Tag: disease

Categories : Diseases, Syndromes and ConditionsTags :

Double Threat of Flu and S. Pneumoniae Unravelled

On By ModernMedia
Streptococcus pneumoniae bacteria. Image by CDC on Unsplash

Researchers have found a further reason for why flu and Streptococcus pneumonia are such a deadly combination, by a surface protein causing it to stick to dead or dying lung cells. The finding by University of Alabama at Birmingham (UAB) follows thirty years after the discovery of the surface protein, called pneumococcal surface protein A, or PspA.

This new mechanism had been overlooked because it facilitates bacterial adherence only to dead or dying lung epithelial cells, not to living cells. Previously, researchers typically used healthy lung cell monolayers to search for bacterial adhesins that aid infection. In flu, the virus killing off lung cells was found to set the stage for S. pneumonia attachment to the airway, thereby worsening disease and pneumonia.

Study leaders Carlos Orihuela, PhD, and David Briles, PhD, professor at UAB, said their findings provide further explanation for how an infection by influenza A flu virus — followed by S. pneumoniae superinfection — causes severe pneumonia and a high death rate. Understanding of this mechanism could also lead to improvements for disease treatment and vaccination.

A historical example of the deadly synergy of flu infection followed by S. pneumoniae superinfection is found in banked lung samples from the 1918 Spanish influenza pandemic that killed 40 million to 50 million people — the vast majority of these samples showed co-infection or secondary infection with S. pneumonia.

The UAB research on PspA began with puzzling results from experimental lung infections of mice with influenza A, followed by either wild-type S. pneumonia that has the intact PspA gene, or a mutant S. pneumoniae that lacks PspA. Lung homogenates from mice infected with the wild-type had much higher numbers of S. pneumonia bacteria than lungs infected with the mutant. However, when researchers washed the interiors of the lungs and collected that bronchoalveolar lavage fluid, they counted similar numbers of the wild-type S. pneumonia and the mutant.

“This unexpected result was interpreted to mean that wild-type S. pneumoniae were more resistant to dislodgement than S. pneumonia with a pspA gene deletion, and it served as rationale for further experimentation,” Dr Orihuela said.

From this, the researchers were then able to show that PspA functions as an adhesin to dying host cells, as well as its previously established virulence mechanisms. The researchers also detailed the molecular mechanism of this bacterial adherence.

Both influenza A infection and release of the S. pneumoniae toxin pneumolysin cause death of lung epithelial cells. As they are dying, cells’ phosphatidylserine residues wind up on the outer cell membrane, where they bind the host enzyme glyceraldehyde-3-phosphate dehydrogenase, or GAPDH. In turn, the S. pneumoniae PspA on the bacteria surface binds to the GAPDH. PspA-GAPDH-mediated binding to lung cells increased S. pneumoniae localisation in the lower airway, and this was enhanced by pneumolysin exposure or co-infection with influenza A virus.

One of the fragments of protein responsible for the binding was introduced into the lungs of influenza-infected mice and reduced the disease severity of S. pneumoniae superinfection, presumably through binding competition.

“Our findings support the targeting of regions of PspA for therapeutic and vaccine development against influenza A/Streptococcus pneumoniae superinfections,” Dr Orihuela said. “Importantly, and despite more than 30 years since its discovery, PspA was not previously shown to function as an adhesin. Thus, our finding of PspA’s role in adherence substantially advances our knowledge on the interactions of S. pneumoniae with its host.”

Source: University of Alabama at Birmingham

Journal information: Sang-Sang Park et al, Streptococcus pneumoniae binds to host GAPDH on dying lung epithelial cells worsening secondary infection following influenza, Cell Reports (2021). DOI: 10.1016/j.celrep.2021.109267

Categories : Diseases, Syndromes and Conditions New Compounds and TreatmentsTags :

New Antimalarial Compound Traps Parasites in Cells

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Photo by Егор Камелев on Unsplash

To combat the growing resistance of malaria to current treatments, researchers at the Francis Crick Institute and the Latvian Institute of Organic Synthesis have designed a new antimalarial compound which interrupts the malaria parasite life cycle by trapping them in their host cells.

While drugs and mosquito control have reduced levels of malaria over recent decades, with malaria being effectively wiped out in North America by the 1950s, the parasite still kills over 400 000 people every year, 90% of whom live in sub-Saharan Africa. It has now developed resistance to many existing antimalarial drugs, meaning new treatments that work in different ways are urgently needed.

If we can effectively trap malaria in the cell by blocking the parasite’s exit route, we could stop the disease in its tracks and halt its devastating cycle of invading cells.
Mike Blackman

The researchers developed an array of compounds designed to prevent the parasites bursting out of blood cells, a vital replication step. One compound in particular was found to be very effective in human cell tests.

“Malaria parasites invade red blood cells where they replicate many times, before bursting out into the bloodstream to repeat the process. It’s this cycle and build-up of infected red blood cells which causes the symptoms and sometimes fatal effects of the disease,” says Mike Blackman, lead author and group leader of the Malaria Biochemistry Laboratory at the Crick.  

“If we can effectively trap malaria in the cell by blocking the parasite’s exit route, we could stop the disease in its tracks and halt its devastating cycle of invading cells.”

Blocking the parasite’s emergence

The compound works by blocking an enzyme called SUB1, needed for them to burst out of cells. Current antimalarials kill the parasite within the cell, so the researchers hope this alternative drug action will overcome the resistance the parasite has acquired.

The compound can penetrate both the cell wall and the compartment within where the parasites reside.

The researchers are further refining the compound making it smaller and more potent. Further tests are needed before it can be trialled in humans.

Study author Chrislaine Withers-Martinez and researcher in the Malaria Biochemistry Laboratory, said: “Many existing antimalarial drugs are plant derived and while they’re incredibly effective, we don’t know the precise mechanisms behind how they work. Our decades of research have helped us identify and understand pathways crucial to the malaria life cycle allowing us to rationally design new drug compounds based on the structure and mechanism of critical enzymes like SUB1.

“This approach, which has already been highly successful at finding new treatments for diseases including HIV and Hepatitis C, could be key to sustained and effective malaria control for many years to come.” 

Source: Francis Crick Institute

Categories : Diseases, Syndromes and ConditionsTags :

Night Shifts Increase Risk of Infection

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Shift working and irregular working hours can affect our health and disrupt immune response, especially in men, according to new research from the University of Waterloo.

These health-related issues occur because the body’s circadian rhythm can be disrupted by inconsistent changes in the sleep-wake schedule and feeding patterns often caused by shift work. To study this, researchers at Waterloo developed a mathematical model to investigate how a disruption in the circadian clock affects the immune system in fighting off illness.

“Because our immune system is affected by the circadian clock, our ability to mount an immune response changes during the day,” said Anita Layton, professor of Applied Mathematics, Computer Science, Pharmacy and Biology at Waterloo. “How likely are you to fight off an infection that occurs in the morning than midday? The answer depends on whether you are a man or a woman, and whether you are among [the] quarter of the modern-day labor force that has an irregular work schedule.”

The researchers created new computational models, separately for men and women, which simulate the interplay between the circadian clock and the immune system. The model is composed of the core clock genes, their related proteins, and the regulatory mechanism of pro- and anti-inflammatory mediators. By adjusting the clock, the models can simulate male and female shift-workers.

The researchers’ simulation results demonstrate that the immune response varies with the time of infection. The model simulation indicates that the time just before people go to sleep is the “worst” time to get an infection. At this point during the day, the human body is least prepared to produce the pro- and anti-inflammatory mediators needed during an infection. An individual’s sex also impacts the effect significantly.

“Shift work likely affects men and women differently,” said Stéphanie Abo, a PhD candidate in Waterloo’s Department of Applied Mathematics. “Compared to females, the immune system in males is more prone to overactivation, which can increase their chances of sepsis following an ill-timed infection.”

Source: Medical Xpress

More information: Stéphanie M. C. Abo et al. Modeling the circadian regulation of the immune system: Sexually dimorphic effects of shift work, PLOS Computational Biology (2021). DOI: 10.1371/journal.pcbi.1008514

Categories : Diseases, Syndromes and ConditionsTags :

Premature Death Risk Doubled for Patients With Superbug on Their Skin

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Adults middle-aged or older who carry methicillin-resistant Staphylococcus aureus (MRSA) ‘superbug’ on their skin are twice as likely to die within the next decade as people who do not, according to a study by the University of Florida (UF).

“Very few people who carry MRSA know they have it, yet we have found a distinct link between people with undetected MRSA and premature death,” said lead author Arch Mainous, PhD, a professor in the department of health services research, management and policy at UF.

The findings suggest that routine screening for undetected MRSA may be warranted in older people to prevent deaths from infection.

A third of Americans carry Staphylococcus aureus, or staph, on their skin or in nasal passages, and of these about 1% carry MRSA, the notorious antibiotic resistant staph strain.

MRSA carriers may not even be aware that they carry the bacteria unless they develop an infection or are tested for it. A quarter of people who carry MRSA without an active infection, known as colonised MRSA for at least a year, eventually develop a MRSA infection.

“MRSA can be part of normal body flora, but it can lead to infection when immune systems are compromised, especially in people who are hospitalized, have underlying disease, or after antibiotic use,” said Prof Mainous, also vice chair for research in the UF College of Medicine’s department of community health and family medicine.

According to a 2017 Centers for Disease Control and Prevention report, 119 000 Americans experienced a staph bloodstream infection and nearly 20 000 died. Hospitalised patients with colonised MRSA may be particularly vulnerable to  infection in hospital or after discharge. Among carriers, wounds, surgical incisions and use of medical devices, such as catheters, may also lead to MRSA infection.

In this study, researchers analysed data from the 2001-2004 National Health and Nutrition Examination Survey, a nationally representative study combining survey questions with laboratory testing, which includes nasal swabs for detecting MRSA.

Adjusting for risk factors including gender and ethnicity, the researchers linked data on participants ages 40-85 with data from the National Death Index to track deaths over an 11-year period.

The mortality rate among participants without MRSA was about 18% compared with 36% among those with colonised MRSA. There was no increased mortality risk for those with non-MRSA staph bacteria on their skin.

Although some states and hospital systems require MRSA testing for patients before hospital admission, policies for testing and treatment of colonised MRSA, which may include antibiotics use, vary widely betweens hospitals, Prof Mainous said.

“Without a uniform strategy, we are missing an opportunity to help prevent deaths caused by MRSA,” he said. “Maybe we should know who is carrying MRSA.”

Source: Medical-News.Net

Journal information: Mainous, A. G., et al. (2021) Methicillin-Resistant Staphylococcus Aureus Colonization and Mortality Risk Among Community Adults Aged 40-85. Journal of the American Board of Family Medicine.

Categories : Environmental EffectsTags :

Proximity to Deforested Areas Can Increase Outbreak Risk

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Aerial view of logging activities. Photo by Pok Rie from Pexels

A new study has found that human proximity to deforested areas poses an increased risk of the outbreak of zoonotic viruses.  

This adds to a growing body of evidence that human encroachment on the natural environment is resulting in zoonotic disease outbreaks.

Deforested areas and even monocultures such as commercial forests planted by humans are linked to the outbreak of diseases, the researchers found.

The researchers explained that a forest’s healthy diverse ecosystem with a range of species, blocks and filters viruses. However, in the case of monocultures where single species of plants are cultivated, like a palm oil plantation, specialist species die off and are replaced by generalists such as rats which then spread pathogens on to humans.

“I was surprised by how clear the pattern was,” said one of the study authors, Serge Morand, of the French National Centre for Scientific Research. “We must give more consideration to the role of the forest in human health, animal health and environmental health. The message from this study is ‘don’t forget the forest’.”

Using a number of databases from sources such as the World Health Organization, the researchers analysed the relationship between changes in forest cover, plantations, population and disease around the globe.
Over 1990 to 2016, the study period covered 3884 outbreaks of 116 zoonotic diseases that crossed over into humans and 1996 outbreaks of 69 vector-borne infectious diseases, largely carried by mosquitoes, ticks or flies.

“Everyone in the field of planetary health is worried about what is happening to biodiversity, climate and public health in Brazil,” Morand emphasised. “The stress there is growing. The Amazon is near a tipping point due to climate change, which is not good at all for the world ecosystem. If we reach the tipping point, the outcomes will be very bad in terms of drought, fires and for sure in terms of disease.”

The rainforests of the Congo basin and south-east Asia, and monoculture afforestation projects around the world were also cause for concern. “Our results clearly suggest that it is not only forest clearance that is responsible for outbreaks of infectious diseases, but also reforestation or afforestation, particularly in countries outside the tropical zone,” the paper noted.

Morand’s next study involves examining forest cover with satellite imagery and exploring links with that to disease.

Source: The Guardian

Categories : Diseases, Syndromes and ConditionsTags :

Key Cellular Defence Functions Found for Heparanase

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A recent study has shown that there is a poorly understood protein, heparanase (HPSE), that is in fact a key regulator of cellular innate defence systems. High levels of HPSE are linked to cancer metastasis. 

Cellular innate defence systems are an array of built-in mechanisms that are common to species throughout evolution. These can be spurred into action by the presence of pathogens or environmental toxins and dysfunctional cells that may build up over time in the body. A clearer understanding of the interplay between these different processes has the potential to open up a whole new range of multi-target drugs to treat a wide range of conditions and diseases.

Researchers from the University of Illinois Chicago (UIC) used a systems approach to track changes in important components in cells and mice that have been genetically engineered to lack HPSE.

In this collaborative multidisciplinary study, Agelidis and coauthors for the first time demonstrated that HPSE is a mediator for antiviral immunity, proliferative signals and cell death.

“HPSE has been long known to drive late-stage inflammatory diseases yet it was once thought that this was primarily due to enzymatic activity of the protein breaking down heparan sulfate, a sugar molecule present in chains on the surface of virtually all cells,” Agelidis said.

While their study largely focussed on mechanisms of pathogenesis of herpes simplex virus (HSV-1), these findings hold a range of implications for treating diseases that involve the dysregulation of HPSE, including cancer, atherosclerosis and autoimmune disorders.

Source: Medical Xpress

Journal information: Alex Agelidis et al, Disruption of innate defense responses by endoglycosidase HPSE promotes cell survival, JCI Insight (2021). DOI: 10.1172/jci.insight.144255

Categories : Diseases, Syndromes and Conditions Medical Research & TechnologyTags :

Researchers Study Enzyme Processes for New Drugs

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Traditional discovery has produced drugs that effectively target proteins directly involved with disease, but options are starting to run out and researchers are looking to more complex and obscure interactions for drug targets.

So far, drug discovery has used the ‘small molecule’ approach, where a specific protein is targetted in a cancer cell to shut it down and bring down the cancer cell as a whole. Up until this point, traditional drugs have only been able to target proteins that are involved in the disease that also have activities that are amenable to the small molecule approach, leaving a vast number of proteins unaddressed. Many of these other proteins may be involved in disease processes behind the scenes.

“It’s starting to get to the point where we’ve kind of taken traditional drug discovery as far as we can, and we really need something new,” explained University of Nevada, Las Vegas biochemist Gary Kleiger.

“Cancer cells are clever,” Kleiger said. “They can evolve very, very quickly. So, a drug might be working at first—targeting an enzyme and telling that enzyme, ‘stop doing your activity,’ which can stop the cancer cells from growing. Those cancer cells appear to lie dormant, but all the while there are still little things that happen that eventually enable those cancer cells to bypass that drug.” Therefore, in order to stay ahead of cancer’s capacity to evolve drug resistance, it is necessary to target many additional disease-causing proteins, and thus, limiting the landscape of druggable proteins is a serious disadvantage.

The new approach by investigated by Kleiger and collaborators uses a family of human enzymes called ubiquitin ligases found in human cells. Of about 20 000 known proteins in the human body, some 5-10% are enzymes.

Kleiger’s team uses cutting edge cryo electron microscopes that can image the ubiquitin ligases when they’re at work. To test their hypotheses, Kleiger and collaborators measure the activity of ‘mutated’ enzymes that should now be defective in their activities.

Kleiger compared the process to how a 50 000 year old society might view a bicycle. They could identify its purpose and general properties, but could test the importance of a certain gear; if it was bent, the bicycle would no longer function. “We can do that at the molecular level with the enzymes,” he said.

Source: Medical Xpress

Journal information: Daniel Horn-Ghetko et al, Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly, Nature (2021). DOI: 10.1038/s41586-021-03197-9