses, like Epstein-Barr virus, a common virus linked to mononucleosis and associated with certain types of cancer and multiple sclerosis.

“Understanding the molecular processes underlying antiviral responses is key to treating or possibly preventing severe viral infections that change patients’ and families’ lives,” Dr Gack said. “Our findings on critical immune defence proteins may translate into new therapies in the future.”

Source: Cleveland Clinic

Categories : Diseases, Syndromes and Conditions NeurologyTags :

Huntington’s Disease Impacts Neuron Types Differently

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A healthy neuron.
A healthy neuron. Credit: NIH

In patients with Huntington’s disease, neurons in a part of the brain called the striatum are some of the worst affected. Degeneration of these neurons contributes to patients’ loss of motor control, which is one of the major hallmarks of the disease.

Neuroscientists at MIT have now shown that two distinct cell populations in the striatum are affected differently by Huntington’s disease. Reporting their results in Nature Communication, they believe that neurodegeneration of one of these populations leads to motor impairments, while damage to the other population, located in structures called striosomes, may explain the mood disorders that are often see in the early stages of the disease.

“As many as 10 years ahead of the motor diagnosis, Huntington’s patients can experience mood disorders, and one possibility is that the striosomes might be involved in these,” says Ann Graybiel, an MIT Institute Professor and one of the senior authors of the study.

Using single-cell RNA sequencing to analyse the genes expressed in mouse models of Huntington’s disease and postmortem brain samples from Huntington’s patients, the researchers found that cells of the striosomes and another structure, the matrix, begin to lose their distinguishing features as the disease progresses. The researchers hope that their mapping of the striatum and how it is affected by Huntington’s could help lead to new treatments that target specific cells within the brain.

This kind of analysis could also shed light on other brain disorders that affect the striatum, such as Parkinson’s disease and autism spectrum disorder, the researchers say.

Neuron vulnerability

Huntington’s disease leads to degeneration of brain structures called the basal ganglia, which are responsible for control of movement and also play roles in other behaviors, as well as emotions. For many years, Graybiel has been studying the striatum, a part of the basal ganglia that is involved in making decisions that require evaluating the outcomes of a particular action.

Many years ago, Graybiel discovered that the striatum is divided into striosomes, which are clusters of neurons, and the matrix, which surrounds the striosomes. She has also shown that striosomes are necessary for making decisions that require an anxiety-provoking cost-benefit analysis.

In a 2007 study, Richard Faull of the University of Auckland discovered that in postmortem brain tissue from Huntington’s patients, the striosomes showed a great deal of degeneration. Faull also found that while those patients were alive, many of them had shown signs of mood disorders such as depression before their motor symptoms developed.

To further explore the connections between the striatum and the mood and motor effects of Huntington’s, Graybiel teamed up with Kellis and Heiman to study the gene expression patterns of striosomal and matrix cells. To do that, the researchers used single-cell RNA sequencing to analyze human brain samples and brain tissue from two mouse models of Huntington’s disease.

Within the striatum, neurons can be classified as either D1 or D2 neurons. D1 neurons are involved in the “go” pathway, which initiates an action, and D2 neurons are part of the “no-go” pathway, which suppresses an action. D1 and D2 neurons can both be found within either the striosomes and the matrix.

The analysis of RNA expression in each of these types of cells revealed that striosomal neurons are harder hit by Huntington’s than matrix neurons. Furthermore, within the striosomes, D2 neurons are more vulnerable than D1.

The researchers also found that these four major cell types begin to lose their identifying molecular identities and become more difficult to distinguish from one another in Huntington’s disease. “Overall, the distinction between striosomes and matrix becomes really blurry,” Graybiel says.

Striosomal disorders

The findings suggest that damage to the striosomes, which are known to be involved in regulating mood, may be responsible for the mood disorders that strike Huntington’s patients in the early stages of the disease. Later on, degeneration of the matrix neurons likely contributes to the decline of motor function, the researchers say.

In future work, the researchers hope to explore how degeneration or abnormal gene expression in the striosomes may contribute to other brain disorders.

Previous research has shown that overactivity of striosomes can lead to the development of repetitive behaviors such as those seen in autism, obsessive compulsive disorder, and Tourette’s syndrome. In this study, at least one of the genes that the researchers discovered was overexpressed in the striosomes of Huntington’s brains is also linked to autism.

Additionally, many striosome neurons project to the part of the brain that is most affected by Parkinson’s disease (the substantia nigra, which produces most of the brain’s dopamine).

“There are many, many disorders that probably involve the striatum, and now, partly through transcriptomics, we’re working to understand how all of this could fit together,” Graybiel says.

Source: Massachusetts Institute of Technology

Categories : Diseases, Syndromes and Conditions Immune SystemTags :

Iron Holds a Clue to New Lupus Treatments

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Source: Wikimedia CC0

A new approach for treating systemic lupus erythematosus (SLE) could lie in targeting iron metabolism in immune system cells. Researchers found that blocking an iron uptake receptor reduces disease pathology and promotes the activity of anti-inflammatory regulatory T cells in a mouse model of SLE. The findings were published in the journal Science Immunology.

Treatments for lupus aim to control symptoms, reduce immune system attack of tissues, and protect organs from damage. Only one targeted biologic agent has been approved for treating SLE, belimumab in 2011.

“It has been a real challenge to come up with new therapies for lupus,” said Jeffrey Rathmell, PhD, Vanderbilt University professor. “The patient population and the disease are heterogeneous, which makes it difficult to design and conduct clinical trials.”

Rathmell’s group has had a long-standing interest in lupus as part of a broader effort to understand mechanisms of autoimmunity.

When postdoctoral fellow Kelsey Voss, PhD, began studying T cell metabolism in lupus, she noticed that iron appeared to be a “common denominator in many of the problems in T cells,” she said. She was also intrigued by the finding that T cells from patients with lupus have high iron levels, even though patients are often anaemic.

“It was not clear why the T cells were high in iron, or what that meant,” said Voss.

To explore T cell iron metabolism in lupus, Voss and Rathmell drew on the expertise of other investigators at VUMC.

First, Voss used a CRISPR genome editing screen to evaluate iron-handling genes in T cells. She identified the transferrin receptor, which imports iron into cells, as critical for inflammatory T cells and inhibitory for anti-inflammatory regulatory T cells.

The researchers found that the transferrin receptor was more highly expressed on T cells from SLE-prone mice and T cells from patients with SLE, which caused the cells to accumulate too much iron.

“We see a lot of complications coming from that – the mitochondria don’t function properly, and other signalling pathways are altered,” Voss said.

An antibody that blocks the transferrin receptor reduced intracellular iron levels, inhibited inflammatory T cell activity, and enhanced regulatory T cell activity. Treatment of SLE-prone mice with the antibody reduced kidney and liver pathology and increased production of the anti-inflammatory factor, IL-10.

“It was really surprising and exciting to find different effects of the transferrin receptor in different types of T cells,” Voss said. “If you’re trying to target an autoimmune disease by affecting T cell function, you want to inhibit inflammatory T cells but not harm regulatory T cells. That’s exactly what targeting the transferrin receptor did.”

In T cells from patients with lupus, expression of the transferrin receptor correlated with disease severity, and blocking the receptor in vitro enhanced production of IL-10.

Since the transferrin receptor mediates iron uptake in many cell types, the researchers want to develop transferrin receptor antibodies that bind specifically to T cells, to minimise off-target effects. They are also interested in studying the details of their unexpected discovery that blocking the transferrin receptor enhances regulatory T cell activity.

Source: Vanderbilt University Medical Center

Categories : Diseases, Syndromes and Conditions Immune SystemTags :

Training Cells to Fight Both Chronic Inflammatory and Infectious Diseases

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T cell
Scanning Electron Micrograph image of a human T cell. Credit: NIH/NIAID

Researchers from the University of Queensland have identified a pathway in cells that could be used to reprogram the body’s immune system to fight back against both chronic inflammatory and infectious diseases such as E. Coli.

Reporting their findings in the open-access journal PNAS, Dr Kaustav Das Gupta and Professor Matt Sweet found that a glucose-derived molecule in immune cells can both stop bacteria growing and dampen inflammatory responses.

According to Dr Das Gupta, the discovery is a critical step towards future therapeutics that train immune cells.

“The effects of this molecule called ribulose-5-phosphate on bacteria are striking – it can cooperate with other immune factors to stop disease-causing strains of the E. coli bacteria from growing,” Dr Das Gupta said.

“It also reprograms the immune system to switch off destructive inflammation, which contributes to both life-threatening infectious diseases such as sepsis as well as chronic inflammatory diseases like respiratory diseases, chronic liver disease, inflammatory bowel disease, rheumatoid arthritis, heart disease, stroke, diabetes and dementia.”

The research was carried out on a strain of E. coli bacteria, responsible for 80% of urinary tract infections and also a common cause of sepsis. Pre-clinical trials confirmed the role of this pathway in controlling bacterial infections.

Professor Sweet said that human cells were also used to demonstrate that ribulose-5-phosphate reduces the production of molecules that drive chronic inflammatory diseases.

“Host-directed therapies which train our immune systems to fight infections, will become increasingly important as more types of bacteria become resistant to known antibiotics,” Professor Sweet said.

“A bonus is that this strategy also switches off destructive inflammation, which gives it the potential to combat chronic disease.

“By boosting the immune pathway that generates ribulose-5-phosphate, we may be able to give the body the power to fight back against inflammatory and infectious diseases – not one, but two of the major global challenges for human health.”

Many current anti-inflammatory therapies target proteins on the outside of cells but because this pathway occurs inside cells, the researchers devised a new approach to target the pathway using mRNA technology.

Source: University of Queensland

Categories : Diseases, Syndromes and ConditionsTags :

Strep A Toxin Serves as Both Weapon and Shield

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Streptococcus pyrogenese bound to human neutrophil
Streptococcus pyogenese bound to a human neutrophil. Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health

Griffith University researchers have unlocked one of the secrets as to why some forms of Streptococcus Group A (Strep A) are associated with severe invasive infection. The results, published in mBio, suggest that a toxin it secretes not only damages cells but helps Strep A resist host defence.

Around the world, invasive Strep A diseases are responsible for more than 163 000 deaths annually and a recent increase in cases of invasive Strep A disease has been observed internationally.

For the past 10 years, Institute for Glycomics Associate Professor Manisha Pandey and Professor Michael Good have been researching the pathways in which Strep A can spread through the body.

“The findings from this study will have far-reaching implications as Strep A is responsible for a significant number of invasive and non-invasive infections which cause significant morbidity and mortality globally,” Associate Professor Pandey said.

“The reason for this is that invasive organisms express significantly more of the toxin, streptolysin O (SLO), which was the main focus of this study.

“SLO exerts potent cell and tissue destructive activity and promotes Strep A resistance to clearance by white cells in the body which is the critical first element of host defence against invasive Strep A infection.”

Professor Good said: “We found SLO alters interactions with host cell populations and increases Strep A viability at sites in the body such as the blood and spleen, and that its absence results in significantly less virulence.”

“Essentially, the less SLO present, the less severe the case of Strep A.”

SLO is secreted by nearly all Strep A isolates, but those that secrete the most SLO are the most virulent.

This work underscores the importance of SLO in Strep A virulence while highlighting the complex nature of Strep A pathogenesis.

This improved insight into host-pathogen interactions will enable a better understanding of host immune evasion mechanisms and inform streptococcal vaccine development programs.

Dr Pandey said a key finding was the presence of SLO in invasive organisms did not impair the ability of the Strep A vaccine candidate developed by Griffith University’s Institute for Glycomics and which is now in a clinical trial.

The Strep A virulence study was part of a PhD project undertaken by Dr Emma Langshaw.

Source: Griffith University

Categories : COVID Diseases, Syndromes and ConditionsTags :

Prior COVID Infection Linked to New Autoimmune Conditions

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Photo by Mufid Majnun on Unsplash

In a new entry to the growing list of lasting complications from COVID infection, a large German cohort study of over 600 000 COVID patients indicates that new autoimmune conditions may result from previous COVID infection. The findings, which are awaiting peer review on the MedRxiv preprint server, show that the odds of new autoimmune conditions appear to increase in line with the severity of COVID infection.

After the acute phase of infection, some people may develop long-lasting symptoms, known as post-COVID, which are consistent with COVID infection and last more than 12 weeks. Most studies to date have focused on symptoms that partly wane over time. Many studies examined a small selective sample of patients, and only a few studies included a control group or information on chronic health conditions, such as SARS-CoV-2 infection.

Compared to post-COVID emergence of cardiovascular and other diseases, autoimmune diseases are less discussed in the literature, although autoantibodies could be found in patients after SARS-CoV-2 infection. So far there is limited evidence on newly manifested autoimmune diseases after an infection based on several case reports and one recent cohort study using UK health record data. In addition, COVID itself has some similarities with systemic autoimmune rheumatic diseases, which could make diagnosis difficult.

The researchers selected a cohort from German routine health care data, identifying individuals with polymerase chain reaction (PCR)-confirmed COVID through December 31, 2020. Patients were matched 1:3 to control patients without COVID. Both groups were followed up until June 30, 2021. We used the four quarters preceding the index date until the end of follow-up to analyse the onset of autoimmune diseases during the post-acute period. The researchers calculated the incidence rates (IR) per 1000 person-years for each outcome and patient group, and estimated incidence rate ratios (IRRs) of developing an autoimmune disease conditional on a preceding COVID.

In total, 641 704 patients with COVID were included. When comparing the incidence rates in the COVID and matched control groups, the researchers found a 42.63% higher likelihood of acquiring autoimmunity for patients who had suffered from COVID. This estimate was similar for common autoimmune diseases, such as Hashimoto thyroiditis, rheumatoid arthritis, or Sjögren syndrome. The highest IRR was observed for autoimmune disease of the vasculitis group. Patients with a more severe course of COVID were at a greater risk for incident autoimmune diseases. These risk increases were as follows:

  • 41% higher risk of Grave’s disease
  • 42–45% higher risk of rheumatoid arthritis
  • 25% higher risk of type 1 diabetes
  • 27-29% higher risk of Crohn’s disease

The researchers concluded that SARS-CoV-2 infection is associated with an increased risk of developing new-onset autoimmune diseases after the acute phase of infection.

Categories : Antibiotics Diseases, Syndromes and ConditionsTags :

Antibiotic Regimen may be Ineffective in TB Meningitis

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Tuberculosis bacteria
Tuberculosis bacteria. Credit: CDC

Research in animal models published in Nature Communications shows that an approved antibiotic regimen for multidrug-resistant (MDR) tuberculosis (TB) may not work for TB meningitis. Limited human studies also provide evidence that a new combination of drugs is needed to develop effective treatments for TB meningitis due to MDR strains.

In the study from Johns Hopkins Children’s Center, the investigators showed that the Food and Drug Administration (FDA)-approved regimen of three antibiotics – bedaquiline, pretomanid and linezolid (BPaL) – used for treating TB of the lungs due to MDR strains, is not effective in treating TB meningitis because bedaquiline and linezolid struggle to cross the blood-brain barrier.

Tuberculosis, caused by the bacteria Mycobacterium tuberculosis, is a global public health threat. About 1%–2% of TB cases progress into TB meningitis, the worst form of TB, which leads to an infection in the brain that causes increased fluid and inflammation.

“Most treatments for TB meningitis are based on studies of treatments for pulmonary TB, so we don’t have good treatment options for TB meningitis,” explains Sanjay Jain, M.D., senior author of the study and director of the Johns Hopkins Medicine Center for Infection and Inflammation Imaging Research.

In 2019, the FDA approved the BPaL regimen to treat MDR strains of TB, specifically those that lead to pulmonary TB. However, there are limited data on how well these antibiotics cross the blood-brain barrier.

In an effort to learn more, the research team synthesised a chemically identical and imageable version of the antibiotic pretomanid. They conducted experiments in mouse and rabbit models of TB meningitis using positron emission tomography (PET) imaging to noninvasively measure pretomanid penetration into the central nervous system as well as using direct drug measurements in mouse brains. In both models, researchers say PET imaging demonstrated excellent penetration of pretomanid into the brain or the central nervous system. However, the pretomanid levels in the cerebrospinal fluid (CSF) that bathes the brain were many times lower than in the brains of mice.

“When we have measured drug concentrations in the spinal fluid, we have found that many times they have no relation to what’s happening in the brain,” says Elizabeth Tucker, MD, a study first author and an assistant professor of anaesthesiology and critical care medicine. “This finding will change how we interpret data from clinical trials and, ultimately, treat infections in the brain.”

Next, researchers measured the efficacy of the BPaL regimen compared with the standard TB treatment for drug-susceptible strains, a combination of the antibiotics rifampin, isoniazid and pyrazinamide. Results showed that the antibacterial effect in the brain using the BPaL regimen in the mouse model was about 50 times lower than the standard TB regimen after six weeks of treatment, likely due to restricted penetration of bedaquiline and linezolid into the brain. The bottom line, says Jain, is that the “regimen that we think works really well for MDR-TB in the lung does not work in the brain.”

In another experiment involving healthy participants, three male and three female aged 20–53 years, first-in-human PET imaging was used to show pretomanid distribution to major organs, according to researchers.

Similar to the work with mice, this study revealed high penetration of pretomanid into the brain or central nervous system with CSF levels lower than those seen in the brain. “Our findings suggest pretomanid-based regimens, in combination with other antibiotics active against MDR strains with high brain penetration, should be tested for treating MDR-TB meningitis,” says study author Xueyi Chen, MD, a paediatric infectious diseases fellow, who is now studying combinations of such therapies.

Limitations included the small quantities of the imageable version of pretomanid per subject (micrograms) used. However, current evidence suggests that studies with small quantities of a drug are a reliable predictor of the drug biodistribution.

Source: Johns Hopkins Medicine

Categories : Diseases, Syndromes and Conditions Lab Tests and ImagingTags :

A Severe Form of Dementia may in Fact be Caused by a Cerebrospinal Fluid Leak

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MRI images of the brain
Photo by Anna Shvets on Pexels

A new study suggests that some patients diagnosed with behavioural-variant frontotemporal dementia (bvFTD) – a presently incurable, mentally debilitating condition – may instead have a cerebrospinal fluid leak, which is detectable on MRI scans and often treatable. The researchers say these findings, published in the peer-reviewed journal Alzheimer’s & Dementia: Translational Research and Clinical Interventions, could lead to a cure.

“Many of these patients experience cognitive, behavioural and personality changes so severe that they are arrested or placed in nursing homes,” said Wouter Schievink, MD, professor of Neurosurgery at Cedars-Sinai. “If they have behavioural-variant frontotemporal dementia with an unknown cause, then no treatment is available. But our study shows that patients with cerebrospinal fluid leaks can be cured if we can find the source of the leak.”

When cerebrospinal fluid (CSF) leaks into the body, the brain can sag, causing dementia symptoms. Schievink said many patients with brain sagging, detectable in MRI, go undiagnosed, and he advises clinicians to take a second look at patients with telltale symptoms.

“A knowledgeable radiologist, neurosurgeon or neurologist should check the patient’s MRI again to make sure there is no evidence for brain sagging,” Schievink said.

Clinicians can also ask about a history of severe headaches that improve when the patient lies down, significant sleepiness even after adequate night-time sleep, and whether the patient has ever been diagnosed with a Chiari brain malformation, a condition in which brain tissue extends into the spinal canal. Brain sagging, Schievink said, is often mistaken for a Chiari malformation.

Even when brain sagging is detected, the source of a CSF leak can be difficult to locate. When the fluid leaks through a tear or cyst in the surrounding membrane, it is visible on CT myelogram imaging with the aid of contrast medium.

Schievink and his team recently discovered an additional cause of CSF leak: the CSF-venous fistula. In these cases, the fluid leaks into a vein, making it difficult to see on a routine CT myelogram. To detect these leaks, technicians must use a specialized CT scan and observe the contrast medium in motion as it flows through the cerebrospinal fluid.

In this study, investigators used this imaging technique on 21 patients with brain sagging and symptoms of bvFTD, and they discovered CSF-venous fistulas in nine of those patients. All nine patients had their fistulas surgically closed, and their brain sagging and accompanying symptoms were completely reversed.

“This is a rapidly evolving field of study, and advances in imaging technology have greatly improved our ability to detect sources of CSF leak, especially CSF-venous fistula,” said Keith L. Black, MD, chair of the department of Neurosurgery at Cedars-Sinai. “This specialised imaging is not widely available, and this study suggests the need for further research to improve detection and cure rates for patients.”

The remaining 12 study participants, whose leaks could not be identified, were treated with nontargeted therapies designed to relieve brain sagging, such as implantable systems for infusing the patient with CSF. However, only three of these patients experienced relief from their symptoms.

“Great efforts need to be made to improve the detection rate of CSF leak in these patients,” Schievink said. “We have developed nontargeted treatments for patients where no leak can be detected, but as our study shows, these treatments are much less effective than targeted, surgical correction of the leak.”

Source: Cedars-Sinai Medical Center