Day: July 11, 2022

Categories : HIVTags :

Innate Immune System Detects HIV-1 with a Two-step Strategy

On By ModernMedia
HIV invading a human cell
HIV invading a human cell: Credit NIH

Scientists have now uncovered how the innate immune system detects even very small amounts of HIV-1. The findings, published in Molecular Cell, reveal a two-step molecular strategy that jolts the innate immune response into action when exposed to HIV-1. This has important implications for developing new HIV treatments and vaccines, as well as helping understand the innate immune response in other contexts such as Alzheimer’s.

“This research delineates how the immune system can recognise a very cryptic virus, and then activate the downstream cascade that leads to immunological activation,” says Sumit Chanda, PhD, professor in the Department of Immunology and Microbiology. “From a therapeutic potential perspective, these findings open up new avenues for vaccines and adjuvants that mimic the immune response and offer additional solutions for preventing HIV infection.”

The innate immune system is activated before the adaptive immune system, which is the body’s secondary line of defense that involves more specialised functions, such as generating antibodies. One of the innate immune system’s primary responsibilities is recognizing between “self” (our own proteins and genetic material) and foreign elements (such as viruses or other pathogens). Cyclic GMP-AMP synthase (cGAS) is a key signaling protein in the innate immune system that senses DNA floating in a cell. If cGAS does detect a foreign presence, it activates a molecular pathway to fight off the invader.

However, because HIV-1 is an RNA virus, it produces very little DNA – so little, in fact, that scientists have not understood how cGAS and the innate immune system are able to detect it and distinguish it from our own DNA.

Scripps Research scientists discovered that the innate immune system requires a two-step security check for it to activate against HIV-1. The first step involves a protein called polyglutamine binding protein 1 (PQBP1), which recognises the HIV-1 outer shell as soon as it enters the cell and before it can replicate. PQBP1 then coats and decorates the virus, acting as an alert signal to summon cGAS. Once the viral shell begins to disassemble, cGAS activates additional immune-related pathways against the virus.

The researchers were initially surprised to find that two steps are required for innate immune activation against HIV-1, as most other DNA-encoding viruses only activate cGAS in one step. This is a similar concept to technologies that use two-factor authentication, such as requiring users to enter a password and then respond to a confirmation email.

This two-part mechanism also opens the door to vaccination approaches that can exploit the immune cascade that is initiated before the virus can start to replicate in the host cell, after PQBP1 has decorated the molecule.

“While the adaptive immune system has been a main focus for HIV research and vaccine development, our discoveries clearly show the critical role the innate immune response plays in detecting the virus,” said Sunnie Yoh, PhD, first author of the study and senior staff scientist in Chanda’s lab. “In modulating the narrow window in this two-step process – after PQBP1 has decorated the viral capsid, and before the virus is able to insert itself into the host genome and replicate – there is the potential to develop novel adjuvanted vaccine strategies against HIV-1.”

By shedding light on the workings of the innate immune system, these findings also illuminate how our bodies respond to other autoimmune or neurodegenerative inflammatory diseases. For example, PQBP1 has been shown to interact with tau – the protein that becomes dysregulated in Alzheimer’s disease – and activate the same inflammatory cGAS pathway. The researchers will continue to investigate how the innate immune system is involved in disease onset and progression, as well as how it distinguishes between self and foreign cells.

Source: Scripps Research Institute

Categories : Diet and Nutrition Neurodegenerative DiseasesTags :

Long-term High-fat Diets Shown to Worsen Cognitive Abilities

On By ModernMedia
Plaques and neurons. Source: NIAH

A study published in Metabolic Brain Disease has established a clear link between mice being fed a high-fat diet for 30 weeks, resulting in diabetes, and a subsequent worsening of their cognitive abilities. This included developing anxiety, depression and worsening Alzheimer’s disease.

Mice with impaired cognitive function were also more likely to gain excessive weight due to poor metabolism caused by brain changes.

Neuroscientist and biochemist Associate Professor Larisa Bobrovskaya, who co-led the study said that the research adds to the growing body of evidence linking chronic obesity and diabetes with Alzheimer’s disease.

“Obesity and diabetes impair the central nervous system, exacerbating psychiatric disorders and cognitive decline. We demonstrated this in our study with mice,” said Associate Prof Bobrovskaya.

In the study, mice were randomised to a standard diet or a high-fat diet for 30 weeks, starting at eight weeks of age. Food intake, body weight and glucose levels were monitored at different intervals, along with glucose and insulin tolerance tests and cognitive dysfunction.

The mice on the high-fat diet gained significant weight, developed insulin resistance and started behaving abnormally compared to those fed a standard diet.

Genetically modified Alzheimer’s disease mice showed a significant deterioration of cognition and pathological changes in the brain while fed the high fat diet.

“Obese individuals have about a 55 per cent increased risk of developing depression, and diabetes will double that risk,” Assoc Prof Bobrovskaya said.

“Our findings underline the importance of addressing the global obesity epidemic. A combination of obesity, age and diabetes is very likely to lead to a decline in cognitive abilities, Alzheimer’s disease and other mental health disorders.”

Source: University of South Australia

Categories : COVID Obstetrics & GynaecologyTags :

Nitrous Oxide Safe and Effective Therapy for Severe COVID in Pregnancy

On By ModernMedia
Pregnant with ultrasound image
Source: Pixabay

High dose inhaled nitric oxide gas (iNO) is a safe and effective respiratory therapy for pregnant women hospitalised with severe COVID pneumonia, resulting in faster weaning from oxygen and shorter hospital stay, according to a study published in Obstetrics & Gynecology. Massachusetts General Hospital (MGH) researchers reported that the addition of twice-daily nitric oxide to standard of care oxygen therapy decreased the respiratory rate of pregnant women with low oxygenation levels of the blood without causing any side effects.

“To date, very few respiratory treatments to complement supplemental oxygenation in COVID pregnant patients have been tested,” explained the study’s senior author, Lorenzo Berra, MD. “Investigators from all four medical centers that participated in our study agreed that administration of high dose nitric oxide through a snug-fitting mask has enormous potential as a new therapeutic strategy for pregnant patients with COVID.”

Pneumonia triggered by COVID is particularly threatening to pregnant women since it may quickly progress to hypoxaemia, requiring hospitalisation and cardiopulmonary support. “Compared to non-pregnant female patients with COVID, pregnant women are three times more likely to need intensive care unit admission, mechanical ventilation, or advanced life support, and four times more likely to die,” noted lead author Carlo Valsecchi, MD. “They also face a greater risk of obstetric complications such as preeclampsia, preterm delivery, and stillbirth.”

Nitric oxide is a therapeutic gas that was initially approved by the U.S. Food and Drug Administration in 1999 for inhalation treatment of intubated and mechanically ventilated newborns with hypoxic respiratory failure. With MGH driving many early studies, iNO in high concentrations was also shown to be effective as an antimicrobial in reducing viral replication of SARS-CoV-1 and, more recently, SARS CoV-2. During the first wave of COVID, MGH treated six non-intubated pregnant patients with iNO at high doses of up to 200 parts per million (ppm). Favourable outcomes with iNO led MGH clinicians to offer this treatment to other pregnant patients, and motivated the present study.

Researchers and clinicians from multiple departments in four hospitals – including critical care medicine, respiratory care, and maternal foetal medicine – studied 71 pregnant patients with severe COVID pneumonia admitted to these hospitals, 20 of whom received iNO200 twice daily. The study found that iNO therapy at this dosage, when compared to standard of care alone, resulted in reductions in the need for supplemental oxygen and in hospital and ICU lengths of stay. No adverse events related to the intervention were reported in either mothers or their babies.

“Being able to wean patients from respiratory support quicker could have other profound implications, including reducing stress on women and their families, lowering the risk of hospital-acquired infections, and relieving the burden on the health care system,” noted Dr Berra. “Above all, our study supports the safety of high dose nitric oxide in the pregnant population, and we hope more physicians will consider incorporating it into carefully monitored treatment regimens.”

Source: Massachusetts General Hospital

Categories : COVID Healthcare Politics and RegulationsTags :

Employees’ Rights: What Does The Law Say about COVID Vaccination?

On By ModernMedia
Photo by Gustavo Fring on Pexels

In the past year, the Commission for Conciliation, Mediation and Arbitration (CCMA) has delivered several arbitration awards which have upheld the dismissals of employees who refused to get vaccinated against COVID.

But a recent award has created some confusion about whether this is still allowed and under what circumstances.

On 22 June, CCMA Commissioner Richard Byrne found that it was unfair and unconstitutional for Baroque Medical, which supplies and sells medical equipment, to retrench Kgomotso Tshatshu for refusing to get a Covid vaccination. The company was ordered to pay her 12 months’ salary as compensation (the maximum allowed).

But this contradicts an earlier CCMA award by Commissioner Piet van Staden, delivered in May, who found that Baroque Medical was within its rights to retrench another employee, Cecilia Bessick, who had also refused to get a COVID vaccine.

These conflicting decisions may be understandable, because CCMA arbitration awards do not create binding legal precedent in the same way as court judgments. The most recent CCMA ruling therefore does not set a binding legal precedent that employees cannot be dismissed for refusing to get a COVID vaccine.

The Labour Court has also not yet delivered any binding judgment about whether an employer can fairly dismiss an employee who refuses to get a Covid vaccination. Until this occurs, it is likely the CCMA will continue to give conflicting decisions about whether employers can fairly dismiss employees who refuse to get a vaccine.

Below, we explain what the law currently says about whether an employee can be dismissed for refusing to get a COVID vaccine and under what circumstances.

Labour Relations Act

The Labour Relations Act (LRA) says that an employee can only be dismissed for these reasons: when they are guilty of misconduct; suffer from an incapacity, such as ill health or injury, which prevents them from performing their duties; have to be retrenched because of the economic, structural, technological or similar needs of their employer.

The LRA also requires an employer to follow a fair procedure before dismissing an employee. Usually, this would involve explaining to an employee why they could be dismissed if they refuse to get a Covid vaccine and give the employee an opportunity to explain why they should not be dismissed.

The LRA, however, does not explain whether an employee who refuses to get vaccinated can be dismissed for misconduct or incapacity. The LRA also does not explain whether an employee who refuses to get a Covid vaccine can be retrenched.

Occupational Health and Safety Act

But the Occupational Health and Safety Act does require employers to take all reasonable steps to provide their employees with a safe and healthy working environment. The act also requires employers to take reasonable steps to ensure other people who may be affected by their business activities (such as customers or suppliers) are not exposed to a hazard to their health or safety – such as Covid.

During March, the Minister of Labour issued a Code of Good Practice which explains the steps that an employer should take to manage Covid in their workplace and to comply with their legal duties to provide a safe and healthy working environment.

This code was enacted after a previous directive on managing Covid in the workplace was repealed after the State of Disaster came to an end.

Code of Good Practice

According to the new Code of Good Practice, every employer with at least 20 employees must conduct a “risk assessment” and must develop a COVID plan with the measures it will implement regarding vaccination of employees and when they should be fully vaccinated. When developing the plan, the employer must consult with any representative trade union in its workplace or an employee representative.

The risk assessment and plan, among other things, should identify employees who must be vaccinated and must notify them of their duty to get a vaccination.

The code also states employers can require employees to disclose their vaccination status and to produce a vaccine certificate in order to give effect to the code.

The code further states that employees can lawfully refuse work when there exists a serious risk that they may imminently be exposed to COVID in the workplace. Should this occur, the employer cannot take any action against that employee for refusing to work, such as later dismissing or suspending them from work.

There may be situations where a refusal by employees to work because other employees refuse to get vaccinated, could justify the dismissal of the employees who refuse to get a COVID vaccine. This is because the refusal of many employees to work could affect the ability of a company or business to operate. This could potentially justify retrenchment of employees who refuse to get a COVID vaccine.

However, should an employee refuse to get vaccinated, the code also says that the employer should take steps to reasonably accommodate them in a position that does not require them to be vaccinated. Should an employee produce a valid medical certificate, which provides legitimate reasons why they cannot be vaccinated, the employer can send that employee to another doctor at their own expense.

The code does recognise that it would be unfair to dismiss employees who cannot be vaccinated on valid medical grounds. But, the duty to accommodate employees who refuse to get vaccinated on other grounds would depend on whether an employer has another position available which does not require that employee to be vaccinated. Should the employer not have an alternative position which does not require the employee to be vaccinated, this could be a fair reason to dismiss them.

It is important to note that the code does state that it reflects the policy position of the Department of Labour and that it should be applied until any of its provisions are reversed by a court judgment. Until the Labour Court delivers a binding judgment on when employees can be dismissed for refusing to get a COVID vaccination, it would seem it would be best to follow the provisions of the code.

By Geoffrey Allsop

Republished from GroundUp under a Creative Commons Attribution-NoDerivatives 4.0 International License.

Source: GroundUp