Tag Archives: Cell Biology

Harvard Scientists Uncover How the Brain Senses Infection

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.

New discoveries made regarding autism onset in mouse models

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.

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.

Antibiotics can destroy many types of bacteria, but increasingly, bacterial pathogens are gaining resistance to many commonly used …

Antibiotics can destroy many types of bacteria, but increasingly, bacterial pathogens are gaining resistance to many commonly used types. As the threat of antibiotic resistance looms large, researchers have sought to find new antibiotics and other ways to destroy dangerous bacteria. But new antibiotics can be extremely difficult to identify and test. Bacteriophages, which are viruses that only infect bacterial cells, might offer an alternative. Bacteriophages (phages) were studied many years ago, before the development of antibiotic drugs, and they could help us once again.

Image credit: Pixabay

If we are going to use bacteriophages in the clinic to treat humans, we should understand how they work, and how bacteria can also become resistant to them. Microbes are in an arms race with each other, so while phages can infect bacteria, some bacterial cells have found ways to thwart the effects of those phages. New research reported in Nature Microbiology has shown that when certain bacteria carry a specific genetic mutation, phages don’t work against them anymore.

In this study, the researchers used a new technique so they could actually see a phage attacking bacteria. Mycobacteriophages infect Mycobacterial species, including the pathogens Mycobacterium tuberculosis and Mycobacterium abscessus, as well as the harmless Mycobacterium smegmatis, which was used in this research.

The scientists determined that Mycobacterial gene called lsr2 is essential for many mycobacteriophages to successfully infect Mycobacteria. Mycobacteria that carry a mutation that renders the Lsr2 protein non-functional are resistant to these phages.

Normally, Lsr2 aids in DNA replication in bacterial cells. Bacteriophages can harness this protein, however, and use it to reproduce the phage’s DNA. Thus, when Lsr2 stops working, the phage cannot replicate and it cannot manipulate bacterial cells.

In the video above, by first study author Charles Dulberger, a genetically engineered mutant phage infects Mycobacterium smegmatis. First, one phage particle (red dot at 0.42 seconds) binds to a bacterium. The phage DNA (green fluorescence) is injected into the bacterial cell (2-second mark). The bright green dots at the cells’ ends are not relevant. For a few seconds, the DNA forms a zone of phage replication, and fills the cell. Finally, the cell explodes at 6:25 seconds. (About three hours have been compressed to make this video.)

The approach used in this study can also be used to investigate other links between bacteriophages and the bacteria they infect.

“This paper focuses on just one bacterial protein,” noted co-corresponding study author Graham Hatfull, a Professor at the University of Pittsburgh. But there are many more opportunities to use this technique. “There are lots of different phages and lots of other proteins.”

Sources: University of Pittsburgh, Nature Microbiology

Carmen Leitch

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

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

In recent years, we have learned a lot about the crucial role gut microbes play in our health …

In recent years, we have learned a lot about the crucial role gut microbes play in our health and well being. The extent of their influence can be surprising at times. Research has shown that gut microbes can impact the repair of tissue damage by fueling the production of a type of immune cell called Tregs, or regulatory T cells. These cells reside in various tissues and help regulate inflammation and immunity in different organs. But new work has shown that Tregs can also move around the body and respond when they are called to help fix injuries and tissue damage, such as in the muscles and liver. The findings, which used a mouse model and still have to be confirmed in humans, have been reported in the journal Immunity.

Image credit: Pixabay

There are Tregs that reside in the colon, and these cells are known to play an important role in the maintenance of gut health. The immune system in the gut has to protect us from infection while also ignoring the harmless or beneficial microbes in the gut microbiome. Gut microbes have also been known to affect Treg production. But colonic Tregs were thought to stay in the gut. In this study, the investigators found colonic Tregs among muscle cells.

First study author Bola Hanna, a research fellow in immunology at Harvard Medical School (HMS) noticed cells that looked like gut-derived Tregs among muscle tissue. The researchers wanted to known more about these mysterious cells. First, they confirmed the identity of the Tregs by analyzing gene expression and molecular characteristics. This indicated that these cells were just like colonic Tregs. Next, the investigators tagged those cells and watched as they moved around the bodies of a mouse model. The researchers assessed the antigens on these cells as well, confirming that they were equivalent to Tregs from the gut.

When a mouse model was created to lack these Tregs, and was then subjected to muscle injury, the mice had high levels of inflammation and difficulty healing. When healing did happen, it was accompanied by scarring.

In another experiment, mice were given antibiotics to reduce the levels of gut microbes. Once again, when muscle injury occurred, it took longer to heal. But if the gut microbiome was restored, normal healing commenced.

The colonic Tregs are promoting healing in muscles by reducing the levels of an inflammatory molecule called IL-17.

The investigators also found evidence of gut Tregs in different organs including the kidneys, liver, and spleen. In a mouse model of fatty liver disease, there were unusually high levels of colonic Tregs compared to healthy mice, suggesting that Tregs are influencing inflammation in a variety of tissues.

In the mouse model of fatty liver disease, symptoms got worse when the mice lacked Tregs, which also seems to confirm that colonic Tregs are playing an important role in countering the effects of inflammation due to fatty liver disease.

“Our observations indicate that gut microbes drive the production of a class of regulatory T cells that are constantly exiting the gut and act as sentries that sense damage at distant sites in the body and then act as emissaries to repair that damage,” explained senior study author Diane Mathis, a professor of immunology in the Blavatnik Institute at HMS. This work may also help scientists create therapies for fatty liver disease.

Sources: Harvard Medical School, Immunity

Carmen Leitch

The SARS-CoV-2 virus and the illness it causes, COVID-19, have made an indelible mark on our lives. It …

The SARS-CoV-2 virus and the illness it causes, COVID-19, have made an indelible mark on our lives. It seems that is also true in more ways than one; new research has shown that when the virus infects cells, portions of the viral genome integrate into the genome of host cells in a phenomenon known as reverse transcription. While this is a relatively rare even for SARS-CoV-2, so many people have been infected with the virus that integration has probably happened many times. Scientists have now used several techniques to show that SARS-CoV-2 can integrate into a host cell genome, and the findings have been reported in the journal Viruses. This study is confirmation of previous work reported in the Proceedings of the National Academy of Sciences in 2021.

Colorized scanning electron micrograph of a cell (red) infected with the Omicron strain of SARS-CoV-2 virus particles (blue), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID

This research may help explain why some people continue to test positive for the virus long after their infection has subsided and they have recovered. In reverse transcription, RNA molecules, in this case from SARS-CoV-2, are transcribed into cDNA, a flip of the typical process in which active genes are transcribed into RNA molecules. Those reverse-transcribed cDNA molecules are then stitched into the host cell genome. If some of those cells are captured during a COVID-19 test, PCR would recognize and amplify the viral DNA in the host cell, causing a positive test result.

This study has also shown that simply inserting viral RNA into cells is not enough to cause genomic integration, so it seems unlikely based on the evidence we have now that mRNA from the COVID-19 vaccines would cause integration into cells’ DNA.

“This paper puts our data on a very firm footing. Hopefully, it will clarify some of the issues raised in the discussion that followed the first paper, and provide some reassurance to people who were worried about the implications for the vaccine,” said corresponding study author Rudolf Jaenisch, a founding member of the Whitehead Institute.

Since the integration of the SARS-CoV-2 genome into cells’ DNA is unusual, the researchers had to use a very sensitive method called digital PCR, which detects very specific genetic sequences, to identify instances in which viral RNA had been integrated into the genome of a cell.

The digital PCR results found viral RNA that had been reverse-transcribed to cDNA in about 4 to 20 of every 1,000 cells, but this includes all molecules of the sort, whether they ended up being integrated into a genome or not. Thus, the researchers suggested that viral integration is even more rare than that.

Whole genome sequencing can be used to show when that integration also occurred, because those events are typically accompanied by a reverse transcription complex called LINE1. The LINE1 sequences act as an indicator of integration. However, WGS is usually only used on a handful of cells, so when other investigators looked for those sequences, they could not usually be found.

“Because the human cell genome coverage by whole genome sequencing is very limited, you would need to run the sequencing experiment many times in order to have a good chance of detecting one viral genome copy,” explained postdoctoral researcher and first study author Liguo Zhang.

In this study, the researchers created cells that would overexpress LINE1, and make viral integration more common artificially. This time, the digital PCR showed that viral cDNA appeared in fourteen to twenty of every 1,000 cells, and WGS identified instances of integration along with LINE1. Further work with a tool called TagMap confirmed viral integration without overexpressing LINE1.

“This is unambiguous proof of viral genomic integration,” Zhang said. When this approach was repeated with cells that were treated with SARS-CoV-2 vaccine, there was no evidence of integration.

“We need to do further testing, but our results are consistent with vaccine RNA not integrating,” Jaenisch said.

Sources: Whitehead Institute for Biomedical Research, Viruses

Carmen Leitch

Adult T-cell leukemia/lymphoma (ATLL) is a rare type of cancer that impacts T cells, a crucial immune cell …

Adult T-cell leukemia/lymphoma (ATLL) is a rare type of cancer that impacts T cells, a crucial immune cell that plays an important role in fighting infection. ATLL tends to be aggressive, and can manifest in the blood as leukemia, in the lymph nodes as lymphoma, or other tissues like the skin. ATLL has been associated with human T-cell lymphotropic virus type 1 (HTLV-1) infections, although fewer than five percent of people with this virus end up developing ATLL. Right now, clinicians cannot predict which people with HTLV-1 infections will get ATLL. While some types of ATLL tumors can be surgically removed, survival prospects for these patients is not good.

Image credit: Pixabay

A recent article published in Genes & Cancer noted that even though a monoclonal antibody that can treat ATLL called mogamulizumab has recently been approved, the survival rate is still poor.

Viruses are known to change gene expression in host cells, and HTLV-1 is no different. Previous work reported in PLOS Pathogens showed that when HTLV-1 infects cells, it causes a huge number of genetic and epigenetic changes with viral proteins it generates called Tax and HBZ. These many genetic changes could be interfering with chemotherapeutics and may render them less effective, suggested researcher Tatsuro Jo of the Nagasaki Genbaku Hospital.

In the HTLV-1 genome, there is an opportunity, however. Its genome is completely different from the human genome, so the viral proteins generated during HTLV-1 infection are excellent therapeutic targets. ATLL survivors have been found to carry cytotoxic T lymphocytes that work against the HTLV-1 Tax protein. People who survive ATLL over the long term may have been able to activate strong antitumor mechanisms.

Jo added that some people who have lived for a long time after an ATLL diagnosis, and prior to the approval of mogamulizumab, had also developed herpesvirus infections. It’s been suggested that herpes infections can trigger powerful cellular immunity mechanisms.

“Although contracting herpes simplex or herpes zoster is unpleasant, the mechanism by which these herpesvirus infections can produce a therapeutic effect on refractory ATLL via the activation of the host’s cellular immunity is extremely interesting and worth further study,” said Jo.

Sources: Impact Journals LLC, Genes & Cancer

Carmen Leitch

Scientists have found that a gene that has been previously identified in many animals and their associated microbes …

Scientists have found that a gene that has been previously identified in many animals and their associated microbes can enable resistance to antimicrobial drugs. The resistance gene encodes for an enzyme called EstT, which can deactivate antibiotic drugs known as macrolides. The enzyme can disrupt the chemical ring structure of these antibiotics through hydrolysis. When the ring is broken or opened with water, the antibiotic loses both its active shape, and its target affinity, explained study leader Dr. Tony Ruzzini PhD, an assistant professor at the Western College of Veterinary Medicine (WCVM) of the University of Saskatchewan. The findings have been reported in the Proceedings of the National Academy of Sciences.

Image credit: Pixabay

This gene can take macrolide antibiotics out of commission, and illnesses can no longer be treated effectively. Macrolides such as tylosin, tilmicosin and tildipirosin are often used to treat cattle with bovine respiratory disease or liver abscesses, and may also be used to treat other diseases in livestock and companion animals.

In this study, the researchers analyzed genes that were found within microbes that were living in watering bowls at a beef cattle feedlot in western Canada. The investigators isolated the microbes that were in the water, and compared the genes in the microbes to databases of antimicrobial resistance genes.

A bacterium called Sphingobacterium faecium WB1 was found to carry the EstT gene, which was contained within a cluster of three antibiotic resistance genes (ARGs). It was also near plasmids and retrotransposons, suggesting it can move easily from one microbe to another. EstT is commonly found in microbes in the human microbiome too.

“This gene, even though we found it in an environmental organism, it is also present in pathogens that are responsible for causing bovine respiratory disease,” noted Ruzzini.

“Our finding adds to the considerable database of ARGs, which can be crossmatched to a bacteria’s DNA to determine if the bacterium has the potential to be resistant to a particular antimicrobial,” said first study author Dr. Poonam Dhindwal PhD, a postdoctoral fellow at WCVM.

The researchers are continuing to study EstT to learn more about how it works.

“As [antimicrobial resistance] surveillance systems rely more on molecular tools for detection, our knowledge of this specific gene and its integration into those systems will help to better inform antimicrobial use,” said Ruzzini.

Sources: University of Saskatchewan, Proceedings of the National Academy of Sciences (PNAS)

Carmen Leitch

In a first, scientists have used bat cells to create bat induced pluripotent stem cells (iPSCs), which can …

In a first, scientists have used bat cells to create bat induced pluripotent stem cells (iPSCs), which can now serve as a tool to study the connections between bats and the viruses they host. Many viruses, including Ebola, Marburg, Nipah, MERS-CoV, SARS-CoV, and SARS-CoV-2 have been linked to different species of bats, even if other animals have acted as infection reservoirs. Bats are known to harbor more viruses than other mammals, and bats themselves are the second most diverse order of mammals on Earth (after rodents). Even though we know that novel pathogens may emerge from bats to infect humans, bat virus ecology has been poorly understood. This model can help change that.

Scanning electron micrograph of Ebola virus particles (purple) both budding and attached to the surface of infected VERO E6 cells (green)/ Image captured at the NIAID Integrated Research Facility in Fort Detrick, Maryland. Credit: NIAID

Researchers can now use bat iPSCs to learn more about the growth and spread of viruses that bats carry. Bats also have special characteristics that enable them to carry these viral reservoirs without getting sick, and this model may help us understand how they defend themselves from disease. The work has been reported in Cell.

The scientists used cells from the wild greater horseshoe bat (Rhinolophus ferrumequinum), the most common asymptomatic host of coronaviruses, including relatives of SARS-CoV-2, to create induced pluripotent stem cells. These cells are made by changing the expression of a few genes of skin or blood cells, such that they resemble newborn stem cells. The bat iPSCs can be used to generate any other bat cell type.

Bat iPSCs were compared to iPSCs from other mammals, revealing a unique biology, noted study co-author Adolfo García-Sastre, Ph.D., a Professor of Medicine and Director of the Global Health and Emerging Pathogens Institute at Icahn Mount Sinai. “The most extraordinary finding was the presence of large virus-filled vesicles in bat stem cells representing major viral families, including coronaviruses, without compromising the cells’ ability to proliferate and grow. This could suggest a new paradigm for virus tolerance as well as a symbiotic relationship between bats and viruses.”

This study has suggested that bats have certain biological mechanisms that allow them to tolerate many viral sequences, and bats could be more entwined with viruses that we knew, noted senior study author Thomas Zwaka, MD, Ph.D., a Professor at the Icahn School of Medicine at Mount Sinai. Bats can survive the presence of viruses that often kill humans, such as Marburg, which may be due to a modulation of their immune response, added Zwaka.

This study could help researchers answer some crucial questions, and protect humans from emerging viruses; we may be able to use tactics like those in bats to prevent viral infection or illness. Ultimately, it could help scientists learn why bats hold a unique position as viral reservoirs, noted Dr. García-Sastre. “And that knowledge could provide the field with broad new insights into disease and therapeutics while preparing us for future pandemics.”

Bat stem cell research will “directly impact every aspect of our understanding of bat biology, including bats’ amazing adaptations of flight and ability to locate distant or invisible objects through echolocation, the location of objects reflected by sound, as well as their extreme longevity and unusual immunity,” Zwaka concluded.

Sources: The Mount Sinai Hospital, Cell

Carmen Leitch

Partners can accomplish amazing things, and it seems that is true for bacteria. Large colonies of bacteria called …

Partners can accomplish amazing things, and it seems that is true for bacteria. Large colonies of bacteria called biofilms become very resilient and can even gain new abilities. New research has shown that different types of bacteria can even work cooperatively to become more powerful. Scientists have revealed a collaborative relationship between Klebsiella pneumoniae and Acinetobacter baumannii, bacterial pathogens that can cause illnesses including pneumonia and urinary tract infections. They can even cause deadly infections of the bloodstream.

An SEM image of a human neutrophil (blue) interacting with two multidrug-resistant (MDR), Klebsiella pneumoniae bacteria (pink), which are known to cause severe hospital acquired, nosocomial infections. / Credit: National Institute of Allergy and Infectious Diseases (NIAID) / David Dorward; Ph.D.; NIAID

Both of these microbial pathogens have been highlighted by the World Health Organization because new antibiotics are needed to fight them. They are often identified in so-called polymicrobial infections, in which combinations of bacteria, fungi, parasites, and viruses cause illness. They are also a common problem in hospital-acquired infections.

This study has shown that Klebsiella produces metabolic byproducts that provide nutrition to Acinetobacter, and in return, Acinetobacter acts as a shield, releasing enzymes that degrade Klebsiella-destroying antibiotics. A combination of methods from various fields including microbiology, microscopy, and genetics were used in this effort; it illustrated an example of syntrophy, in which bacterial species are in a mutually symbiotic relationship, with one consuming the byproducts of another. The findings have been reported in Nature Communications.

In this research, the investigators analyzed strains of microbes isolated from a co-infection, and used an animal model to reveal “a mutually beneficial relationship” between Klebsiella and Acinetobacter. This allows Klebsiella to survive significantly higher antibiotic concentrations significantly than it would by itself, said Dr. Lucie Semenec of Macquarie University.

Co-lead study author Associate Professor Amy Cain of Macquarie University noted that the findings highlight the importance of screening for polymicrobial infections in clinical settings, because together, these pathogens are more dangerous and they feed off one another.

“This research is significant because diagnostic methods commonly look for the most dominant pathogen and therefore treatment is targeted at that,” noted Semenec. “New drugs now can be informed in future research by the molecular mechanisms we find in this work.”

Sources: Macquarie University, Nature Communications

Carmen Leitch