Tag Archives: Skin

Microbiology

NIH Scientists Discover Protein Behind Rare Genetic Skin Disorder

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Genome sequencing reveals genetic basis for disabling pansclerotic morphea, a severe inflammatory disease.

Researchers at the National Institutes of Health (NIH) and their colleagues have identified genomic variants that cause a rare and severe inflammatory skin disorder, known as disabling pansclerotic morphea, and have found a potential treatment. Scientists discovered that people with the disorder have an overactive version of a protein called STAT4, which regulates inflammation and wound healing. The work also identified a drug that targets an important feedback loop controlled by the STAT4 protein and significantly improves symptoms in these patients. The results were published in the New England Journal of Medicine.

The study was led by researchers at the National Human Genome Research Institute (NHGRI), part of NIH, in collaboration with researchers from the University of California, San Diego (UCSD) and the University of Pittsburgh. Researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases, both part of NIH, also participated in the study.

Only a handful of patients have been diagnosed with disabling pansclerotic morphea, a disorder first described in the medical literature around 100 years ago. The disorder causes severe skin lesions and poor wound healing, leading to deep scarring of all layers of the skin and muscles. The muscles eventually harden and break down while the joints stiffen, leading to reduced mobility. Because the disorder is so rare, its genetic cause had not been identified until now.

“Researchers previously thought that this disorder was caused by the immune system attacking the skin,” said Sarah Blackstone, a predoctoral fellow within NHGRI’s Inflammatory Disease Section, a medical student at the University of South Dakota and co-first author of the study. “However, we found that this is an oversimplification, and that both skin and the immune system play an active role in disabling pansclerotic morphea.”

The researchers used genome sequencing to study four individuals with disabling pansclerotic morphea and found that all four have genomic variants in the STAT4 gene. The STAT4 gene encodes a type of protein that helps turn genes on and off, known as a transcription factor. The STAT4 protein not only plays a role in fighting infections but also controls important aspects of wound healing in the skin.

The scientists found that the STAT4 genomic variants result in an overactive STAT4 protein in these four patients, creating a positive feedback loop of inflammation and impaired wound healing that worsens over time. To stop this harmful feedback loop, they targeted another protein in the inflammatory pathway that interacts with the STAT4 molecule and is called Janus kinase, also known as JAK. When the researchers treated the patients with a JAK-inhibiting drug called ruxolitinib, the patients’ rashes and ulcers dramatically improved.

“So far, there has not been a standard treatment for this disorder because it’s so rare and not well-understood. However, our study gives an important new treatment option for these patients,” said Blackstone.

Existing treatments for disabling pansclerotic morphea are designed to halt the progression of the disorder, but previous therapies have been mostly ineffective, often with severe side effects. People with the disorder typically don’t live more than 10 years after their diagnosis.

The study suggests that ruxolitinib could be an effective treatment for patients with this disorder. Ruxolitinib is part of a broader class of drugs called JAK inhibitors, which are commonly used to treat arthritis, eczema, ulcerative colitis, and other chronic inflammatory diseases.

“The findings of this study open doors for JAK inhibitors to be a potential treatment for other inflammatory skin disorders or disorders related to tissue scarring, whether it is scarring of the lungs, liver, or bone marrow,” said Dan Kastner, M.D., Ph.D., an NIH distinguished investigator, head of NHGRI’s Inflammatory Disease Section and a senior author of the paper.

“We hope to continue studying other molecules in this pathway and how they are altered in patients with disabling pansclerotic morphea and related conditions to find clues to understanding a broader array of more common diseases,” said Lori Broderick, M.D., Ph.D., a senior author of the paper and an associate professor at UCSD.

Reference: “Variant STAT4 and Response to Ruxolitinib in an Autoinflammatory Syndrome” by Hratch Baghdassarian, B.S., Sarah A. Blackstone, B.S., Owen S. Clay, M.D., Ph.D., Rachael Philips, Ph.D., Brynja Matthiasardottir, M.Sc., Michele Nehrebecky, N.P., Vivian K. Hua, B.S., Rachael McVicar, B.S., Yang Liu, Ph.D., Suzanne M. Tucker, M.D., Davide Randazzo, Ph.D., Natalie Deuitch, M.S., Sofia Rosenzweig, B.S., Adam Mark, M.S., Roman Sasik, Ph.D., Kathleen M. Fisch, Ph.D., Pallavi Pimpale Chavan, M.D., Elif Eren, Ph.D., Norman R. Watts, Ph.D., Chi A. Ma, Ph.D., Massimo Gadina, Ph.D., Daniella M. Schwartz, M.D., Anwesha Sanyal, Ph.D., Giffin Werner, B.S., David R. Murdock, M.D., Nobuyuki Horita, M.D., Ph.D., Shimul Chowdhury, Ph.D., David Dimmock, M.D., Kristen Jepsen, Ph.D., Elaine F. Remmers, Ph.D., Raphaela Goldbach-Mansky, M.D., M.H.S., William A. Gahl, M.D., Ph.D., John J. O’Shea, M.D., Joshua D. Milner, M.D., Nathan E. Lewis, Ph.D., Johanna Chang, M.D., Daniel L. Kastner, M.D., Ph.D., Kathryn Torok, M.D., Hirotsugu Oda, M.D., Ph.D., Christopher D. Putnam, Ph.D. and Lori Broderick, M.D., Ph.D., 31 May 2023, New England Journal of Medicine.
DOI: 10.1056/NEJMoa2202318

National Human Genome Research Institute (NHGRI)

Microbiology

Long-ignored antibiotic could help fight against multi-drug resistant bacteria

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Reviewed by Megan Craig, M.Sc.May 16 2023

“The end of modern medicine as we know it.” That’s how the then-director general of the World Health Organization characterized the creeping problem of antimicrobial resistance in 2012. Antimicrobial resistance is the tendency of bacteria, fungus and other disease-causing microbes to evolve strategies to evade the medications humans have discovered and developed to fight them. The evolution of these so-called “super bugs” is an inevitable natural phenomenon, accelerated by misuse of existing drugs and intensified by the lack of new ones in the development pipeline.

Without antibiotics to manage common bacterial infections, small injuries and minor infections become potentially fatal encounters. In 2019, more than 2.8 million antimicrobial-resistant infections occurred in the United States, and more than 35,000 people died as a result, according to the Centers for Disease Control and Prevention (CDC). In the same year, about 1.25 million people died globally. A report from the United Nations issued earlier this year warned that number could rise to ten million global deaths annually if nothing is done to combat antimicrobial resistance.

For nearly 25 years, James Kirby, MD, director of the Clinical Microbiology Laboratory at Beth Israel Deaconess Medical Center (BIDMC), has worked to advance the fight against infectious diseases by finding and developing new, potent antimicrobials, and by better understanding how disease-causing bacteria make us sick. In a recent paper published in PLOS Biology, Kirby and colleagues investigated a naturally occurring antimicrobial agent discovered more than 80 years ago.

Using leading-edge technology, Kirby’s team demonstrated that chemical variants of the antibiotic, called streptothricins, showed potency against several contemporary drug-resistant strains of bacteria. The researchers also revealed the unique mechanism by which streptothricin fights off bacterial infections. What’s more, they showed the antibiotic had a therapeutic effect in an animal model at non-toxic concentrations. Taken together, the findings suggest streptothricin deserves further pre-clinical exploration as a potential therapy for the treatment of multi-drug resistant bacteria.

We asked Dr. Kirby to tell us more about this long-ignored antibiotic and how it could help humans stave off the problems of antimicrobial resistance a little longer.

Q: Why is it important to look for new antimicrobials? Can’t we preserve the drugs we have through more judicious use of antibiotics?

Stewardship is extremely important, but once you’re infected with one of these drug-resistant organisms, you need the tools to address it.

Much of modern medicine is predicated on making patients temporarily — and sometimes for long periods of time — immunosuppressed. When these patients get colonized with these multidrug-resistant organisms, it’s very problematic. We need better antibiotics and more choices to address multidrug resistance.

We have to realize that this is a worldwide problem, and organisms know no borders. So, a management approach for using these therapies may work well in Boston but may not in other areas of the world where the resources aren’t available to do appropriate stewardship.

Q: Your team investigated an antimicrobial discovered more than 80 years ago. Why was so little still known about it?

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The first antibiotic, penicillin, was discovered in 1928 and mass produced for the market by the early 1940s. While a game-changing drug, it worked on only one of the two major classes of bacteria that infect people, what we call gram-positive bacteria. The gram-positive bacteria include staphylococcal infections and streptococcal infections which cause strep throat, skin infections and toxic shock. There still was not an antibiotic for the other half of bacteria that can cause human infections, known as gram-negative organisms.

In 1942, scientists discovered this antibiotic that they isolated from a soil bacterium called streptothricin, possibly addressing gram-negative organisms. A pharmaceutical company immediately licensed the rights to it, but the development program was dropped soon after when some patients developed renal or kidney toxicity. Part of the reason for not pursuing further research was that several additional antibiotics were identified soon thereafter which were also active against gram-negatives. So, streptothricin got shelved.

Q: What prompted you to look at streptothricin specifically now?

It was partly serendipity. My research laboratory is interested in finding new, or old and forgotten, solutions to treat highly drug-resistant gram-negative pathogens like E. coli or Klebsiella or Acinetobacter that we commonly see in hospitalized, immunocompromised patients. The problem is that they’re increasingly resistant to many if not all of the antibiotics that we have available.

Part of our research is to understand how these superbugs cause disease. To do that, we need a way to manipulate the genomes of these organisms. Commonly, the way that’s done is to create a change in the organism linked with the ability to resist a particular antibiotic that’s known as a selection agent. But for these super resistant gram-negative pathogens, there was really nothing we could use. These bugs were already resistant to everything.

We started searching around for drugs that we could use, and it turns out these super resistant bugs were highly susceptible to streptothricin, so we were able to use it as a selection agent to do these experiments.

As I read the literature on streptothricin and its history, I had the realization that it was not sufficiently explored. Here was this antibiotic with outstanding activity against gram-negative bacteria – and we confirmed that by testing it against a lot of different pathogens that we see in hospitals. That raised the question of whether we could get really good antibiotic activity at concentrations that are not going to cause damage to the animal or person in treatment.

Q: But it did cause kidney toxicity in people in 1942. What would be different now?

What scientists were isolating in 1942 was not as pure as what we are working with today. In fact, what was then called streptothricin is actually a mixture of several streptothricin variants. The natural mixture of different types of streptothricins is now referred to as nourseothricin.

In animal models, we tested whether we could kill the harmful microorganism without harming the host using a highly purified single streptothricin variant. We used a very famous strain of Klebsiella pneumoniae called the Nevada strain which was the first pan-drug-resistant, gram-negative organism isolated in the United States, an organism for which there was no treatment. A single dose cleared this organism from an infected animal model while avoiding any toxicity. It was really remarkable. We’re still in the very early stages of development, but I think we’ve validated that this is a compound that’s worth investing in further studies to find even better variants that eventually will meet the properties of a human therapeutic.

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Q. How does nourseothricin work to kill gram-negative bacteria?

That’s another really important part of our study. The mechanism hadn’t been figured out before and we showed that nourseothricin acts in a completely new way compared to any other type of antibiotic.

It works by inhibiting the ability of the organism to produce proteins in a very sneaky way. When a cell makes proteins, they make them off a blueprint or message that tells the cell what amino acids to link together to build the protein. Our studies help explain how this antibiotic confuses the machinery so that the message is read incorrectly, and it starts to put together gibberish. Essentially the cell gets poisoned because it’s producing all this junk.

In the absence of new classes of antibiotics, we’ve been good at taking existing drugs like penicillin for example and modifying them; we’ve been making variations on the same theme. The problem with that is that the resistance mechanisms against penicillin and other drugs already exist. There’s a huge environmental reservoir of resistance out there. Those existing mechanisms of resistance might not work perfectly well against your new variant of penicillin, but they will evolve very quickly to be able to conquer it.

So, there’s recognition that what we really want is new classes of antibiotics that act in a novel way. That’s why streptothricin’s action uncovered by our studies is so exciting. It works in a very unique way not seen with any other antibiotic, and that is very powerful because it means there’s not this huge environmental reservoir of potential resistance.

Q. You emphasize these are early steps in development. What are the next steps?

My lab is working very closely with colleagues at Northeastern University who figured out a way to synthesize streptothricin from scratch in a way that will allow us to cast many different variants. Then we can look for ones that have the ideal properties of high potency and reduced toxicity.

We are also continuing our collaboration with scientists at Case Western Reserve University Medical Center, diving more deeply to understand exactly how this antibiotic works. Then we can use that fundamental knowledge in our designs of future variants and be smarter about how we try to make the best antibiotic.

We have great collaborators that have allowed us to pursue a project that crosses multiple fields. This work is an example of collaborative science really at its best.

Co-authors included first author Christopher E. Morgan and Edward W. Yuof Case Western Reserve; Yoon-Suk Kang,Alex B. Green, Kenneth P. Smith, Lucius Chiaraviglio, Katherine A. Truelson, Katelyn E. Zulauf, Shade Rodriguez, and Anthony D. Kang of BIDMC; Matthew G. Dowgiallo,Brandon C. Miller, and Roman Manetsch of Northeastern University.

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Source:

Beth Israel Deaconess Medical Center

Microbiology

Breast milk microbes shape infant gut health

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Dr. Liji Thomas, MDBy Dr. Liji Thomas, MDMay 9 2023Reviewed by Benedette Cuffari, M.Sc.

A new paper published in the Frontiers in Microbiology explores the contribution of human breast milk to the establishment of the infant gut microbiome.

Study: Human milk-associated bacterial communities associate with the infant gut microbiome over the first year of life. Image Credit: Pavel Ilyukhin / Shutterstock.com Study: Human milk-associated bacterial communities associate with the infant gut microbiome over the first year of life. Image Credit: Pavel Ilyukhin / Shutterstock.com

Introduction

Breastfeeding is encouraged as the first and exclusive food of infants for at least the first six months of life. In addition to its nutritional content, breast milk contributes significantly to the formation of the infant gut microbiome. This is because of its high content of immune cells, oligosaccharides carrying glycosyl residues, fatty acids, and some microbes.

Both breast milk bacteria and skin microbes from the maternal nipple reach and establish themselves in the infant’s gut. Bacteria may be shielded by secretory immunoglobulin A (sIgA) covering the immune system, thus allowing them to enter the gut intact.   

The infant gut microbiome (IGMB) is important for both infant development and immunity, as well as modulating conditions like atopy and body mass composition. However, earlier research on potential associations between the IGMB and breast milk microbiota has been limited to analyzing samples from corresponding time points.

The current study included almost 190 dyads from New Hampshire. Breast milk and infant stool samples were collected at around six weeks, four months, six months, nine months, and one year from birth, which allowed the scientists to identify correlations that developed over time.

What did the study show?

In the study population, with a mean age of 32 years, most were White and had a normal body mass index (BMI) during pregnancy. About 25% of deliveries occurred through Cesarean section (C-section), and antibiotic exposure prior to lactation occurred in over half of mothers.

Most babies were almost full term at birth, with only 3% being exposed to antibiotics by four months of life. By one year, about 30% of infants had been exposed to antibiotics.

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About 75% and 40% of infants did not receive any formula up to six weeks and four months, respectively. Most infants began eating solid food by six months.

Three breast milk microbiome types (BMTs) were identified in the six-week breast milk samples. These could be differentiated by the relative proportions of four bacterial genera, including Streptococcus, Staphylococcus, Pseudomonas, and Acinetobacter, as well as by the microbial diversity.

At six weeks, the gut microbiome in infants exhibited four six-week infant gut microbiome types (6wIGMTs). These had different abundances of Bifidobacterium, Bacteroides, Clostridium, Streptococcus, and Escherichia/Shigella.

The 6wIGMT correlated with the 6wBMT in male infants and those born by C-section. Notably, the same microbe was likely to be the most abundant within the dyads at this point.

By age one, the predominant difference in microbiome composition was due to Bacteroides. There was no association between the 6wBMT and 12mIGMT, which is likely due to the intake of solid foods by infants at this age. The transition to a primarily solid diet causes the infant microbiome to be dominated by other microbes, such as Bifidobacterium and Bacteroidetes, both of which are more abundant in the adult gut.

At six weeks, the BMT was associated with 6wIGMT in all infants but more strongly in male infants born by C-section. Male infants also had a higher proportion of microbes from breast milk present in their stool.

While infants delivered by C-section have a reduced colonization by maternal stool microbiota, their colonization by breast milk microbiota is higher than vaginally delivered infants.”

This could be due to the reduced microbial diversity and Bacteroides depletion in the IGMB of C-section-delivered infants, which makes it easier for breast milk microbes to colonize the gut.

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Male infants appeared to show a greater effect of the breast milk microbes on their gut microbiome. This may be because they exhibit less microbial diversity, with fewer Clostridiales and more Enterobacteriales abundance than is observed in female infants. The male infant’s gut microbiota is also more susceptible to stress and environmental exposures.

Overall, the breast milk microbial communities correlated most strongly with those found in infant stool samples that were collected at a later time point. For example, Pantoea in breast milk at four and six months was correlated with infant stool collected at nine and twelve months, respectively. These findings require further validation in future research.

What are the implications?

The identification of microbial clusters in human milk and infant feces that were shared within the mother-infant pair at six weeks is a striking finding in this study. The delay in cluster sharing and the association with C-section were associated with stronger correlations.

The findings of this study agree with earlier reports on the associations of various microbes in breast milk and the infant gut. Notably, the current study adds to previous data by identifying correlations between different taxa in these two sites.

The scientists postulate that microbes within communities may show direct interactions, such as the transmission of a microbe present in the infant oral cavity to the breast in this case, as well as the intake of breast milk by the infant. In addition, they may show indirect interactions through nutrients like fatty acids and milk sugars or other bacterial metabolites that influence both communities.

With the observed shift in breast milk microbial diversity over time, long-term studies may be needed to understand the breadth of microbial exposures during infancy. The change in IGMTs over time should also be better characterized and their relevance assessed.

These results suggest that milk microbial communities have a long-term effect on the infant gut microbiome both through sharing of microbes and other molecular mechanisms.”

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Journal reference:
  • Lundgren, S. N., Madan, J. C., Karagas, M. R., et al. (2023). Human milk-associated bacterial communities associate with the infant gut microbiome over the first year of life. Frontiers in Microbiology. doi:10.3389/fmicb.2023.1164553.
Microbiology

Diet has a much stronger impact on intestinal microbiota than defensins

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Reviewed by Emily Henderson, B.Sc.May 3 2023

Researchers at Umeå University, Sweden, have found that among the many factors that shape the intestinal microbiota composition, diet has a much stronger impact than defensins, which are intestinal defence molecules produced by the body. Instead, they identified a possible role for these molecules in preventing increased blood glucose levels after consumption of high-caloric “Western-style diet”.

While the effect of defensins in shaping the adult microbiota composition is rather minor when compared to diet, defensins still have a very important role in protecting us against microbial infections; and our research highlights their protective role against the metabolic complications that can arise after the intake of a high-fat and high-sugar Western-style diet.”

Fabiola Puértolas Balint, PhD Student at the Department of Molecular Biology at Umeå University

She is working in Björn Schröder’s research group, which is also affiliated to Umeå Centre of Microbial Research, UCMR, and The Laboratory for Molecular Infection Medicine Sweden, MIMS, at Umeå University.

The gut microbiota refers to the community of trillions of microorganisms that live inside everyone’s gut. Over the past decades, the abundance of specific bacteria in this community has been extensively studied due to its connection to many diseases, including inflammatory bowel diseases, obesity and diabetes, and even psychological disorders. The microbial community is seeded during birth, after which several internal and external factors help shaping the community to its final composition. These factors include, among others, diet (especially fibre), genetics, medication, exercise, and defence molecules, the so-called antimicrobial peptides.

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Antimicrobial peptides can be regarded as the body´s own naturally produced antibiotic molecules. In particular, the largest group of antimicrobial peptides – the defensins – is produced by all body surfaces, including the skin, the lungs and the gastrointestinal tract. Defensins are considered the immune system´s first line of defence against infections but at the same time they have also been thought to be essential in shaping the microbiota composition in the small intestine. However, it was so far unclear how big their effect was as compared to diet, which is known to have a major impact.

To investigate this, the researchers from Björn Schröder lab used normal healthy mice and compared their microbiota composition in the small intestine to mice that could not produce functional defensins in the gut, and then both mouse groups were fed either a healthy diet or a low-fibre Western-style diet.
“When we analysed the microbiota composition inside the gut and at the gut wall of two different regions in the small intestine, we were surprised – and slightly disappointed – that defensins had only a very minor effect on shaping the overall microbiota composition,” says Björn Schröder.
However, the intestinal defensins still had some effect directly at the gut wall, where the defensins are produced and secreted. Here, a few distinct bacteria seemed to be affected by the presence of defensins, among them Dubosiella and Bifidobacteria, likely due to selective antimicrobial activity of the defensins.

“To our surprise, we also found that the combination of eating a Western-style diet and lacking functional defensins led to increased fasting blood glucose values, which indicated that defensins may help to protect against metabolic disorders when eating an unhealthy diet,” says Björn Schröder.
The results suggest that strategies that aim to positively modulate the microbiota composition should rather focus on diet, as modulation of the composition via increased production of own host defense molecules, such as defensins, may have only a small impact on the overall composition. However, it is possible that especially early in life, when the microbiota community is not fully matured yet, defensins may have a stronger effect on the microbial composition. Still, increasing the production of defensins may be a valuable option to prevent the development of metabolic disorders.

The results have been published in the scientific journal Microbiology Spectrum.

Source:

Umeå University

Journal reference:

Puértolas-Balint, F., & Schroeder, B. O. (2023). Intestinal α-Defensins Play a Minor Role in Modulating the Small Intestinal Microbiota Composition as Compared to Diet. Microbiology Spectrum. doi.org/10.1128/spectrum.00567-23.

Microbiology

Most kids recover from Lyme disease within six months of completing antibiotic treatment

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Reviewed by Emily Henderson, B.Sc.Apr 21 2023

A majority of parents of children diagnosed with Lyme disease reported that their kids recovered within six months of completing antibiotic treatment, according to a new joint study from Children’s National Research Institute and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, published in Pediatric Research. The findings, based on Lyme disease treatment outcome data from 102 children in the United States, also revealed that a notably small percentage of children took longer than six months to recover and experienced a significant impact on their daily functioning.

Lyme disease is the most common vector-borne disease in the United States, with most cases caused by the bacterium Borrelia burgdorferi transmitted through the bites of infected blacklegged or deer ticks. Children between the ages 5 and 9 years account for a large proportion of the approximately 476,000 Lyme disease cases diagnosed and treated annually in the United States. Common symptoms of Lyme disease include: fever; headache; fatigue; and a distinct skin rash called erythema migrans. Without treatment, the infection can spread to joints, the heart and the nervous system. Antibiotic treatment resulting in full recovery is successful in most Lyme cases. For some, however, symptoms of pain, fatigue, or difficulty thinking persist or return after antibiotic treatment. Symptoms that substantially reduce levels of activity and impact quality of life for more than six months after treatment are classified as post-treatment Lyme disease (PTLD) syndrome.

This research studied the long-term outcomes of children with Lyme disease through a cross-sectional evaluation using validated surveys. The study collected survey responses from the parents of 102 children ages 5 to 18 years who had been diagnosed with Lyme disease between six months and 10 years before enrollment. Adolescents ages 10 to 18 years old were also invited to complete adolescent-specific questionnaires. According to these parent survey responses, 75% of children fully recovered within six months of completing treatment: 31% of all children recovered within one month; 30% recovered in one-to-three months; and 14% recovered in four-to-six months. Approximately 22% of children in the study experienced at least one symptom that persisted six or more months after completing treatment; of those, 9% had symptoms classified as PTLD syndrome. Six percent of the children were not fully recovered at the time of the survey, with 1% experiencing symptoms significant enough to impair daily functioning, the authors noted.

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According to the authors, this study supports previous data showing an excellent overall prognosis for children with Lyme disease, which should help alleviate understandable parental stress associated with lingering non-specific symptoms among infected children. They note that the findings of this study can help clinicians manage families’ expectations about the varying post-treatment recovery times of pediatric Lyme disease patients. The researchers suggest this new data could help reduce the potential for families seeking dangerous alternative therapies for children who experience prolonged recovery times. PTLD syndrome remains poorly understood in children and adults, and more research is needed to better understand these prolonged symptoms and identify treatment targets, according to the authors.

This study was supported through a partnership between NIAID and the Children’s National Research Institute (CNRI). Researchers at the Center for Translational Research at CNRI and the NIAID Laboratory of Clinical Immunology and Microbiology conducted the study.

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Source:

NIH/National Institute of Allergy and Infectious Diseases

Journal reference:

Monaghan, M., et al. (2023). Pediatric Lyme disease: systematic assessment of post-treatment symptoms and quality of life. Pediatric Research. doi.org/10.1038/s41390-023-02577-3.

Microbiology

Genomic study reveals Babesia duncani’s pathogenicity and virulence

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

‘Tis the season for hiking now that spring has arrived and temperatures are on the upswing. But with hikes come insect bites and on the increase in North America is babesiosis, a malaria-like disease spread especially between May and October by a tick.

Indeed, recent research suggests an increase in the incidence of diseases transmitted by ticks around the world, not just the United States and Canada, due likely to climate change and other environmental factors. Among the tick-borne pathogens, Babesia parasites, which infect and destroy red blood cells, are considered a serious threat to humans and animals. All cases of human babesiosis reported in the United States have been linked to either Babesia microti, B. duncani, or a B. divergens-like species.

Now a research team led by scientists at the University of California, Riverside, and Yale University reports the first high-quality nuclear genome sequence and assembly of the pathogen B. duncani. The team also determined the 3D genome structure of this pathogen that resembles Plasmodium falciparum, the malaria-causing parasite.

“Our data analysis revealed that the parasite has evolved new classes of multigene families, allowing the parasite to avoid the host immune response,” said Karine Le Roch, a professor of molecular, cell and systems biology at UC Riverside, who co-led the study with Choukri Ben Mamoun, a professor of medicine at Yale University.

According to Le Roch, who directs the UCR Center for Infectious Disease Vector Research, the study, published today in Nature Microbiology, not only identifies the molecular mechanism most likely leading to the parasite’s pathogenicity and virulence, but also provides leads for the development of more effective therapies.

By mining the genome and developing in vitro drug efficacy studies, we identified excellent inhibitors of the development of this parasite -; a pipeline of small molecules, such as pyrimethamine, that could be developed as effective therapies for treating and better managing human babesiosis. Far more scientific and medical attention has been paid to B. microti. The genome structure of B. duncani, a neglected species until now, will provide scientists with important insights into the biology, evolution, and drug susceptibility of the pathogen.”

Karine Le Roch, professor of molecular, cell and systems biology at UC Riverside

Human babesiosis caused by Babesia duncani is an emerging infectious disease in the U.S. and is often undetected because healthy individuals do not usually show symptoms. It has, however, been associated with high parasite burden, severe pathology, and death in multiple cases. Despite the highly virulent properties of B. duncani, little was known about its biology, evolution, and mechanism of virulence, and recommended treatments for human babesiosis against B. duncani are largely ineffective.

A strong immune system is required to fight the pathogen. A compromised immune system could lead to flu-like illness. The tick that spreads babesiosis is mostly found in wooded or grassy areas and is the same tick that transmits bacteria responsible for Lyme disease. As a result, around 20% of patients with babesiosis are co-infected with Lyme disease.

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}

B. duncani mostly infects deer, which serve as the reservoir host during the pathogen’s asexual development. The parasite’s sexual cycle occurs in the tick after the tick bites the infected deer. When this tick bites humans, infection begins. The full life cycle of Babesia parasites has not yet been determined. The tick that spreads babesiosis, called Dermacentor albipictus, lives longer than mosquitoes and could facilitate a long life cycle for B. duncani.

Even though scientists are discovering more Babesia species, diagnostics are mostly developed for B. microti. Le Roch is already working with Stefano Lonardi, a professor of computer science and engineering at UCR and co-first author of the study, on new Babesia strains that have evolved.

“The Babesia genomes are not very long,” said Lonardi, who assembled the B. duncani strain. “But they are challenging to assemble due to their highly repetitive content and can require years of research. Once the genome is assembled and annotated, it can provide valuable information, such as how the genes are organized, which genes are transcribed during infection, and how the pathogen avoids the host’s immune system.”

In older and immunocompromised people, if B. duncani is left unattended, babesiosis could worsen and lead to death. Once the pathogen enters the body and red blood cells start to get destroyed, fever, headache, and nausea can follow. People who get bitten by the ticks often don’t feel the bite, which complicates diagnosis. Skin manifestations of babesiosis are rare, Lonardi said, and difficult to separate from Lyme disease.

Le Roch and Lonardi urge people to be mindful of ticks when they go hiking.

“Check yourself for tick bites,” Le Roch said. “When you see your physician don’t forget to let them know you go hiking. Most physicians are aware of Lyme disease but not of babesiosis.”

Next the team plans to study how B. duncani survives in the tick and find novel vector control strategies to kill the parasite in the tick.

Le Roch, Mamoun, and Lonardi were joined in the study by colleagues at UCR, Yale School of Medicine, Université de Montpellier (France), Instituto de Salud Carlos III (Spain), Universidad Nacional Autónoma de México, and University of Pennsylvania. Pallavi Singh at Yale and Lonardi contributed equally to the study. The B. duncani genome, epigenome, and transcriptome were sequenced at UCR and Yale.

The study was supported by grants from the National Institutes of Health, Steven and Alexandra Cohen Foundation, Global Lyme Alliance, National Science Foundation, UCR, and Health Institute Carlos III.

Source:

University of California – Riverside

Journal reference:

Singh, P., et al. (2023). Babesia duncani multi-omics identifies virulence factors and drug targets. Nature Microbiology. doi.org/10.1038/s41564-023-01360-8.

Microbiology

Innies, outies and omphalophobia: 7 navel-gazing questions about belly buttons answered

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Everyone has one, but you might not know much about it. Here biologist Sarah Leupen, who teaches human and comparative animal physiology, explains the ins and outs of belly buttons.

Your belly button, or navel – clinically, your umbilicus – is the permanent scar left from where your umbilical cord connected your circulatory system, when you were a fetus, to the placenta. Fetuses don’t breathe, eat or eliminate waste, so the placenta provides an exchange site for the mother to deliver oxygen and nutrients from her bloodstream to the fetus, as well as collecting its wastes to eliminate from her body.

After the baby is born, the physician or other attendant cuts the cord and clamps off the stub, which then dries and falls off after about a week, leaving the point of connection – your belly button – remaining.

If the cord is not cut, as has been the practice in some times and places and as is becoming trendy again in others, it will close off after an hour or so, then naturally detach a few days after birth. Some health care practitioners are concerned that this “lotus birth” could be an infection risk, since the umbilical cord remains attached to the placenta, which is dead tissue once out of the mother’s body.

If you injure just the outer layers of your skin, as in a cut or burn, the scar will soon completely disappear, especially in young people. And newborns are very young people. But unlike in those situations, the umbilicus involves more tissue layers — not just the skin but the connective tissue underneath – so it makes sense it doesn’t just blend in with the rest of your abdominal wall once it’s healed.

What about some pretty complicated surgeries that don’t leave scars? Doctors perform many operations in ways that deliberately avoid scarring, which is not nature’s way. In fact, one way to minimize scarring for surgeries uses this existing scar – surgeons can take advantage of the navel as an incision site for removing your appendix or gall bladder or for weight-loss surgery.

But if you don’t like the way your umbilical scar looks, plastic surgery to change its appearance, called umbilicoplasty, is possible. People sometimes take this cosmetic option after pregnancy or the removal of a piercing, or just to make an “outie” into an “innie.”

The look of your belly button is not related to the location of the clamp or where your doctor cut the cord.

Outies are simply an example of normal human variation, like the way some people have curly hair or dimples. When the tip of the umbilical cord’s remnant pokes out past the skin around it, you have an outie; about 10% of people have these. Any concave navel is called an “innie” and a convex one an “outie.”

Sometimes outies can be caused by an umbilical hernia in the baby or another medical problem, but most of it is just due to what your genes encoded. You might also temporarily have an outie during late pregnancy, when the abdominal pressure from the growing fetus stretches your navel and may push it out.

You can probably easily probe the depth of your own navel – there are no hidden recesses there. What’s under it is the same as what’s under the skin of the rest of your abdomen: your abdominal muscles, to which the navel is attached by a short umbilical stalk, and the peritoneum, the membrane that lines the abdominal cavity. Under that lie your guts – that is, your intestines and other abdominal organs. If you keep following this imaginary journey back, you’ll get to your spine – the belly button is usually lined up between the third and fourth lumbar vertebrae (L3 and L4).

Because the navel is a scar from where the umbilical cord connected the fetus to the placenta, all placental mammals have them. That includes all mammals except marsupials (like kangaroos and possums) and monotremes (like platypuses and echidnas).

Your cat or dog or guinea pig does have a belly button, but because it’s a flatter scar than a person’s rather than a concave one, and is covered in fur, you might have missed it.

Like any concave surface, if you have an innie, it probably gathers bits of debris occasionally. Your navel also has a microbiota, just like the rest of your skin. Because it’s pretty protected from soap and abrasion, a more stable and diverse bacterial community lives in your navel than elsewhere on your skin’s surface.

The innovative Belly Button Biodiversity project at North Carolina State University has revealed a lot about these little friends. The researchers found over 2,000 species of bacteria in the first 60 belly buttons they investigated.

It looks like most people have a set of eight common belly button bacteria, but the project is discovering new ones all the time.

There hasn’t really been much research into why some people find belly buttons to be repulsive.

It may overlap with omphalophobia, the fear of belly buttons and touching them. There’s no specific treatment beyond the therapy or anti-anxiety medications a doctor might prescribe for any other phobia.

Whatever your feelings about belly buttons, they’re harmless. What’s more, they’re part of your evolutionary legacy as a mammal, the group of animals so invested in their offspring that they invented a way to deliver nutrients and oxygen, the mother’s bread and breath, straight into their developing young. Your navel can be a reminder of that first life-sustaining care you received from another person before you were even born.


Sarah Leupen

The Conversation

Microbiology

Mosquitoes’ saliva contains immune-dampening substances to increase infectivity of dengue viruses

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Reviewed by Emily Henderson, B.Sc.Apr 4 2023

The saliva of mosquitoes infected with dengue viruses contains a substance that thwarts the human immune system and makes it easier for people to become infected with these potentially deadly viruses, new research reveals.

Dengue has spread in recent years to Europe and the Southern United States in addition to longstanding hotspots in tropical and subtropical areas such as Southeast Asia, Africa and Latin America. The new discovery, from a University of Virginia School of Medicine scientist and his collaborators, helps explain why the disease is so easily transmitted and could eventually lead to new ways to prevent infection.

“It is remarkable how clever these viruses are – they subvert mosquito biology to tamp down our immune responses so that infection can take hold,” said Mariano A. Garcia-Blanco, MD, PhD, who recently joined UVA as chair of the Department of Microbiology, Immunology and Cancer Biology. “There is no doubt in my mind that better understanding of the fundamental biology of transmission will eventually lead to effective transmission-blocking measures.”

Further, Garcia-Blanco suspects that researchers will find similar immune-dampening substances accompanying other mosquito-borne infections such as Zika, West Nile and yellow fever.

Our findings are almost certainly going to be applicable to infections with other flaviviruses. The specific molecules here are unlikely to apply to malaria, but the concept is generalizable to viral infections.”

Mariano A. Garcia-Blanco, MD, PhD, UVA

Understanding dengue

Approximately half the world’s population is at risk for dengue, and roughly 400 million people are infected every year. Dengue’s symptoms, including fever, nausea and skin rash, are often mistaken for other diseases. Most people will have mild cases, but about 1 in 20 will develop severe illness that can lead to shock, internal bleeding and death. Unfortunately, it’s possible to contract dengue repeatedly, as it is caused by four related viruses transmitted primarily by the Aedes aegypti species of mosquito. There is no treatment, but the new discovery from Garcia-Blanco and his colleagues identifies an important contributor to the disease’s spread as researchers seek to find better ways to combat it.

Garcia-Blanco and his team found that infected mosquitoes’ saliva contained not just the expected dengue virus but a powerful conspirator: molecules produced by the virus that can blunt the body’s immune response. The injection of these molecules, called sfRNAs, during the mosquito bite makes it more likely that the victim will become infected with dengue, the scientists conclude.

“By introducing this RNA at the biting site, dengue-infected saliva prepares the terrain for an efficient infection and gives the virus an advantage in the first battle between it and our immune defenses,” the researchers write in a new scientific paper outlining their findings.

Scientists who study mosquitoes previously had suspected that the insects’ saliva might contain some type of payload to enhance the potential for infection. Garcia-Blanco’s team’s new findings pinpoints one weapon in the viruses’ arsenal and opens the door to finding new ways to help reduce transmission and control the disease’s spread. For now, the best way to avoid getting seriously sick with dengue remains to avoid getting bitten.

“It’s incredible that the virus can hijack these molecules so that their co-delivery at the mosquito bite site gives it an advantage in establishing an infection,” said researcher Tania Strilets, a graduate student with Garcia-Blanco and co-first author of the scientific paper. “These findings provide new perspectives on how we can counteract dengue virus infections from the very first bite of the mosquito.”

Findings published

The researchers have published their findings in the scientific journal PLOS Pathogens. The team consisted of Shih-Chia Yeh, Strilets, Wei-Lian Tan, David Castillo, Hacène Medkour, Félix Rey-Cadilhac, Idalba M. Serrato-Pomar, Florian Rachenne, Avisha Chowdhury, Vanessa Chuo, Sasha R. Azar, Moirangthem Kiran Singh, Rodolphe Hamel, Dorothée Missé, R. Manjunatha Kini, Linda J. Kenney, Nikos Vasilakis, Marc A. Marti-Renom, Guy Nir, Julien Pompon and Garcia-Blanco. Most of Garcia-Blanco’s work on the project was conducted while he was at Duke-NUS Medical School and the University of Texas Medical Branch.

Source:

University of Virginia Health System

Journal reference:

Yeh, S.-C., et al. (2023). The anti-immune dengue subgenomic flaviviral RNA is present in vesicles in mosquito saliva and is associated with increased infectivity. PLOS Pathogens. doi.org/10.1371/journal.ppat.1011224.

Microbiology

Scientists identify a distinct role of retinoic acid during immune response of the gut

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Reviewed by Emily Henderson, B.Sc.Mar 28 2023

A team of scientists from the Renaissance School of Medicine (RSOM) at Stony Brook University have identified a distinct role of retinoic acid, a metabolite of vitamin A, during the immune response of the gut. This finding, detailed in a paper published in the Journal of Experimental Medicine, and highlighted in a broader piece in the journal, could help lead to ways to control the retinoic acid response and therefore be used as a therapy or for vaccine development against infection or even to treat GI tumors.

Led by Brian Sheridan, PhD, Associate Professor in the Department of Microbiology and Immunology and Center for Infectious Diseases, the study involves basic research that centers on unraveling the factors that control the generation of cytotoxic memory CD8 T cells, which are an important arm of the body’s anti-pathogen immune response as they kill pathogen-infected cells and produce anti-pathogen cytokines. In fact, memory CD8 T cells provide long-lived and frontline protection at barrier tissues, highlighting their importance in vaccine design.

To date scientists have known that retinoic acid in the gut-draining lymph nodes promotes effector CD8 T cell migration to the intestines, enhancing the immune response. Additionally, vitamin A deficiency is associated with increased infections and poor vaccine efficiency.

Sheridan and his co-authors, including Zhijuan Qiu, PhD, a post-doctoral fellow in the department, identified a new role for retinoic acid, which is a key part of the immune process in the gut. They demonstrated in the lab that T cell activation in gut-associated lymph nodes regulates memory CD8 T cell differentiation in the intestine. They also demonstrated in contrast that T cells activated at other sites were impaired in the ability to differentiate into memory CD8 T cells after entry into the intestine.

During this process, they demonstrated that activation within the gut-associated lymph nodes, but not in other sites, promotes intestinal memory CD8 T cell development and that retinoic acid signals provided during this window of T cell activation in the lymph nodes enhances intestinal memory CD8 T cell development to a wider degree.

Our study highlights a fundamental new role of T cell activation on the generation of the intestinal memory CD8 T cells that appears distinct from other barrier sites like the lungs and skin. Remarkably, we can alter intestinal T cell development by promoting or limiting retinoic acid signals during T cell activation, independent of the role of retinoic acid on T cell migration.”

Brian Sheridan, PhD, Associate Professor in the Department of Microbiology and Immunology and Center for Infectious Diseases

Because the research team was able to replicate this limiting or promoting of retinoic acid signals in the gut, they believe that manipulating retinoic acid signals during T cell activation may provide a strategy for clinicians to promote or limit intestinal CD8 T cells to improve vaccine outcomes or limit immunopathology.

This research is supported in part by a grant (R01AI172919) from the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID) to Brian Sheridan.

Source:

Stony Brook University

Journal reference:

Qiu, Z., et al. (2023). Retinoic acid signaling during priming licenses intestinal CD103+ CD8 TRM cell differentiation. Journal of Experimental Medicine. doi.org/10.1084/jem.20210923.

Microbiology

NIH scientists discover an autoinflammatory disease caused by mutations in the LYN gene

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Reviewed by Emily Henderson, B.Sc.Mar 28 2023

Scientists have identified an autoinflammatory disease caused by mutations in the LYN gene, an important regulator of immune responses in health and disease. Named Lyn kinase-associated vasculopathy and liver fibrosis (LAVLI), the identification sheds light on how genes linked to certain illnesses can potentially be targets for treatment by repurposing existing drugs. The research, published in Nature Communications, was led by Adriana A. de Jesus, M.D. Ph.D., and Raphaela Goldbach-Mansky, M.D., M.H.S. of the Translational Autoinflammatory Diseases Section of the Laboratory of Clinical Immunology and Microbiology at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

LAVLI was first discovered in a pediatric patient through genetic testing, which detected a mutation in LYN, the gene that encodes the Lyn kinase protein. Two additional, unrelated pediatric patients were later discovered to have two more mutations in the same gene. All three patients developed diseases linked to the LYN genetic mutation shortly after birth. Two patients developed liver fibrosis—excessive amounts of scar tissue caused by inflammation and repeated liver damage—in the first year of life. All three patients had perinatal onset of neutrophilic cutaneous small vessel vasculitis. This is an immune disorder characterized by inflammation from high numbers of neutrophils—white blood cells of the immune system—that can damage small blood vessels.

The study revealed Lyn kinase was always active and unable to shut down in the three patients with the LYN mutation, which increased neutrophil migration, altered inflammatory signals and activated scar and fibrosis-inducing liver cells. The results of this study suggest that Lyn kinase may be a potential therapeutic target for drugs that treat forms of non-syndromic small vessel vasculitis and other types of inflammation-induced liver fibrosis.

Source:

National Institutes of Health

Journal reference:

de Jesus, A. A., et al. (2023). Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome. Nature Communications. doi.org/10.1038/s41467-023-36941-y.