Tag Archives: Brain

Microbiology

New Study Reveals How Heavy Alcohol Consumption Increases Brain Inflammation

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People with alcohol use disorder (AUD) experience a never-ending vicious cycle of changes in the brain and behavior. AUD can disrupt communication pathways in the brain, leading to an escalation of drinking behavior and further exacerbating the condition.

Scientists at Scripps Research have uncovered new insights into the role of the immune system in the cycle of alcohol use disorder (AUD). In a study published in Brain, Behavior, and Immunity, they found that the levels of the immune signaling molecule interleukin 1β (IL-1β) are elevated in the brains of mice with alcohol dependence. Furthermore, the IL-1β pathway operates differently in these mice, leading to inflammation in crucial regions of the brain that are associated with decision-making.

“These inflammatory changes to the brain could explain some of the risky decision-making and impulsivity we see in people with alcohol use disorder,” says senior author Marisa Roberto, Ph.D., the Schimmel Family Chair of Molecular Medicine and a professor of neuroscience at Scripps Research. “In addition, our findings are incredibly exciting because they suggest a potential way to treat alcohol use disorder with existing anti-inflammatory drugs targeting the IL-1β pathway.”

AUD is characterized by uncontrolled and compulsive drinking, and it encompasses a range of conditions including alcohol abuse, dependence, and binge drinking. Researchers have previously discovered numerous links between the immune system and AUD—many of them centered around IL-1β. People with certain mutations in the gene that codes for the IL-1β molecule, for instance, are more prone to developing AUD. In addition, autopsies of people who had AUD have found higher levels of IL-1β in the brain.

“We suspected that IL-1β was playing a role in AUD, but the exact mechanisms in the brain have been unclear,” says first author Florence Varodayan, Ph.D., an assistant professor at Binghamton University and former postdoctoral fellow in the Roberto lab.

In the new study, Roberto, Varodayan, and their colleagues compared alcohol-dependent mice with animals drinking moderate or no alcohol at all. They discovered that the alcohol-dependent group had about twice as much IL-1β in the medial prefrontal cortex (mPFC), a part of the brain that plays a role in regulating emotions and behaviors.

The team then went on to show that IL-1β signaling in the alcohol-dependent group was not only increased but also fundamentally different. In mice that had not been exposed to alcohol, as well as in mice that had drunk moderate amounts of alcohol, IL-1β activated an anti-inflammatory signaling pathway. In turn, this lowered levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), a signaling molecule known to regulate neural activity in the brain.

However, in alcohol-dependent mice, IL-1β instead activated pro-inflammatory signaling and boosted levels of GABA, likely contributing to some of the changes in brain activity associated with AUD. Notably, these changes in IL-1β signaling in the alcohol-dependent mice persisted even during alcohol withdrawal.

Drugs that block the activity of IL-1β are already approved by the U.S. Food and Drug Administration to treat rheumatoid arthritis and other inflammatory conditions. More work is needed to determine whether these existing drugs could have utility in treating AUD.

“We plan to follow up on this study with more work on exactly how targeting specific components of the IL-1β pathway might be useful in treating alcohol use disorder,” says Roberto.

Reference: “Chronic ethanol induces a pro-inflammatory switch in interleukin-1β regulation of GABAergic signaling in the medial prefrontal cortex of male mice” by F.P. Varodayan, A.R. Pahng, T.D. Davis, P. Gandhi, M. Bajo, M.Q. Steinman, W.B. Kiosses, Y.A. Blednov, M.D. Burkart, S. Edwards, A.J. Roberts and M. Roberto, 28 February 2023, Brain, Behavior, and Immunity.
DOI: 10.1016/j.bbi.2023.02.020

The study was funded by the National Institutes of Health, The Schimmel Family Chair, The Pearson Center for Alcoholism and Addiction Research, and The Scripps Research Institute’s Animal Models Core Facility.

Scripps Research Institute

Microbiology

New study focuses on genetic diversity of E. coli bacteria in hospitalized patients

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Reviewed by Emily Henderson, B.Sc.Mar 13 2023

The human intestine is an environment inhabited by many bacteria and other microorganisms collectively known as the gut microbiome, gut microbiota or intestinal flora. In most people, it contributes to wellness. A healthy gut indicates a stronger immune system, improved metabolism, and a healthy brain and heart, among other functions.

Escherichia coli is one of the bacteria found in practically everyone’s gut microbiota, where it performs important functions, such as producing certain vitamins.

But there’s a vast amount of genetic diversity in the species. Some of its members are pathogenic and can cause diseases such as urinary tract infections. E. coli is the main agent of this type of infection among both healthy people and hospitalized patients or users of healthcare services.”

Tânia Gomes do Amaral, Head of the Experimental Enterobacterial Pathogenicity Laboratory (LEPE), Federal University of São Paulo’s Medical School (EPM-UNIFESP), Brazil

Amaral is first author of an article published in the journal Pathogens on the virulence of these bacteria and their resistance to antibiotics in hospitalized patients.

“Our study focused on hospitalized patients because patients who stay in hospital for a long period are more likely to undergo various procedures, such as urine catheter insertion or venous access. Although these procedures are performed to assure life support, they may facilitate the entry of bacteria into the organism and cause an infection,” Amaral explained.

She earned a PhD in microbiology from EPM-UNIFESP in 1988, conducting part of her research at New York University Medical School and the Center for Vaccine Development at the University of Maryland, Baltimore (UMB) in the United States.

The article reports the findings of a broader study led by Amaral, with 12 co-authors who are researchers and graduate students, on the virulence and drug resistance of E. coli strains associated with urinary tract infections. The study was supported by FAPESP via three projects (18/17353-7, 19/21685-8 and 17/14821-7).

The main aim of this part of the study, described in the master’s dissertation of José Francisco Santos Neto, was to evaluate the diversity and drug resistance of pathogenic E. coli strains isolated from the gut microbiota of inpatients, and to analyze the frequency of endogenous infection (caused by bacteria from the patient’s own microbiota).

The UNIFESP group first investigated the genetic diversity and drug resistance of E. coli strains isolated from the gut microbiota of hospitalized patients, sequencing these strains as well as others isolated from their urine and comparing the results in order to evaluate dissemination of the bacteria in the hospital environment.

“We also compared the genomes of these strains with those of E. coli strains isolated in different parts of the world in order to see if any globally disseminated pathogenic bacteria were present in the study sample,” said Ana Carolina de Mello Santos, a postdoctoral researcher working on the LEPE team.

Urinary tract infections proved to be endogenous for the vast majority of the patients in the study (more than 70%). The results also showed that the patients’ gut microbiota contained at least two genetically different populations of E. coli and that about 30% were colonized by non-lactose-fermenting E. coli strains, which are less common, with some of the patients studied having only such strains in their gut microbiota.

“This finding is most interesting because previous research conducted in other countries to analyze the composition of human gut microbiota didn’t investigate non-lactose-fermenting E. coli,” Santos said.

The authors also note the presence of bacteria with all the genetic markers required for classification as pathogenic and the detection of pathogenic bacteria in the gut microbiota of all patients that had not yet developed an infection. “Hospitalized patients are more susceptible to infection because by definition they are already unwell. Colonization by pathogens is the first step in the spread of hospital-acquired infections now so frequent worldwide,” Santos said.

With regard to antibiotics and other antimicrobials, the authors stress that drug resistance is also a growing global problem, and enterobacterial resistance to third-generation cephalosporins as well as colistin is critical. In all patients whose gut microbiota was colonized by drug-resistant bacteria, the same bacteria also caused endogenous urinary tract infections. In other words, the multidrug-resistant bacteria colonized the gut and traveled to the urinary tract, where they caused an infection.

“In light of these findings, early assessment of gut microbiota in hospitalized patients, at least in cases of E. coli infection, can facilitate and guide their treatment, while also identifying patients who risk progressing to extra-intestinal diseases such as urinary tract infections, which were part of the focus for our study,” Amaral said. “We don’t yet know whether the findings also apply to other bacteria found in gut microbiota, such as the genera Klebsiella, Enterobacter, Pseudomonas and others that can cause infections when they travel to extra-intestinal sites.”

These bacterial genera tend to be even more drug-resistant than E. coli, representing a major public health problem in the hospital environment. As the researchers noted, the World Health Organization (WHO) considers E. coli strains resistant to cephalosporin and colistin to be a critical global health threat. “The presence in human gut microbiota of drug-resistant bacteria associated with severe infectious disease is a matter of great concern, not least because they could spread to people outside the hospital environment,” Amaral said.

Another point raised by the study is the importance of finding out when colonization of the patient’s gut by drug-resistant virulent bacteria occurred. The authors of the article were unable to determine whether the bacteria resistant to cephalosporins and colistin colonized the patients before or after they were hospitalized.

By analyzing the genomes of the strains, however, the researchers were able to identify global risk clones that can cause severe disease and are associated with antimicrobial resistance. “One such clone found in the gut microbiota of two patients was identical to others isolated from urinary tract infections in Londrina, Paraná [a state in South Brazil], and in the United States, as well as European and Asian countries. This shows that some strains found in the study are clones generally associated with infections in all regions of the world,” Amaral said.

This type of information is important when patients are hospitalized. Knowledge of bacterial virulence and drug resistance can be used to prevent infection in parts of the organism outside the intestine and stop the bacteria from spreading to other patients in the same hospital.

Source:

São Paulo Research Foundation (FAPESP)

Journal reference:

Santos-Neto, J.F., et al. (2023) Virulence Profile, Antibiotic Resistance, and Phylogenetic Relationships among Escherichia coli Strains Isolated from the Feces and Urine of Hospitalized Patients. Pathogens. doi.org/10.3390/pathogens11121528.

Microbiology

Harvard Scientists Uncover How the Brain Senses Infection

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A recent study led by researchers at Harvard Medical School sheds new light on how the brain becomes aware of the presence of an infection in the body.

The team, through their study of mice, uncovered that a small group of airway neurons play a crucial role in informing the brain about a flu infection. They also observed evidence of a secondary pathway from the lungs to the brain that becomes active during later in the infection.

The study was recently published in the journal Nature.

Although most people are sick several times a year, scientific knowledge of how the brain evokes the feeling of sickness has lagged behind research on other bodily states such as hunger and thirst. The paper represents a key first step in understanding the brain-body connection during an infection.

“This study helps us begin to understand a basic mechanism of pathogen detection and how that’s related to the nervous system, which until now has been largely mysterious,” said senior author Stephen Liberles, professor of cell biology in the Blavatnik Institute at HMS and an investigator at Howard Hughes Medical Institute.

The findings also shed light on how nonsteroidal anti-inflammatory drugs such as ibuprofen and aspirin alleviate influenza symptoms.

If the results can be translated into humans, the work could have important implications for developing more-effective flu therapies.

The Liberles lab is interested in how the brain and body communicate to control physiology. For example, it has previously explored how the brain processes sensory information from internal organs, and how sensory cues can evoke or suppress the sensation of nausea.

In the new paper, the researchers turned their attention to another important type of sickness that the brain controls: sickness from a respiratory infection.

During an infection, Liberles explained, the brain orchestrates symptoms as the body mounts an immune response. These can include broad symptoms such as fever, decreased appetite, and lethargy, as well as specific symptoms such as congestion or coughing for a respiratory illness or vomiting or diarrhea for a gastrointestinal bug.

The team decided to focus on influenza, a respiratory virus that is the source of millions of illnesses and medical visits and causes thousands of deaths in the United States every year.

Through a series of experiments in mice, first author Na-Ryum Bin, HMS research fellow in the Liberles lab, identified a small population of neurons embedded in the glossopharyngeal nerve, which runs from the throat to the brain.

Importantly, he found that these neurons are necessary to signal to the brain that a flu infection is present and have receptors for lipids called prostaglandins. These lipids are made by both mice and humans during an infection, and they are targeted by drugs such as ibuprofen and aspirin.

Cutting the glossopharyngeal nerve, eliminating the neurons, blocking the prostaglandin receptors in those neurons, or treating the mice with ibuprofen similarly reduced influenza symptoms and increased survival.

Together, the findings suggest that these airway neurons detect the prostaglandins made during a flu infection and become a communication conduit from the upper part of the throat to the brain.

“We think that these neurons relay the information that there’s a pathogen there and initiate neural circuits that control the sickness response,” Liberles said.

The results provide an explanation for how drugs like ibuprofen and aspirin work to reduce flu symptoms — and suggest that these drugs may even boost survival.

The researchers discovered evidence of another potential sickness pathway, this one traveling from the lungs to the brain. They found that it appears to become active in the second phase of infection as the virus infiltrates deeper into the respiratory system.

This additional pathway doesn’t involve prostaglandins, the team was surprised to find. Mice in the second phase of infection didn’t respond to ibuprofen.

The findings suggest an opportunity for improving flu treatment if scientists are able to develop drugs that target the additional pathway, the authors said.

The study raises a number of questions that Liberles and colleagues are eager to investigate.

One is how well the findings will translate to humans. Although mice and humans share a lot of basic sensory biology, including having a glossopharyngeal nerve, Liberles emphasized that researchers need to conduct further genetic and other experiments to confirm that humans have the same neuron populations and pathways seen in the mouse study.

If the findings can be replicated in humans, it raises the possibility of developing treatments that address both the prostaglandin- and nonprostaglandin pathways of flu infection.

“If you can find a way to inhibit both pathways and use them in synergy, that would be incredibly exciting and potentially transformative,” Liberles said.

Bin is already delving into the details of the nonprostaglandin pathway, including the neurons involved, with the goal of figuring out how to block it. He also wants to identify the airway cells that produce prostaglandins in the initial pathway and study them in more depth.

Liberles is excited to explore the full diversity of sickness pathways in the body to learn whether they specialize for different types and sites of infection. A deeper understanding of these pathways, he said, can help scientists learn how to manipulate them to better treat a range of illnesses.

Reference: “An airway-to-brain sensory pathway mediates influenza-induced sickness” by Na-Ryum Bin, Sara L. Prescott, Nao Horio, Yandan Wang, Isaac M. Chiu and Stephen D. Liberles, 8 March 2023, Nature.
DOI: 10.1038/s41586-023-05796-0

The study was funded by the National Institutes of Health, the Chan Zuckerberg Initiative, a Banting Postdoctoral Fellowship, and a Harvard Medical School Goldberg Fellowship.

Liberles is a consultant for Kallyope.

Harvard Medical School

Microbiology

New discoveries made regarding autism onset in mouse models

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Reviewed by Emily Henderson, B.Sc.Mar 10 2023

Although autism is a common neurodevelopmental disorder, the multiple factors behind its onset are still not fully understood. Animal models of idiopathic autism, especially mice, are often used to help researchers understand the complicated mechanisms behind the disorder, with BTBR/J being the most commonly used mouse model in the world.

Now, an international research collaboration including Kobe University’s Professor TAKUMI Toru and Researcher Chia-wen Lin et al. have made new discoveries regarding autism onset in mouse models.

In their detailed series of experiments and analyses of BTBR/J mice and the other subspecies BTBR/R, they revealed that endogenous retrovirus activation increases a fetus’s susceptibility to autism. They also discovered that BTBR/R exhibits autistic-like behaviors without reduced learning ability, making it a more accurate model of autism than the widely-used BTBR/J model.

It is hoped that further research will contribute towards better classification of autism types, as well as the creation of new treatment strategies for neurodevelopmental disorders.

These research results were published in Molecular Psychiatry on March 7, 2023

Main points

  • The researchers analyzed BTBR/J, a widely used mouse model of autism, and its subspecies BTBR/Rusing MRI. This revealed that the corpus callosum, which connects the left and right hemispheres of the brain, was impaired in BTBR/J mice but not in BTBR/R mice.
  • Genome and transcription analysis showed that BTBR mice have increased levels of endogenous retrovirus genes.
  • Furthermore, single-cell RNA analysis of BTBR/R mice revealed changes in the expression of various genes (including stress response genes) that are indicative of endogenous retrovirus activation.
  • Even though BTBR/J and BTBR/R mice have the same ancestry, the results of various behavioral analysis experiments revealed differences in spatial learning ability and other behaviors between the two types of model mice.

Research background

Autism (autism spectrum disorder) is a neurodevelopmental disorder that remains largely unexplored despite the rapidly increasing number of patients. Reasons for this continuing increase in people diagnosed with autism include changes to diagnostic criteria and older fathers becoming more common. Autism is strongly related to genetic factors and can be caused by abnormalities in DNA structure, such as copy number variations. Animal models, especially mice, are often used in research to illuminate the pathology of autism. Among these models, BTBR/J is a mouse model of the natural onset of autism that is commonly used. Studies have reported various abnormalities in BTBR/J mice including impairment of the corpus callosum (which connects the left and right hemispheres of the brain) and excessive immune system signaling. However, it is not fully understood why this particular lineage displays autistic-like behavioral abnormalities.

The aim of the current study was to shed light on the onset mechanism of these autistic-like behavioral abnormalities by conducting comparative analysis on BTBR/J and its subspecies BTBR/R.

Research findings

First of all, the researchers conducted MRI scans on BTBR/J and BTBR/R mice to investigate structural differences in each region of the brain. The results revealed that there were differences between BTBR/J and BTBR/R mice in 33 regions including the amygdala. A particularly prominent difference discovered was that even though BTBR/J’s corpus callosum is impaired, BTBR/R’s is normal.

Next, the research group used the array CGH method to compare BTBR/R’s copy number variations with that of a normal mouse model (B6). They revealed that BTBR/R mice had significantly increased levels of endogenous retroviruses (ERV) in comparison to B6 mice. Furthermore, qRT-PCR tests revealed that these retroviruses were activated in BTBR/R mice. On the other hand, in B6 mice there was no change in the expression of LINE ERV (which is classified in the same repetitive sequence), indicating that this retroviral activation is specific to BTBR.

Subsequently, the researchers carried out single-cell RNA analysis on the tissue of embryonic BTBR mice (on the AGM and yolk sac). The results provide evidence of ERV activation in BTBR mice, as expression changes were observed in a group of genes downstream of ERV.

Lastly, the researchers comprehensively investigated the differences between BTBR/J and BTBR/R on a behavioral level. BTBR/R mice were less anxious than BTBR/J and showed qualitative changes in ultrasound vocalizations, which are measured as a way to assess communicative ability in mice. BTBR/R mice also exhibited more self-grooming behaviors and buried more marbles in the marble burying test. These two tests were designed to detect repetitive behavioral abnormalities in autistic individuals. From the results, it was clear that BTBR/R exhibits more repetitive behaviors (i.e. it is more symptomatic) than BTBR/J. The 3-chamber social interaction test, which measures how closely a mouse will approach another mouse, also revealed more pronounced social deficits in BTBR/R than BTBR/J mice (Figure 4i). In addition, a Barnes maze was used to conduct a spatial learning test, in which BTBR/J mice exhibited reduced learning ability compared to B6 (normal mice). BTBR/R mice, on the other hand, exhibited similar ability to B6.

Overall, the study revealed that retrovirus activation causes the copy number variants in BTBR mice to increase, which leads to the differences in behavior and brain structure seen in BTBR/J and BTBR/R mice (Figure 5).

Further developments

BTBR/J mice are widely used by researchers as a mouse model of autism. However, the results of this study highlight the usefulness of the other lineage of BTBR/R mice because they exhibit autistic-like behavior without compromised spatial learning ability. The results also suggest that it may be possible to develop new treatments for autism that suppress ERV activation. Furthermore, it is necessary to classify autism subtypes according to their onset mechanism, which is a vital first step towards opening up new avenues of treatment for autism.

Source:

Kobe University

Journal reference:

Lin, C-W., et al. (2023) An old model with new insights: endogenous retroviruses drive the evolvement toward ASD susceptibility and hijack transcription machinery during development. Molecular Psychiatry. doi.org/10.1038/s41380-023-01999-z.

Microbiology

Study finds two substances capable of inhibiting proliferation of glioblastoma cells

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Reviewed by Emily Henderson, B.Sc.Mar 7 2023

Glioblastoma is a malignant tumor of the central nervous system (brain or spinal cord) and one of the deadliest types of cancer. Few drugs have proved effective at combating this uncontrolled growth of glial cells, which anyway constitute a large proportion of the brain tissue in mammals. The standard treatment is surgical removal of the tumor, followed by chemotherapy with temozolomide, radiation therapy, and then nitrosoureas (such as lomustine). Patient survival has improved moderately over the years, but the prognosis remains poor. These tumors are typically resistant to existing drugs and often grow back after surgery.

Promising results have now been reported in a study involving two substances found to inhibit proliferation of glioblastoma cells. An article on the study is published in the journal Scientific Reports.

The researchers conducted in vitro tests to evaluate the biological effects of 12 compounds obtained through total synthesis of apomorphine hydrochloride against glioblastoma cells. They found that two of these compounds – an isoquinoline derivative called A5 and an aporphine derivative called C1 – reduced the viability of glioblastoma cells, suppressed the formation of new tumor stem cells and boosted the effectiveness of temozolomide.

More research is needed to glean a better understanding of the action of these compounds on tumor cells and normal cells, but the results so far suggest a potential therapeutic application as novel cytotoxic agents to control glioblastomas.”

Dorival Mendes Rodrigues-Junior, first author of the article and postdoctoral researcher, University of Uppsala’s Department of Medical Biochemistry and Microbiology, Sweden

In designing the study, the researchers leveraged the apomorphine hydrochloride production process, in which each step in a sequence of chemical reactions creates compounds that are consumed in the next step. Previous research conducted by the group to evaluate the effectiveness of 14 of these compounds against head and neck squamous cell cancer had shown that A5 and C1 were promising, and they decided to conduct more tests. “Given the importance and urgency of identifying novel therapeutic substances that can be used to treat glioblastoma, we evaluated the same panel as in the previous study but now for this other type of tumor,” Rodrigues-Junior said.

The project on molecular markers of head and neck cancer was supported by FAPESP and also involved André Vettore, another author of the recently published article. Vettore is a professor in the Department of Biological Sciences at the Federal University of São Paulo (UNIFESP) in Diadema, Brazil.

“The findings of this study are interesting, but they’re only the first steps in a long journey. In vivo studies are still required to confirm the effects of A5 and C1 on glioblastoma cells and non-tumorigenic nerve cells,” Vettore said.

If the results of this future research are also promising, he added, it will be possible to move on to clinical trials to confirm the effectiveness of the compounds. “Once all these stages are completed, the compounds may finally be used to treat glioblastoma patients.”

Natural bioactive products

The study was conducted in vitro to evaluate the antitumor activity of 12 aromatic compounds obtained as intermediates in total synthesis of apomorphine, an alkaloid that interacts with the dopamine pathway and is widely used to control the motor alterations caused by Parkinson’s disease.

Alkaloids are a well-known class of natural products with multiple pharmacological properties and are studied for their anticonvulsant, antiplatelet aggregation, anti-HIV, dopaminergic, antispasmodic and anticancer effects.

FAPESP fosters studies of these substances via a project on bioactive natural products led at UNIFESP’s Department of Chemistry in Diadema by Cristiano Reminelli, second author of the Scientific Reports article. The other authors are Haifa Hassanie, Gustavo Henrique Goulart Trossini, Givago Prado Perecim, Laia Caja and Aristidis Moustakas.

Source:

São Paulo Research Foundation (FAPESP)

Journal reference:

Rodrigues-Junior, D.M., et al. (2023) Aporphine and isoquinoline derivatives block glioblastoma cell stemness and enhance temozolomide cytotoxicity. Scientific Reports. doi.org/10.1038/s41598-022-25534-2.

Microbiology

Infections with many different types of bacteria including Streptococcus pneumonia, Listeria monocytogens, and Neisseria mengitidis can cause bacterial …

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Infections with many different types of bacteria including Streptococcus pneumonia, Listeria monocytogens, and Neisseria mengitidis can cause bacterial meningitis. It’s estimated that every year over 1.2 million cases of bacterial meningitis happen around the world, and without treatment, this deadly disease is fatal to seven of ten people who are sickened by it. Even with antibiotic treatments, three of ten patients die. Survivors are left with issues like chronic headaches, seizures, loss of vision or hearing, and other neurological consequences. New research reported in Nature has revealed how bacteria are able to penetrate the meninges that surround and protect the brain to cause bacterial meningitis. The findings have shown that bacteria use neurons to evade immunity and infect the brain, and the work may aid in the creation of new therapeutics.

A digitally-colorized SEM image depicts of Streptococcus pneumoniae bacteria (lavender), as they were being attacked by a white blood cell (pink). / Credit: CDC/ Dr. Richard Facklam

Right now, antibiotics can help eliminate the bacterial pathogens that cause this illness. But steroids are also needed to control the dangerous inflammation that can occur along with the infection. However, reducing inflammation also weakens the immune response, making it harder to get rid of the infection.

In this research, the scientists used Streptococcus pneumoniae and Streptococcus agalactiae bacteria, which can both cause bacterial meningitis in humans. They determined that when these bacteria get to the meninges, they release a toxin, which activates neurons in the meninges that sense pain. This pain neuron activation could explain why bacterial meningitis patients get horrible headaches, noted the researchers.

The activated pain neurons then release a signaling molecule called CGRP, which binds to a receptor called RAMP1 on the surface of immune cells called macrophages. Once CGRP binds to RAMP1 on macrophages, the immune cells are basically disabled, and they stop responding to bacterial infections like they normally would.

The link between CGRP and RAMP1 on macrophages also stops them from signaling to other immune cells, which allows the bacterial infection to not only penetrate the meninges but to spread infection.

This work was confirmed with the use of a mouse model that lacked the pain neurons that are activated by bacteria. Compared to mice with those neurons, the engineered mice had less severe brain infections when they were exposed to bacteria that cause meningitis. There were also lower levels of CGRP in the engineered mice compared to normal mice. The normal mice, however, had higher levels of bacteria in the meninges.

Additional experiments also showed that when mice were treated with drugs that block RAMP1, the severity of the bacterial infection was reduced. Mice treated with RAMP1 blockers were able to clear their infections faster too.

It may be possible to help the immune system clear cases of bacterial meningitis with medications that block either CGRP or RAMP1, potentially in conjunction with antibiotics. There are already drugs that can do this, and they are generally used to treat migraine.

Sources: Harvard Medical School, Nature


Carmen Leitch

Microbiology

UTHSC researchers secure $308,000 grant from Department of Defense for dementia study

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Reviewed by Emily Henderson, B.Sc.Feb 19 2023

Repeated traumatic brain injuries (TBI) in soldiers and military personnel can cause behavioral, neurological, and cognitive effects and lead to dementia. There is currently no treatment for that type of dementia, but a $308,000 grant from the United States Department of Defense aims to help researchers at the University of Tennessee Health Science Center find one.

TBI can lead to the development of frontotemporal degeneration (FTD), a progressive process marked by atrophy of the frontal and temporal lobes. FTD is one of the most common causes of dementia in people under the age of 65.

Principal investigator Mohammad Moshahid Khan, PhD, associate professor in the Department of Neurology, and co-investigator Tayebeh Pourmotabbed, PhD, professor in the Department of Microbiology, Immunology, and Biochemistry, are working on a project to find the first therapeutic intervention to prevent frontotemporal dementia or slow its progression in a mouse model linked with the condition.

The team is aiming to use a novel gene therapy called DNAzymes to target pathological tau aggregates, which cause frontotemporal dementia and its resulting cognitive impairment and progressive neuropathological symptoms. The team is examining the effective dose, frequency, and duration of treatment as well as its potential in reducing neurodegeneration and behavioral deficits in mice.

Our preliminary data suggest that DNAzyme is a novel therapeutic approach and has a great potential for preventing the accumulation of pathological tau. The results of this proposal would be foundational for future studies examining the clinical use of DNAzyme for other neurological diseases associated with traumatic brain injury and other tauopathies.”

Dr. Mohammad Moshahid Khan, PhD, associate professor in the Department of Neurology

“DNAzyme is a powerful gene therapy technique that can be used to prevent production of proteins associated with diseases, like tau protein in Alzheimer’s disease and dementia,” Dr. Pourmotabbed said. “We have used DNAzyme as a potential therapy for breast cancer, glioma, and Huntington’s disease in preclinical animal models with great success. Hopefully, with the use of DNAzyme technology, we would be able to reduce the risk of dementia after traumatic brain injury in veterans and other individuals that deal with this debilitating disease.”

Source:

University of Tennessee Health Science Center

Microbiology

Even after decades of research, the cause of the most common form of dementia, Alzheimer’s disease, is unclear. …

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Even after decades of research, the cause of the most common form of dementia, Alzheimer’s disease, is unclear. Evidence that pointed to plaques and tangles of disordered proteins called amyloid beta and tau has been called into question since therapeutics that aim at the protein clumps have not been particularly effective at relieving disease. In recent years, scientists have also found evidence that viral infections may be to blame for some serious long-term diseases; multiple sclerosis, for example, seems to only develop in people who have been infected with Epstein-Barr virus (EBV). The pandemic coronavirus SARS-CoV-2 also appears to have neurological impacts in some people.

Influenza B virus particles, colorized blue, isolated from a patient sample and then propagated in cell culture. Both influenza A and B can cause seasonal flu; however, unlike influenza A virus, which can also infect animals, influenza B only infects humans. Microscopy by John Gallagher and Audray Harris, NIAID Laboratory of Infectious Diseases. Credit: NIAID

Researchers have now used the power of biobanks that contain health data from hundreds of thousands of people to look for links between viral infections like influenza and EBV and neurodegenerative diseases including Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), generalized dementia, and Parkinson’s disease. Data from FinnGen on over 300,000 people was used to look for associations that were then assessed in the nearly half a million people in the UK Biobank for confirmation. An additional cohort of almost 100,000 people who had not had any neurodegenerative disorder was used as a control group. COVID-19 hospitalizations were not included in this study. The findings have been reported in Neuron.

The research showed that there is a connection between viral infections and neurodegeneration, which is particularly significant for viruses that are able to cross the blood brain barrier and infect the central nervous system, perhaps unsurprisingly. The study authors suggested that these so-called neurotropic viruses may be causing neurodegeneration because of neuroinflammation.

A first pass of the data suggested there were 45 significant associations between viral infections and neurodegenerative disease. After querying the UK Biobank, the researchers refined it to 22 associations.

The top candidate was generalized dementia, which was linked to infections with six different viruses: all influenza, flu and pneumonia, viral pneumonia, viral encephalitis, viral warts, and other viral diseases seem to raise the risk of generalized dementia. The research also showed that anyone who had viral encephalitis was 20 times more likely or more to receive an Alzheimer’s diagnosis compared to people who have not had viral encephalitis.

Severe flu was connected to a greater likelihood of different types of neurodegeneration. Influenza and pneumonia exposures were also linked to an increased risk of all neurodegenerative disorders except multiple sclerosis.

Senior study author Michael Nalls, Ph.D., the NIH Center for Alzheimer’s Related Dementias (CARD) Advanced Analytics Expert Group leader, also noted that the viral infections that are being considered in this study were quite severe and led to hospitalizations; they were not mild cases of the common cold.

“Nevertheless, the fact that commonly used vaccines reduce the risk or severity of many of the viral illnesses observed in this study raises the possibility that the risks of neurodegenerative disorders might also be mitigated,” said Nalls.

“Our results support the idea that viral infections and related inflammation in the nervous system may be common and possibly avoidable risk factors for these types of disorders,” added study co-author Andrew B. Singleton, Ph.D., the director of CARD.

Sources: National Institutes of Health, Neuron


Carmen Leitch

Microbiology

Cancer immunotherapy does not interfere with COVID-19 immunity in vaccinated patients, study shows

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Reviewed by Emily Henderson, B.Sc.Jan 31 2023

Research findings published in Frontiers in Immunology show that cancer immunotherapy does not interfere with COVID-19 immunity in previously vaccinated patients. These findings support recommending vaccination for patients with cancer, including those receiving systemic therapies, say Saint Louis University scientists.

Immunotherapy is a treatment strategy that boosts a patient’s immune system to attack cancerous cells. In this novel study led by Ryan Teague, Ph.D., professor of molecular microbiology and immunology at Saint Louis University’s School of Medicine, the Teague lab studied T cell responses and antibody responses against the SARS-CoV-2 spike protein in vaccinated and unvaccinated patients receiving immunotherapy.

Their research found data to support the clinical safety and efficacy of COVID-19 vaccination in patients receiving immune checkpoint inhibitors, a class of immunotherapy drugs.

It was thought that patients who had recently been vaccinated for or exposed to COVID-19 may have boosted inflammatory responses after immune checkpoint blockade treatment. The study found that immunotherapy did not tend to boost immune responses against COVID-19 in vaccinated patients, supporting the safety of receiving immune checkpoint inhibitors and the vaccine simultaneously.”

Ryan Teague, Ph.D., professor of molecular microbiology and immunology at Saint Louis University’s School of Medicine

Teague notes that several timely factors came together to enable this research. In July 2022, the Teague lab published a study in Cancer Immunology Immunotherapy using a new technique known as Single-Cell RNA Sequencing, which allows researchers to study genetic information at the individual cell level to characterize immune responses after cancer treatment to identify biomarkers that could predict better patient outcomes.

Having collected blood from more than 100 patients with cancer during the COVID-19 pandemic, Teague recognized the opportunity to extend the benefit of this collection toward improving our understanding of patient immune responses against the vaccine.

“The COVID paper came from a unique window of time where we had a pandemic, and we had this valuable collection of patient samples that we could use to ask this timely question,” Teague said.

Additional authors include graduate students Alexander Piening, Emily Ebert, Niloufar Khojandi, and Assistant Professor Elise Alspach, Ph.D., from the Department of Molecular Microbiology and Immunology at SLU’s School of Medicine.

This work was supported by grant number NIH NCI R01 CA238705 from the National Institutes of Health.

Source:

Saint Louis University School of Medicine

Journal reference:

Piening, A., et al. (2022) Immune responses to SARS-CoV-2 in vaccinated patients receiving checkpoint blockade immunotherapy for cancer. Frontiers in Immunology. doi.org/10.3389/fimmu.2022.1022732.

Microbiology

Normally, the measles virus only infects immune and epithelial cells, leaving cells of the nervous system alone. But …

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Normally, the measles virus only infects immune and epithelial cells, leaving cells of the nervous system alone. But measles can also lead to a neurological disorder called subacute sclerosing panencephalitis, or SSPE. This complication of measles infections is rare, but it can happen years after the acute phase is over, and can be fatal. Researchers have now learned how the virus gains the ability to disrupt the nervous system.

An illustration of a measles virus particle. Tubercular studs (maroon) are H-proteins (hemagglutinin); F-proteins (grey). / Credit: CDC/ Allison M. Maiuri, MPH, CHES / Illustrator: Alissa Eckert

This study, reported in Science Advances, has shown that the measles virus may persist in the body, and acquire mutations over time. If mutations happen in one particular viral protein, it can affect how the virus infects cells. Mutant and normal forms of the measles virus can then interact, and enable the virus to infect the brain.

Measles is caused by one of the most contagious viruses ever to have affected humans. While vaccinations have dramatically reduced the incidence of measles infections, the virus is experiencing a resurgence. The COVID-19 pandemic caused a major disruption to the distribution and use of typical vaccines, like the one many kids receive for measles. Vaccine hesitancy is also a growing public health problem in some countries including the United States, and people are starting to get measles more often, though the US once came close to eradicating the disease.

“Despite its availability, the recent COVID-19 pandemic has set back vaccinations, especially in the global South,” noted corresponding study author Yuta Shirogane, an assistant professor at Kyushu University.

The measles virus is encased by a lipid bilayer, which carries a receptor that binds to the hemagglutinin (H) protein and fusion (F) proteins. The H protein binds to a target cell receptor, then the conformation of the F protein changes, which fuses the membranes of the virus and target cell to cause infection.

Previous work by this team has shown that mutations in the F protein lead to a “hyperfusongenic” state that allows it to infect the brain. After assessing mutations in measles virus samples that were isolated from SSPE patients, the researchers identified various mutations affecting the F protein. Some mutations increased infection activity while others decreased it.

“It is almost counter to the ‘survival of the fittest’ model for viral propagation. In fact, this phenomenon where mutations interfere and/or cooperate with each other is called ‘Sociovirology.’ It’s still a new concept, but viruses have been observed to interact with each other like a group. It’s an exciting prospect,” noted Shirogane.

The researchers are hopeful that these findings will open up new treatment options for SSPE patients, and help us learn more about other viruses.

Sources: Kyushu University, Science Advances


Carmen Leitch