Day: May 13, 2022

Sarin Gas Likely the Cause of Mysterious Gulf War Illness

Photo by Pablo Stanic on Unsplash

Since the 1990s, scientists have debated the underlying cause of Gulf War illness (GWI), a constellation of unexplained and chronic symptoms affecting veterans of the Persian Gulf War. Now researchers have solved the mystery, showing through a detailed genetic study that the nerve gas sarin was largely responsible for the syndrome. The findings were published in Environmental Health Perspectives.

Dr Haley’s research group not only discovered that veterans with exposure to sarin were more likely to develop GWI, but also found that the risk was modulated by a gene that helps break down the nerve gas. Sarin-exposed Gulf War veterans with a weak variant of the gene were more likely to develop symptoms of GWI than other exposed veterans with the strong form of the gene.

“Quite simply, our findings prove that Gulf War illness was caused by sarin, which was released when we bombed Iraqi chemical weapons storage and production facilities,” said Robert Haley, MD, at UT Southwestern, a medical epidemiologist who had led that study and has been investigating GWI for 28 years. “There are still more than 100 000 Gulf War veterans who are not getting help for this illness and our hope is that these findings will accelerate the search for better treatment.”

Multiple causes of Gulf War illness suggested

After the Gulf War, more than a quarter of the US and coalition veterans began reporting a range of chronic symptoms, including fatigue, fever, night sweats, memory and concentration problems, difficulty finding words, diarrhoea, sexual dysfunction, and chronic body pain. Since then, military and academic researchers have studied a list of possible causes of GWI, ranging from stress, vaccinations, and burning oil wells to exposure to pesticides, nerve gas, anti-nerve gas medication, and depleted uranium used in weapons.

“What makes this new study a game-changer is that it links GWI with a very strong gene-environment interaction that cannot be explained away by errors in recalling the environmental exposure or other biases in the data.”

Study leader Robert Haley, MD, medical epidemiologist

Over the years, these studies have identified statistical associations with several of these, but no cause has been widely accepted. Most recently, Dr Haley and a colleague reported a large study testing veterans’ urine for depleted uranium that would still be present if it had caused GWI and found none.

Studies have shown statistical associations with several of these causes, though none received wide acceptance. Dr Haley and a colleague recently reported a large study that found no depleted uranium in veterans’ urine, which would have still been present if it had caused GWI.

“As far back as 1995, when we first defined Gulf War illness, the evidence was pointing toward nerve agent exposure, but it has taken many years to build an irrefutable case,” said Dr Haley.

Sarin’s effects

Sarin is a toxic nerve agent, production of which was banned in 1997. When people are exposed to either the liquid or gas form, sarin enters the body through the skin or breathing and attacks the nervous system. High-level sarin often results in death, but studies on survivors have revealed that lower-level sarin exposure can lead to long-term impairment of brain function. A large release of this gas occurred when a chemical weapons storage plant was bombed, causing thousands of nerve gas alarms to sound.

Previous studies have found an association between Gulf War veterans who self-reported exposure to sarin and GWI symptoms. However, this has raised criticisms of recall bias. “What makes this new study a game-changer is that it links GWI with a very strong gene-environment interaction that cannot be explained away by errors in recalling the environmental exposure or other biases in the data,” Dr Haley said.

In the new paper, Dr Haley and his colleagues studied 508 deployed veterans with GWI and 508 deployed veterans who did not develop any GWI symptoms. They asked whether the veterans had heard chemical nerve gas alarms, indicating sarin exposure, and also collected blood and DNA samples.

The role of PON1

The researchers tested the samples for variants of a gene called PON1, which has two variants. The Q variant generates a blood enzyme that efficiently breaks down sarin while the R variant helps the body break down other chemicals but is not efficient at destroying sarin. Everyone has either a QQ, RR or QR genotype.

For Gulf War veterans with the QQ genotype, hearing nerve agent alarms — a proxy for chemical exposure — raised their chance of developing GWI by 3.75 times, those with the QR genotype had an a 4.43 fold risk increase. And for those with RR genotype, the chance of GWI increased by 8.91 times. Those soldiers with both the RR genotype and low-level sarin exposure were over seven times more likely to get GWI due to the interaction per se, over and above the increase in risk from both risk factors acting alone. For genetic epidemiologists, this number leads to a high degree of confidence that sarin is a causative agent of GWI.

“Your risk is going up step by step depending on your genotype, because those genes are mediating how well your body inactivates sarin,” said Dr Haley. “It doesn’t mean you can’t get Gulf War illness if you have the QQ genotype, because even the highest-level genetic protection can be overwhelmed by higher intensity exposure.”

This kind of strong gene-environment interaction is considered a gold standard for showing that an illness like GWI was caused by a particular environmental toxic exposure, he added. The research doesn’t rule out that other chemical exposures could be responsible for a small number of cases of Gulf War illness. However, Dr. Haley and his team carried out additional genetic analyses on the new data, testing other factors that could be related, and found no other contributing causes.

“There’s no other risk factor coming anywhere close to having this level of causal evidence for Gulf War illness,” said Dr Haley.

The team is continuing research on GWI’s impacts on the body, particularly the immune system, whether any of its effects are reversible, and whether there are biomarkers to detect prior sarin exposure or GWI.

Source: UT Southwestern Medical Center

No Added Seizure Risk from Antidepressant Use in Pregnancy

Pregnant with ultrasound image
Source: Pixabay

A large Swedish study in the journal Neurology found that pregnant women taking selective serotonin reuptake inhibitors (SSRIs) or selective norepinephrine reuptake inhibitors (SNRIs) during the first trimester of was not linked to an increased risk for neonatal seizures and epilepsy in childhood.

Any increase in seizures or epilepsy is likely due to other factors, the researchers said.

“It’s not likely the medications themselves that are causing the seizures and epilepsy in children, but rather the reasons why these women are taking the medication,” according to Kelsey Kathleen Wiggs, a PhD candidate at Indiana University in Bloomington. There are also the other background factors that differ between women who do and do not use SSRI/SNRIs.

“When it rains, it pours,” Wiggs said. “Women who are taking antidepressants in pregnancy are doing that for lots of different reasons, and they might be at risk for different things than women who aren’t taking those medications in pregnancy.”

An elevated risk for neonatal seizures (risk ratio [RR] 1.41) and epilepsy in early childhood (HR 1.21) among offspring of mothers who used antidepressants in pregnancy.

Adjustment for maternal indications for SSRI/SNRI use and background factors like smoking during pregnancy revealed that they were drivers for both associations: neonatal seizures (RR 1.10); epilepsy diagnosis at 5 years (HR 0.96). Parental history of epilepsy was not found to affect the association.

The findings provide a “conclusive answer” to these concerns with using SSRI/SNRIs during pregnancy, according to Anne Berg, PhD, and Torin Glass, BM, Bch, BAO.

“[SSRI/SNRIs] have been demonstrated to have serotonergic central nervous system effects and are associated with an observable withdrawal syndrome which may be seen in the neonate following in utero exposure,” noted Drs Berg and Glass, in an accompanying editorial.

“The authors understood that with a population-based data registry and huge sample size, they had more than sufficient statistical power to detect even a modest increase in risk,” the editorialists wrote. “They tested this hypothesis and were able to reject it, definitively!”

In order to determine whether antidepressants had a causal association with infant seizures and childhood epilepsy, the researchers analysed data from national Swedish healthcare registries on a total of 1 721 274 children in Sweden born between 1996 and 2011.

Participants were divided into two groups: one group of mothers who reported use of an SSRI (fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine, escitalopram) or SNRI (venlafaxine, duloxetine) during the first trimester of pregnancy (n = 24 308), and another group with no reported antidepressant use (n = 1 696 966).

Source: MedPage Today

How Kaposi Sarcoma-associated Herpesvirus Evades the Immune System

Kaposi sarcoma on the skin of an AIDS patient. Credit: National Cancer Institute

A study published in Cell Reports has identified a protein in the cancer cell’s nucleus as a critical agent keeping Kaposi sarcoma-associated herpesvirus (KSHV) dormant and hidden from the immune system. The virus, in the same family as Epstein-Barr virus, is linked to AIDS-related Castleman’s disease and cancers such as Kaposi sarcoma.

Up to 50% of the population in some parts of Africa are affected with KSHV, though not everyone with KSHV will develop Kaposi sarcoma. Those who do typically have a weakened immune system due to HIV infection, organ transplant, being older or other factors.

The introduction of antiretroviral therapy significantly reduced AIDS-related Kaposi sarcoma prevalence in Western countries; however, in sub-Saharan Africa, the disease continues to have a poor prognosis.

On entry into a human cell the virus causes a hidden infection in the nucleus: the virus simply latches onto parts of the cell’s chromosomes without replicating.

Researchers studied KSHV’s latent-lytic switch, a process in which the virus exits its dormancy state to replicate in the host cell. This replication phase, called the lytic cycle, ends with the disintegration of the cell and the release of the viruses, infecting neighbouring cells.

“The virus likes to stay silent as long as possible to avoid being detected by the body’s immune system,” said Professor Yoshihiro Izumiya, the study’s senior author.

The team sought to understand the mechanisms behind this latent-lytic switch and the role the host cell environment played in this process.

“Where the virus latches onto the host cell, how it manages to stay dormant, and what triggers its activation were very exciting and important puzzles to solve,” Prof Izumiya said.

The study identified where the virus genome could be found on the host genome.

Izumiya and his team profiled and analysed chromosomal interactions on three cancer cell lines naturally infected with KSHV, locating the virus’s preferred chromosome docking sites. The binding patterns, similar among the three cancer cell lines, showed a nuclear ecosystem that can attract and help keep the virus in its silent form.

The team also found that CHD4 (chromodomain helicase DNA binding protein 4) binds to the virus’s genomic elements. CHD4, a protein in the host cell’s chromosomes, suppresses the work of the gene responsible for viral replication. The study showed that CHD4 is a key regulator of the KSHV latency-lytic switch.

“The location where the virus genome attaches to the host chromosome is not random,” said Ashish Kumar, a postdoctoral researcher in Izumiya Lab and the paper’s first author. “Without having enriched CHD4 protein, the virus starts to replicate, kicking in a cell destructive mode. For the virus to select CHD4 among many other host proteins, CHD4 must play a unique and important role in host cells.”

Virology can help identify cellular proteins essential for cell homeostasis. Over millions of years, the virus’s genome developed to encode or assemble a small number of very efficient proteins, which strategically connect to host cell proteins to keep viral chromatin dormant and impact the host cell’s tumour suppression function.

“We used virology as an entry point to shed light on the function of CHD4 in gene regulation in general. During virus-host co-evolution, KSHV cleverly learned to hijack host proteins that can help keep the gene responsible for viral replication dormant.”

The researchers found a viral protein which could serve as the basis for a replication inhibitor. Since CHD4 is critical for cancer cell growth in a variety of cancers, they hope this virus-host interaction could inform cancer treatment research.

Source: University of California – Davis Health

New Treatment Traps and Kills off Toxoplasma gondii in Host Cells

Toxoplasma gondii, an obligate intracellular human parasite, has a unique cytoskeletal apparatus that is probably used for invading host cells and for parasite replication. Shown here are images of T. gondii constructing daughter scaffolds within the mother cell. Green: YFP-α-Tubulin; bright yellow: mRFP-TgMORN1 (see Hu et al., Figure 6 A-C).
Credit: Image provided by Ke Hu and John M. Murray

A new method blocks the protein regulation of Toxoplasma gondii, causing the parasite to die off inside the host cell, a method which could be adapted to malaria. The approach is detailed in the journal Nature Microbiology.

Toxoplasmosis is one of the most widespread zoonoses worldwide. It is an infectious disease that can be transmitted from cats to humans, and from consumption of raw or undercooked meat. Infection is particularly dangerous for pregnant women, and immunosuppressed HIV/AIDS patients often manifest neurological symptoms.

The cause of the disease is the single-celled parasite T. gondii. Inside the host cell, it forms a parasitophorous vacuole, a tiny compartment facilitating nutrient exchange and synchronised cell division. Up to 64 daughter cells can form inside, connected with each other inside the vacuole via a network. As soon as the offspring are mature, a regulation mechanism prompts the dissolution of the vacuole and the structures that have formed inside it, releasing the daughter cells to invade new host cells.

Hope for the development of new drugs

Previously, it was not known which genes encode the proteins that control the exit from the host cell. To identify them, a team led by Professor Markus Meißner at LMU, collaborated with colleagues from the University of Glasgow in Scotland to develop a novel genetic screening technique based on Cas9 ‘genetic scissors’, and investigate a library of 320 parasite-specific genes. They discovered two genes without which cell egress is impossible.

The targeted destruction of these genes resulted in the exit being trapped and the next generation of parasites dying within the host cell. “This paves the way potentially for the development of active substances that could block the function of the corresponding proteins and so put a halt to propagation,” remarked Prof Markus Meißner.

T. gondii is closely related to the malaria pathogen Plasmodium falciparum. Therefore, the parasite serves as a model organism for the pathogen of the tropical disease, which kills hundreds of thousands of people worldwide every year. “We assume that similar processes control the propagation of the malaria pathogen,” explains LMU parasitologist Dr. Elena Jimenez-Ruiz. “Next, we will investigate what functions these proteins have in the malaria pathogen and whether there are possible starting points for the development of new drugs.”

Source: Ludwig-Maximilians-Universität München

CSF From Young Mice Improves Memory of Older Mice

Mouse
Photo by Kanasi on Unsplash

In a finding reminiscent of how vampires and zombies in fiction get sustenance from their victims, a team of researchers reported in the journal Nature that injecting cerebrospinal fluid (CSF) from young mice into old mice improves the memory and cognitive abilities of the older mice

Such an approach is nothing new, although the chief obstacle was safely harvesting such a tiny amount of CSF from the small animals. About two decades ago, studies had reported that transferring blood from younger mice to older ones notably improved the health of the older mice, giving them a ‘rejuvenating’ effect. It did not take long for people to take note of this discovery, with a startup company offering transfers of young people’s plasma for exorbitant amounts to wealthy older clients in the unproven hopes of reversing ageing. Fears of a dystopian future were averted when the US Food and Drug Administration released a statement stating such transfers had no clinical benefit, and the company folded. However, research continued.

Since ageing is too complex to measure in a clinical trial anyway, scientists have been focusing on tackling specific aspects of it, such as in neurodegenerative diseases like Alzheimer’s and research has continued in this direction. A few years ago, human umbilical cord plasma was shown to revitalise hippocampal function in aged mice, and previous work led by Tony Wryss-Coray, PhD had found that young mouse blood improved age-related impairments in cognition. Studies of fear conditioning had shown that proliferation of oligodendrocyte precursor cells (OPCs) was necessary for fear formation, which raised the question of whether CSF might affect this.

Infusing CSF taken from 10 week old mice over seven days, researchers trained 18 month old mice to associate a flashing light with an electric shock to the foot. The CSF infusion was shown to improve recall of the fear stimulus in the older mice and induce greater OPC proliferation.

“The broad message here is that the aging process is malleable, which of course is not new because of this paper,” senior author Dr Wyss-Coray said in an interview with MedPage Today. “But it adds to the idea that aging is a potential therapeutic target, a process we can start to understand better and start to manipulate.”

“The other message – one that’s more brain-specific – is that if you improve the environment in which neurons live, you can actually have a substantial improvement in function,” he added. “That may be as important, or even more important sometimes, than targeting neuronal processes themselves.”

The researchers isolated fibroblast growth factor 17 (Fgf17) infusion as being necessary for OPC proliferation, and blocking it in young mice impaired cognition.

“This suggests that Fgf17 is not only able to recapitulate some of the useful effects of CSF from young mice, but it also seems to be necessary to make a young brain function at its full capacity,” Dr Wyss-Coray said.