Klebsiella pneumoniae causes many respiratory, intestinal and urinary tract infections. Due to its resistance to most common antibiotics and its high virulence, some of its strains can be fatal for 40% to 50% of infected people. There is an urgent need to develop new therapeutic molecules to counter it. “Since the 1930s, medicine has relied on antibiotics to get rid of pathogenic bacteria,” explains Pierre Cosson, professor in the Department of Cell Physiology and Metabolism at the UNIGE Faculty of Medicine, who led this research. “But other approaches are possible, among which trying to weaken the bacteria’s defence system so that they can no longer escape the immune system. This avenue seems all the more promising as the virulence of Klebsiella pneumoniae stems largely from its ability to evade attacks from immune cells.”

An amoeba as a model

To determine whether or not the bacteria were weakened, the UNIGE scientists used an experimental model with surprising characteristics: the amoeba Dictyostelium. This single-cell organism feeds on bacteria by capturing and ingesting them, using the same mechanisms that immune cells use to kill pathogens. “We genetically modified this amoeba so that it could tell us whether the bacteria it encountered were virulent or not. This very simple system then enabled us to test thousands of molecules and identify those that reduced bacterial virulence,” explains Pierre Cosson.

Weakening the bacteria without killing them

Developing a drug is a long and expensive process, with no guarantee of results. The UNIGE scientists therefore opted for a quicker and safer strategy: reviewing existing drugs to identify possible new therapeutic indications. The research team evaluated the effect on Klebsiella pneumoniae of hundreds of drugs already on the market, with a wide range of therapeutic indications. A drug developed to combat herpes, edoxudine, proved particularly promising.

“By altering the surface layer that protects the bacteria from their external environment, this pharmacological product makes it vulnerable. Unlike an antibiotic, edoxudine does not kill the bacteria, which limits the risk of developing resistance, a major advantage of such an anti-virulence strategy,” says the researcher.

Although the effectiveness of such a treatment in human beings has yet to be confirmed, the results of this study are encouraging: edoxudine acts even on the most virulent strains of Klebsiella pneumoniae, and at lower concentrations than those prescribed to treat herpes. “Sufficiently weakening the bacteria without killing them is a subtle strategy, but one that could prove to be a winner in the short and long terms,” concludes Pierre Cosson.

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First developed by the World Health Organisation, Psychological First Aid (PFA) is the globally recommended training for people, such as healthcare workers, who support others during emergencies.

It offers guidance on delivering psychosocial care in the immediate aftermath of an emergency event.

Although PFA training was originally created for people to support others, scientists from Northumbria University and the University of Highlands and Islands (UHI) have now also identified it as a suitable way of helping care workers look after their own mental health and wellbeing.

As part of the national response to the COVID-19 pandemic, in June 2020 the UK government introduced free to access online PFA training in an effort to support frontline staff, such the 1.8 million people working in care homes across the country.

Evaluating the effectiveness of this initiative, academics at Northumbria and UHI investigated the uptake of PFA training among healthcare workers in UK care homes and assessed its effects on their wellbeing.

Funded by the Royal College of Nursing Foundation, the study was the first of its kind and makes recommendations regarding further implementation of Psychological First Aid.

The researchers found that while the uptake of PFA training was low among healthcare workers — less than 10% of study participants had done the training — those who had undertaken PFA coped better.

The results suggest that PFA training helped in overcoming stress and coping via self-growth and improving relationships with others, but there was a concern around accessibility, which academics say could possibly explain the low uptake of training.

Some research participants described that it helped them cope better when thinking of giving up their job and promoted resilience, with one person commenting: “(PFA) has helped me cope better, it was a position I was thinking of giving up at one time and now I have the strength to carry on.”

Others described how it helped support them in their experiences of bereavement to overcome the trauma of the pandemic: “I found it (PFA) useful as it helped me cope with bereavement as well as the experience of seeing relatives affected by COVID-19.” Another participant went as far as to say that PFA training “should be made compulsory for all staff especially in nursing and care homes during the pandemic or not.”

Dr Mariyana Schoultz, the project lead and Associate Professor in Mental Health in Northumbria’s Department of Nursing, Midwifery and Health, said: “Findings suggest that PFA training has the potential to: strengthen resilience for staff in health and social care; promote anti-stigma messages and normalise help seeking behaviour; PFA holds the potential to minimise the risk of developing more serious psychological problems such as Post-Traumatic Stress Disorder (PTSD). But we need more research in this area.

“We therefore recommend that consideration be given to funding an integrated programme of research and development to further develop, implement, and evaluate a co-produced iteration of PFA for use in the UK care home sector and beyond.”

Deepa Korea, Director of the RCN Foundation, said “Staff working in social care during the pandemic faced significant pressures which inevitably had an impact on their own mental health and emotional wellbeing. That’s why I am delighted that the RCN Foundation was able to commission this important study which adds to the body of evidence about the practical ways in which we can support health and social care staff.”

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Materials provided by Northumbria University. Note: Content may be edited for style and length.

The findings, published in the November 3, 2022 issue of PLOS Biology, also report that the antiviral drug sofosbuvir, already an approved treatment for hepatitis C, effectively inhibited SARS-CoV-2 replication and reversed neuronal alterations in infected brain organoids.

“Vaccines and emerging treatments have reduced the health consequences of COVID-19 in most patients,” said senior study author Alysson R. Muotri, PhD, professor in departments of Pediatrics and Cellular and Molecular at UC San Diego School of Medicine. “But the phenomenon of Long COVID, characterized by persisting symptoms that include neurological impairment, remains poorly understood and without any specific remedy.

“This work helps explain some of the neurological symptoms of COVID-19 and, more importantly, it suggests that an FDA-approved antiviral drug might be repurposed to restore infected brain cells to health and address long-term neurological outcomes of COVID-19.”

Though primarily considered to be a respiratory disease, COVID-19 can cause temporary or long-lasting neurological symptoms in some patients, ranging from loss of taste and smell, impaired concentration (brain fog), and psychological effects such as depression to stroke, epilepsy, and encephalopathy (a change in brain function or structure).

With evidence accumulating that the SARS-CoV-2 virus can infect and alter brain cells (including in developing fetuses), the research team focused on using organoids — self-organizing, three-dimensional tissues derived from cultured stem cells that can mimic some organ functions.

Researchers exposed the brain organoids to SARS-CoV-2, observed viral infection and replication and noted that the virus rapidly decreased the number of excitatory synapses in neurons within seven days post-infection. Excitatory synapses increase the firing action potential of a neuron, while their counterparts, called inhibitory synapses, decrease that potential.

However, when infected organoids were treated with sofosbuvir, viral replication was inhibited, and observed neurological impairments rescued or restored. The findings echo earlier computational models that suggested sofosbuvir could be a treatment and previous research by Muotri and colleagues that found sofosbuvir effectively protected and rescued neural cells infected by the Zika virus.

“The bottom line is that sofosbuvir appears to have the potential to arrest or prevent the development of neurological symptoms in COVID-19 patients,” Muotri said. “And because it has been shown to present no safety concerns in pregnant women, it might also be an option for preventing SARS-CoV-2 transmission to their unborn children.

“Further studies and clinical trials are needed, of course, but these findings offer a path forward for treating a condition (Long COVID) that has so far stymied remedy for millions of people wordwide.”

Co-authors include: Pinar Mesci, Janaina S. de Souza, Angela Macia, Aurian Saleh, Cedric Snethlage, Jason W. Adams, Angels Almenar-Queralt, Ryan A. Szeto, Gabriela Goldberg and Patrick T. Bruck, all at UC San Diego and Rady Children’s Hospital-San Diego; Laura Martin-Sancho, Yuan Pu and Sumit K. Chandra, Sanford Burnham Prebys Medical Discovery Institute; Simoni H. Avansini and Fabio Papes, UC San Diego and University of Campinas, Brazil; and Roberto H. Herai, Pontificia Universidade Catolica do Parana, Brazil and Lico Kaesemodel Institute, Brazil.