Day: May 17, 2024

Categories : COVID Diseases, Syndromes and ConditionsTags :

New Viruses that could Cause Epidemics on the Horizon

On By ModernMedia
Photo by Artem Podrez on Pexels

There are viruses out there that nobody has on their radar, but they suddenly appear and, like SARS-CoV-2, can trigger major epidemics. They only have a slight genetic difference from before, the exchange of genetic material between different virus species can lead to the sudden emergence of threatening pathogens with significantly altered characteristics. This is suggested by current genetic analyses carried out by an international team of researchers. Virologists from the German Cancer Research Center (DKFZ) were in charge of the large-scale study which appears in PLOS Pathogens.

“Using a new computer-assisted analysis method, we discovered 40 previously unknown nidoviruses in various vertebrates from fish to rodents, including 13 coronaviruses,” reports DKFZ group leader Stefan Seitz. With the help of high-performance computers, the research team, which also includes Chris Lauber’s working group from the Helmholtz Center for Infection Research in Hanover, has sifted through almost 300 000 data sets. According to virologist Seitz, the fact that we can now analyse such huge amounts of data in one go opens up completely new perspectives.

Virus research is still in its relative infancy. Only a fraction of all viruses occurring in nature are known, especially those that cause diseases in humans, domestic animals and crops. The new method therefore promises a quantum leap in knowledge with regard to the natural virus reservoir. Stefan Seitz and his colleagues sent genetic data from vertebrates stored in scientific databases through their high-performance computers with new questions. They searched for virus-infected animals in order to obtain and study viral genetic material on a large scale. The main focus was on so-called nidoviruses, which include the coronavirus family.

Nidoviruses, whose genetic material consists of RNA (ribonucleic acid), are widespread in vertebrates. This species-rich group of viruses has some common characteristics that distinguish them from all other RNA viruses and document their relationship. Otherwise, however, nidoviruses are very different from each other, i.e. in terms of the size of their genome.

One discovery is particularly interesting with regard to the emergence of new viruses: In host animals that are simultaneously infected with different viruses, a recombination of viral genes can occur during virus replication. “Apparently, the nidoviruses we discovered in fish frequently exchange genetic material between different virus species, even across family boundaries,” says Stefan Seitz. And when distant relatives “crossbreed,” this can lead to the emergence of viruses with completely new properties. According to Seitz, such evolutionary leaps can affect the aggressiveness and dangerousness of the viruses, but also their attachment to certain host animals.

“A genetic exchange, as we have found in fish viruses, will probably also occur in mammalian viruses,” explains Stefan Seitz. Bats, which — like shrews — are often infected with a large number of different viruses, are considered a true melting pot. The SARS-CoV-2 coronavirus probably also developed in bats and jumped from there to humans.

After gene exchange between nidoviruses, the spike protein with which the viruses dock onto their host cells often changes. Chris Lauber, first author of the study, was able to show this by means of family tree analyses. Modifying this anchor molecule can significantly change the properties of the viruses to their advantage – by increasing their infectiousness or enabling them to switch hosts. A change of host, especially from animals to humans, can greatly facilitate the spread of the virus, as the corona pandemic has emphatically demonstrated. Viral “game changers” can suddenly appear at any time, becoming a massive threat and – if push comes to shove – triggering a pandemic. The starting point can be a single double-infected host animal.

The new high-performance computer process could help to prevent the spread of new viruses. It enables a systematic search for virus variants that are potentially dangerous for humans, explains Stefan Seitz. And the DKFZ researcher sees another important possible application with regard to his special field of research, virus-associated carcinogenesis: “I could imagine that we could use the new High Performance Computing (HPC) to systematically examine cancer patients or immunocompromised people for viruses. We know that cancer can be triggered by viruses, the best-known example being human papillomaviruses. But we are probably only seeing the tip of the iceberg so far. The HPC method offers the opportunity to track down viruses that, previously undetected, nestle in the human organism and increase the risk of malignant tumours.”

Source: German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

Categories : Allergies Diet and NutritionTags :

Celiac Disease: New Findings on the Effects of Gluten

On By ModernMedia
Photo by Mariana Kurnyk

May 16 is International Celiac Day. Celiac disease is a chronic autoimmune condition that occurs in around 1% of the world’s population. It is triggered by the consumption of gluten proteins from wheat, barley, rye and some oats. A gluten-free diet protects celiac patients from severe intestinal damage. Together with colleagues, chemist Dr Veronica Dodero from Bielefeld University was able to determine new details on how certain gluten-derived molecules trigger leaky gut syndrome in celiac disease.

The key finding of the study: a particular protein fragment formed in active celiac disease forms nanosized structures, the so-called oligomers, and accumulates in a gut epithelial cell model. The technical name of the molecule is 33-mer deamidated gliadin peptide (DGP). The study team has now discovered that the presence of DGP oligomers may open the tightly closed gut lining, leading to the leaky gut syndrome. The study has now been published in the journal Angewandte Chemie.

Wheat peptides causing leaky gut

Gluten proteins cannot be completely broken down by the gut. This can lead to the formation of large gluten fragments (peptides) in our gut. In cases of active coeliac disease, researchers discovered that the enzyme tissue transglutaminase 2 (tTG2) present in humans modifies a specific gluten peptide, resulting in the formation of the 33-mer DGP. This usually happens in a part of our gut called the lamina propria. However, recent research has shown that this process can also occur in the gut lining.

‘Our interdisciplinary team characterized the formation of 33-mer DGP oligomers through high-resolution microscopy and biophysical techniques. We discovered the increased permeability in a gut cell model when DGP accumulates, reports Dr. Maria Georgina Herrera, the first author of the study. She is researcher at the University of Buenos Aires in Argentina and was a postdoctoral fellow at Bielefeld.

When the intestinal barrier is weakened

Leaky gut syndrome occurs when the lining of the intestine becomes permeable, allowing harmful substances to enter the bloodstream, leading to inflammatory responses and different diseases. In celiac disease, there’s debate about the early stages of increased permeability. The mainstream theory suggests that chronic inflammation in coeliac disease leads to a leaky gut. However, there is a second theory that proposes that gluten’s effects on gut lining cells are the primary cause. In this view, gluten directly damages the cells of the intestinal lining, making them permeable, which triggers chronic inflammation and potentially leads to celiac disease in predisposed people.

However, since gluten is consumed daily, what molecular triggers lead to the leaky gut in celiac disease patients? If 33-merDGP oligomers are formed, they may damage the epithelial cell network, allowing gluten peptides, bacteria, and other toxins to pass massively into the bloodstream, leading to inflammation and, in celiac disease, autoimmunity.

‘Our findings reinforce the medical hypothesis that impairment of the epithelial barrier promoted by gluten peptides is a cause and not a result of the immune response in celiac patients,’ says the lead author of the study, Dr Veronica Dodero from the Bielefeld Faculty of Chemistry.

The relationship between 33-mer DGP and Celiac Disease

Human leukocyte antigens (HLAs) are proteins found on the surface of cells in the body. They play a crucial role in the immune system by helping it distinguish between self (the body’s own cells) and non-self (foreign substances like bacteria or viruses). In celiac disease, two specific HLA proteins, namely HLA-DQ2 and HLA-DQ8, are strongly associated with the condition. The 33-mer DGP fits perfectly with HLA-DQ2 or HLA-DQ8 and triggers an immune response, leading to inflammation and small intestine villous atrophy. This strong interaction turns the DGP into what scientists call a superantigen. For those affected, a gluten-free diet is the only lifelong therapy.

Source: Bielefeld University

Categories : Obstetrics & Gynaecology VaccinesTags :

Birth by C-section More than Doubles Odds of Measles Vaccine Failure

On By ModernMedia
Photo by Christian Bowen on Unsplash

A study by the University of Cambridge, UK, and Fudan University, China, has found that a single dose of the measles jab is up to 2.6 times more likely to be completely ineffective in children born by C-section, compared to those born naturally.

Failure of the vaccine means that the child’s immune system does not produce antibodies to fight against measles infection, so they remain susceptible to the disease.

A second measles jab was found to induce a robust immunity against measles in C-section children.

Measles is a highly infectious disease, and even low vaccine failure rates can significantly increase the risk of an outbreak.

A potential reason for this effect is linked to the development of the infant’s gut microbiome — the vast collection of microbes that naturally live inside the gut. Other studies have shown that vaginal birth transfers a greater variety of microbes from mother to baby, which can boost the immune system.

“We’ve discovered that the way we’re born – either by C-section or natural birth – has long-term consequences on our immunity to diseases as we grow up,” said Professor Henrik Salje in the University of Cambridge?’s Department of Genetics, joint senior author of the report.

He added: “We know that a lot of children don’t end up having their second measles jab, which is dangerous for them as individuals and for the wider population.

“Infants born by C-section are the ones we really want to be following up to make sure they get their second measles jab, because their first jab is much more likely to fail.”

The results are published today in the journal Nature Microbiology.

At least 95% of the population needs to be fully vaccinated to keep measles under control but the UK is well below this, despite the Measles, Mumps and Rubella (MMR) vaccine being available through the NHS Routine Childhood Immunisation Programme.

An increasing number of women around the world are choosing to give birth by caesarean section: in the UK a third of all births are by C-section, in Brazil and Turkey over half of all children are born this way.

“With a C-section birth, children aren’t exposed to the mother’s microbiome in the same way as with a vaginal birth. We think this means they take longer to catch up in developing their gut microbiome, and with it, the ability of the immune system to be primed by vaccines against diseases including measles,” said Salje.

To get their results, the researchers used data from previous studies of over 1500 children in Hunan, China, which included blood samples taken every few weeks from birth to the age of 12. This allowed them to see how levels of measles antibodies in the blood change over the first few years of life, including following vaccination.

They found that 12% of children born via caesarean section had no immune response to their first measles vaccination, as compared to 5% of children born by vaginal delivery. This means that many of the children born by C-section did still mount an immune response following their first vaccination.

Two doses of the measles jab are needed for the body to mount a long-lasting immune response and protect against measles. According to the World Health Organization, in 2022 only 83% of the world’s children had received one dose of measles vaccine by their first birthday – the lowest since 2008.

Salje said: “Vaccine hesitancy is really problematic, and measles is top of the list of diseases we’re worried about because it’s so infectious.”

Measles is one of the world’s most contagious diseases, spread by coughs and sneezes. It starts with cold-like symptoms and a rash, and can lead to serious complications including blindness, seizures, and death.

Before the measles vaccine was introduced in 1963, there were major measles epidemics every few years causing an estimated 2.6 million deaths each year.

The research was funded by the National Natural Science Foundation of China.

The original text of this story is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International Licence.

Source: University of Cambridge

Categories : DermatologyTags :

Exploring the Mechanism behind Drug Eruptions in the Skin

On By ModernMedia
Skin cell (keratinocyte). This normal human skin cell was treated with a growth factor that triggered the formation of specialised protein structures that enable the cell to move. We depend on cell movement for such basic functions as wound healing and launching an immune response.
Credit: Torsten Wittmann, University of California, San Francisco

Millions of people worldwide suffer from unpredictable drug toxicities every year. In particular, drug eruptions which manifest through symptoms such as redness, blisters, and itching on the skin, are quite common. Severe drug eruptions can become life-threatening and can have long-lasting consequences.

Previous studies have identified specific variants of certain genes as potential causal agents of drug eruptions. Scientists believe that the genes encoding the human leukocyte antigen (HLA), a protein expressed on the surface of leucocytes known to play an important role in the immune system, are involved in the onset of drug eruption. But current theories cannot explain why HLA-related drug eruptions typically manifest on the skin rather than in multiple organs throughout the body.

To address this knowledge gap, a research team including Lecturer Shigeki Aoki, Kousei Ito, and Akira Kazaoka from the Graduate School of Medical and Pharmaceutical Sciences, Chiba University, conducted an in-depth study on the link between HLA and drug eruptions. Their findings were published in PNAS Nexus.

The researchers first conducted a series of experiments on mice keratinocytes. These keratinocytes, the most common type of skin cell, were engineered to express a specific variant of the HLA gene called HLA-B*57:01, which specifically bind to the antiviral drug abacavir. Then, they validated these findings in genetically modified mice expressing HLA-B*57:01, that were exposed to abacavir.

The researchers found that HLA-B*57:01-expressing keratinocytes that were exposed to abacavir exhibited endoplasmic reticulum (ER) stress responses, such as immediate release of calcium into the cytosol and elevated expression of heat shock protein 70 (HSP70). They also observed an increased production of cytokines and immune cell migration. Abacavir exposure triggered HLA misfolding in the ER, leading to ER stress. Moreover, the researchers observed that the ER stress could be reduced by using 4-phenylbutyrate (4-PB). By alleviating this stress, they managed to suppress the onset of severe drug eruption symptoms. This newfound knowledge could form the basis for innovative treatment options for management of drug eruptions.

HLAs – secondary players for the immune system

But how does this new information contrast with what was already known about HLA? “HLA molecules are an integral component of our immune system, that typically present foreign antigens to white blood cells, which judge these antigens as self or non-self. In this established role, HLAs are usually secondary players,” explains Dr Aoki. “However, our research highlights a novel function of the HLA molecule within skin cells. We revealed that a specific HLA genotype in keratinocytes can recognise certain drugs as foreign, triggering an endoplasmic reticulum stress response.”

Taken together, the findings of this study uncover a new role of HLA proteins in sensing and responding to potential threats in skin cells. Thus, their functions may extend well beyond mere antigen presentation for the immune system. Moreover, considering that the variant of HLA possessed by an individual can be determined through genetic testing, this study could help develop preventive measures and diagnostics against severe adverse drug reactions.

According to Dr Aoki, this is in line with current research directions and trends in medical science.

“In 10 years, we anticipate entering the ‘whole genome era,’ where personalised medicine based on individual genomes will become a standard practice,” he comments. He further adds, “Building on the findings of this study, we believe that a comprehensive understanding of the mechanism underlying HLA-dependent adverse drug reactions will enable the delivery of safe medical care, allowing patients to avoid unnecessary suffering due to side effects.”

Future research might minimise the occurrence of drug eruptions and save people from potentially fatal adverse drug reactions.

Source: Chiba University

Categories : AntibioticsTags :

Supply Shortage Reveals that a Common Antibiotic has Unintended Consequences

On By ModernMedia
Photo by Marcelo Leal on Unsplash

Clinicians often have to make split-second decisions about which antibiotics to give a patient when a life-threatening infection is suspected. By taking advantage of a shortage of a common antibiotic, researchers at U-M found that antibiotic selection may have unintended consequences for patient outcomes.

Beginning in 2015, a 15-month national shortage of a commonly prescribed antibiotic, piperacillin/tazobactam (Zosyn), provided a unique opportunity to compare rates of death in hospitalised patients with sepsis who were administered two different types of antibiotics – one that spares the gut microbiome and one that profoundly alters it.

Piperacillin/tazobactam is a broad-spectrum antibiotic that is commonly administered for sepsis, a life-threatening complication from infection. In its absence, clinicians commonly instead use another antibiotic, cefepime, which has similar activity against common sepsis pathogens but, unlike piperacillin/tazobactam, has minimal effects on anaerobic gut bacteria. The results, published in JAMA Internal Medicine, were surprising.

“We saw this Zosyn shortage as a one-of-a-kind opportunity to ask whether this antibiotic, which we know depletes the gut of anaerobic bacteria, makes a difference in terms of patient outcomes,” said Robert Dickson, MD of the Department of Medicine’s Division of Pulmonary & Critical Care Medicine and Deputy Director of the Weil Institute for Critical Care Research & Innovation.

In health, the gut microbiome is largely populated by anaerobic bacteria that rarely cause disease. Prior work by the study team has revealed that even a single dose of piperacillin/tazobactam kills most of these anaerobic gut bacteria, which play important roles in the body’s metabolism, immunity, and prevention of infections.

Dickson, Rishi Chanderraj, MD of the Division of Infectious Disease, Michael Sjoding, MD of the Division of Pulmonary & Critical Care Medicine and their multidisciplinary team at U-M and the VA Ann Arbor used patient record data to look at outcomes in 7569 patients. The team compared 4523 patients who were treated were piperacillin/tazobactam with 3046 patients who received cefepime.

They found marked differences: treatment with piperacillin-tazobactam was associated with a 5 percent increase in 90-day mortality, more days on a ventilator, and more time with organ failure.

“These are powerful antibiotics that are administered to patients every day in every hospital nationwide,” said Chanderraj. “Clinicians use them because they are trying to treat every possible pathogen that might be causing their patients’ illness. But our results suggest that their effects on the microbiome might also have important effects on patient outcomes.”

The study builds on previous work by the researchers that suggested critically ill patients may do worse when given antibiotics that deplete the gut of anaerobes. They have also seen similar effects when studying animal models.

“Our prior work suggested that there might be harm with piperacillin/tazobactam, but it was an observational study that had some limitations,” said Sjoding, the study’s senior author. “That’s why the drug shortage was such an amazing opportunity. It created an almost perfect natural experiment that let us test the difference between these two drugs on patient outcomes in a very rigorous manner.”

A recent clinical trial pitted these two antibiotics against each other and compared side effects and mortality after two weeks. That trial did not find any differences in the short term – a finding that the U-M team also observed in their analysis.

“When we looked at two-week outcomes in our study, we didn’t find differences either,” said Chanderraj. “But the differences at three months were dramatic.”

Overall, the new findings suggest that treatment with piperacillin/tazobactam instead of cefepime may contribute to one additional death per every 20 septic patients treated.

“A 5% mortality difference has enormous implications because sepsis is so common,” said Dickson. “Every day, thousands of clinicians are deciding which of these drugs to use in septic patients.”

Physicians should give more thought about whether anti-anaerobic antibiotics are warranted before prescribing them, added Chanderraj. “We need to think about antibiotics like chemotherapy. In the right context, treatment can be lifesaving, but in the wrong context, it can be quite harmful.”

Source: Michigan Medicine – University of Michigan