A new study published in Nature [1] draws the most detailed picture yet of SARS-CoV-2 infection in the lung, revealing mechanisms that result in lethal COVID-19, and may explain long-term complications and show how COVID-19 differs from other infectious diseases.

Led by researchers at Columbia University Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center, the study found that in patients who died of the infection, COVID-19 unleashed a detrimental trifecta of runaway inflammation, direct destruction and impaired regeneration of lung cells involved in gas exchange, and accelerated lung scarring.

Though the study looked at lungs from patients who had died of the disease, it provides solid leads as to why survivors of severe COVID may experience long-term respiratory complications due to lung scarring.

“It’s a devastating disease, but the picture we’re getting of the COVID-19 lung is the first step towards identifying potential targets and therapies that disrupt some of the disease’s vicious circuits. In particular, targeting cells responsible for pulmonary fibrosis early on could possibly prevent or ameliorate long-term complications in survivors of severe COVID-19,” says Benjamin Izar, MD, PhD, assistant professor of medicine, who led a group of more than 40 investigators to complete in several months a series of analyses that usually takes years.

This study and a companion paper [2] led by researchers at Harvard/MIT, to which the Columbia investigators also contributed, were published in the journal Nature on April 29.

Study creates atlas of cells in COVID lung

The new study is unique from other investigations in that it directly examines lung tissue (rather than sputum or bronchial washes) using single-cell molecular profiling that can identify each cell in a tissue sample and record each cell’s activity, resulting in an atlas of cells in COVID lung.

“A normal lung will have many of the same cells we find in COVID, but in different proportions and different activation states,” Izar says. “In order to understand how COVID-19 is different compared to both control lungs and other forms of infectious pneumonias, we needed to look at thousands of cells, one by one.”

Izar’s team examined the lungs of 19 individuals who died of COVID-19 and underwent rapid autopsy (within hours of death) – during which lung and other tissues were collected and immediately frozen – and the lungs of non-COVID-19 patients. In collaboration with investigators at Cornell University, the researchers also compared their findings to lungs of patients with other respiratory illnesses.

Drugs targeting IL-1ß may reduce inflammation

Compared to normal lungs, lungs from the COVID patients were filled with immune cells called macrophages, the study found.

Typically during an infection, these cells chew up pathogens but also regulate the intensity of inflammation, which also helps in the fight.

 

 

“In COVID-19, we see expansion and uncontrolled activation of macrophages, including alveolar macrophages and monocyte-derived macrophages,” Izar says. “They are completely out of balance and allow inflammation to ramp up unchecked. This results in a vicious cycle where more immune cells come in causing even more inflammation, which ultimately damages the lung tissue.”
One inflammatory cytokine in particular, IL-1ß, is produced at a high rate by these macrophages.
“Unlike other cytokines such as IL-6, which appears to be universally prevalent in various pneumonias, IL-1ß production in macrophages is more pronounced in COVID-19 compared to other viral or bacterial lung infections,” Izar says. “That’s important because drugs exist that tamp down the effects of IL-1ß.”
Some of these drugs are already being tested in clinical trials of COVID patients.

Severe COVID also prevents lung repair

In a typical infection, a virus damages lung cells, the immune system clears the pathogen and the debris, and the lung regenerates.

But in COVID, the new study found that not only does SARS-CoV-2 virus destroy alveolar epithelial cells important for gas exchange, the ensuing inflammation also impairs the ability of the remaining cells to regenerate the damaged lung.

Though the lung still contains cells that can do the repairs, inflammation permanently traps these cells in an intermediate cell state and leaves them unable to complete the last steps of differentiation needed for replacement of mature lung epithelium.

“Among others, IL-1ß appears to be a culprit in inducing and maintaining this intermediate cell state,” says Izar, “thereby linking inflammation and impaired lung regeneration in COVID-19. This suggests that in addition to reducing inflammation, targeting IL-1ß may help take the brakes off cells required for lung repair.”

Preventing accelerated fibrosis

The researchers also found a large number of specific fibroblast cells, called pathological fibroblasts, that create rapid scarring in COVID-19 lungs. When the fibroblast cells fill the lung with scar tissue, a process called fibrosis, the lung has less space for cells involved in gas exchange and is permanently damaged.

Given the importance of pathological fibroblasts in the disease, Izar’s team closely analysed the cells to uncover potential drug targets. An algorithm called VIPER, developed previously by Andrea Califano, Dr, chair of systems biology at Columbia University Vagelos College of Physicians and Surgeons, identified several molecules in the cells that play an important role and could be targeted by existing drugs.

“This analysis predicted that inhibition of STAT signalling could alleviate some of the deleterious effects caused by pathological fibroblasts,” Izar says.

“Our hope is that by sharing this analysis and massive data resource, other researchers and drug companies can begin to test and expand on these ideas and find treatments to not only treat critically ill patients, but also reduce complications in people who survive severe COVID-19.”

References

[1] A molecular single-cell lung atlas of lethal COVID-19. Nature (2021).
https://doi.org/10.1038/s41586-021-03569-1

[2] COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature (2021).
https://doi.org/10.1038/s41586-021-03570-8

Researchers from the Department of Experimental Psychology at the University of Oxford have developed a new mental health treatment programme to provide frontline healthcare workers with one-to-one support, including fast-track access to post-traumatic stress disorder (PTSD) or depression treatment. This evidence-based programme, called SHAPE Recovery < www.shaperecovery.com >, builds on an outreach programme shown to reduce rates of PTSD and depression.
SHAPE Recovery is working with 3,300 frontline healthcare workers across England and has now been invited to work with 8,000 London Ambulance employees and staff from associated partner organisations.
Around the world, frontline healthcare workers, such as intensive care doctors, nurses, support staff and paramedics, are risking their lives daily to stem the tide of the COVID-19 pandemic. They are at an increased risk of developing mental health problems, such as PTSD as well as depression, sleep problems and anxiety. Although many hospitals offer well-being initiatives, there is little evidence to support their effectiveness and they require staff to come forward for help.
Associate Professor Jennifer Wild, Programme Lead, said: “SHAPE is based on 15 years of research to examine what predicts PTSD and depression in frontline workers. We used the findings from these studies to create a highly effective support programme to prevent the development of PTSD and depression. SHAPE is the outcome of this work. It is evidence-based, affordable, and with ongoing evaluation could, if needed, be incorporated within NHS services within 12 to 24 months. The aim is to support staff to stay well, to recover if unwell, and to continue to be able to work, providing much-valued patient care.”
Zidan Mozumder, a paramedic who has benefitted from the progamme, commented: “Work-related stress has been at an all-time high for my peers due to the current COVID-19 pandemic. Fortunately, though, my weekly calls with my well-being coach have mitigated that stress significantly. For this I am eternally grateful. I feel very lucky to have had all of this support.”
SHAPE is unique because it moves the burden of outreach for help from frontline staff to well-being coaches. This means staff don’t have to come forward for help. Instead, they can access one-to-one confidential help, independent from their employers, on their phones. In addition, SHAPE facilitates fast access to gold-standard treatment for PTSD and depression should it be indicated.
Data collected from the programme will help Oxford researchers determine:

• the effectiveness of this evidence-based, well-being support compared with no support for reducing symptoms of PTSD, depression, anxiety and sleep problems of frontline staff
• whether early intervention for staff who continue to work during the pandemic leads to their recovery from mental ill health
• potential cost savings of the programme to the NHS and society

In one of the most ambitious collaborative initiatives ever undertaken by the pharmaceutical industry, more than 20 leading biopharmaceutical companies in early July announced the launch of the AMR Action Fund, a ground-breaking partnership that aims to bring two to four new antibiotics to patients by 2030. These new treatments are urgently needed to address the rapid rise of antibiotic-resistant infections – or antimicrobial resistance (AMR).
The companies have raised so far nearly US$1 billion to support clinical research of innovative new antibiotics that address the most resistant bacteria and life-threatening infections. Through the AMR Action Fund, pharmaceutical companies will join forces with philanthropies, development banks, and multilateral organizations to strengthen and accelerate antibiotic development. The Fund will focus on urgent public health needs. It will provide much needed financial resources, as well as important technical support to help biotech companies bring novel antibiotics to patients.
The AMR Action Fund, an initiative of the international body representing the R&D pharmaceutical industry (International Federation of Pharmaceutical Manufacturers & Associations, IFPMA), was announced at simultaneous virtual launch events in Berlin, Germany, and Washington, D.C., USA, on 9 July, with a third event in Tokyo, Japan on July 10.
AMR is a looming global crisis that has the potential to dwarf COVID-19 in terms of deaths and economic costs.
Commenting on the Fund, Dr Tedros Adhanom Ghebreyesus, Director General World Health Organization, said: “AMR is a slow tsunami that threatens to undo a century of medical progress. I very much welcome this new engagement of the private sector in the development of urgently-needed antibacterial treatments. WHO looks forward to working with the AMR Action Fund to accelerate research to address this public health crisis.”
New antibiotics
The world urgently needs new antibiotics, but there are few in the pipeline because of a paradox: despite the huge societal costs of AMR, there is currently no viable market for new antibiotics. New antibiotics are used sparingly to preserve effectiveness, so in recent years, a number of antibiotic-focused biotechs have declared bankruptcy or exited this space due to the lack of commercial sustainability, resulting in the loss of valuable expertise and resources. The consequence is a huge public health need for new antibiotics, but a lack of funding available for antibiotic R&D, particularly the later stages of clinical research. This creates a “valley of death” between discovery and patient access.
“With the AMR Action Fund, the pharmaceutical industry is investing nearly US$1 billion to sustain an antibiotic pipeline that is on the verge of collapse, a potentially devastating situation that could affect millions of people around the world,” said David Ricks, Chairman and CEO of Eli Lilly and Company and President of IFPMA. “The AMR Action Fund will support innovative antibiotic candidates through the most challenging later stages of drug development, ultimately providing governments time to make the necessary policy reforms to enable a sustainable antibiotic pipeline.”
With this investment, the AMR Action Fund will be the largest collective venture ever created to address AMR. The AMR Action Fund will:

• Invest in smaller biotech companies focused on developing innovative antibacterial treatments that address the highest priority public health needs, make a significant difference in clinical practice, and save lives.
• Provide technical support to portfolio companies, giving them access to the deep expertise and resources of large biopharmaceutical companies, to strengthen antibiotic development, and support access and appropriate use of antibiotics.
• Bring together a broad alliance of industry and non-industry stakeholders, including philanthropies, development banks, and multilateral organizations, and help encourage governments to create market conditions that enable sustainable investment in the antibiotic pipeline.

The Fund is expected to be operational during the fourth quarter of 2020.
For more details on the AMR Action fund, visit www.AMRactionfund.com