Why is SARS-CoV-2 deadly and different?

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A new study is drawing 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, Ph.D., 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 led by researchers at Harvard/MIT, to which the Columbia investigators also contributed, were published 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-1beta 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-1beta, 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-1beta 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-1beta.”

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-1b 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-1beta 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 analyzed 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 signaling 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.”

Team Effort by Several Columbia Labs

“Pulling this study together in such a short period of time was only possible with the help of several teams of researchers at Columbia,” Izar says.

Critically, in the first few months of the pandemic, Columbia’s Department of Pathology & Cell Biology decided to flash-freeze many tissues from deceased COVID patients to preserve the cells’ molecular state. Hanina Hibshoosh, MD, director of the department’s tissue bank, initiated the collaboration with Izar’s lab, which has expertise in conducting single-cell analyses with frozen tissue. Pathologist Anjali Saqi, MD, professor of pathology & cell biology, was also instrumental in procuring and evaluating the samples.

Jianwen Que, MD, Ph.D., professor of medicine, and his laboratory provided expertise in identifying and characterizing cells in the lung and their regenerative potential. Fibrosis expert Robert Schwabe, MD, associate professor of medicine, was essential in dissecting mechanisms by which COVID-19 propelled lung scarring.

“We are incredibly grateful to all the labs contributing to this effort and very fortunate to be at Columbia with all the necessary expertise at hand in one collaborative environment.”


One of the most serious complications in patients infected with COVID-19 is cardiopulmonary failure termed acute respiratory distress syndrome (ARDS).1

Since 1995, several authors have highlighted the central role of IL-1 Beta (IL-1) in the inflammatory cascade of ARDS.2, 3 There are 2 publications involving more than 20 patients, showing elevated IL-1β levels in plasma and bronchoalveolar lavage. In addition to these publications, many others describe an increase in countless proinflammatory cytokines (IL-1, IL-6, TNF-alpha, IL-8, etc.) in the alveoli of patients with ARDS.4

In 2018, Aranda-Valderrama and Kaynar published a model to determine the flow of cytokines and proinflammatory cells in the pulmonary alveoli of patients affected by ARDS.5 They observed how inactive IL-1β (pro- IL-1β) progresses to active IL-1β inside the alveolar macrophages (Fig. 1 ). This IL-1β generates the activation of the alveolar macrophage, thereby triggering the release of proinflammatory molecules such as IL-6, IL-18, TNF, G-CSF and CCCL2.

Figure 1
Figure 1
Pathogenesis of acute respiratory distress syndrome (ARDS) is triggered after an initial injury that interacts through alarmin receptors and TLRs that activate nuclear transcription factors, including NF-κB. Subsequently, a potent acute immune response triggered primarily by IL-1ß results in macrophage/neutrophil activation and recruitment. The cell-mediated immune response results in tissue damage, which promotes the development of oedema and epithelial damage.
IL: interleukin; MAPK: Mitogen-activated protein kinase; MMPs: Matrix metalloproteinases; NETs: Neutrophil extracellular traps; PAMPS: Pathogen-associated molecular patterns; ROS: Reactive oxygen species; TLR: Toll-like receptor.
Source: version adapted from the original by Aranda-Valderrama P. et al. Scientific illustrator: Miguel Soto.

In 2006, He et al. studied the high number of inflammatory cytokines in patients with ARDS secondary to coronavirus (CoV) infection. Autopsies of these patients showed elevated MCP-1, TGF-β1, TNF-α, IL-1β and IL-6.6

This and other publications7 also study the NLPR3 inflammasome and its influence on alveolar macrophage activation in ARDS patients. This is a complex of proteins that interact in a unidirectional manner generating an inflammatory cascade. Innate immunity responds to infection and tissue damage by activating this molecular platform.

In human clinical research, four classes of inflammasomes related to inflammatory processes have been described: NLRP1, NLRC4, NLRP3 and AIM-2.8 Of these, NLRP3 is the best studied. Inflammasomes have the common purpose of processing and activating caspase-1, the enzyme responsible for the maturation of pro-IL-1β y and pro-IL-18.9, 10

This protein group can detect molecular patterns linked to potential danger, either endogenous (DAMPs) or exogenous (PAMPs) signals that activate various intracellular signalling pathways, mainly through toll-like receptors (TLRs), culminating in the activation of different pro-inflammatory transcription factors such as nuclear factor kappa B (NF-kB) or activator protein 1 (AP-1).

These danger signals can also lead to inflammasome activation and maturation of de IL-1β and IL-18 (Fig. 2 ). The NLRP3 inflammasome can cause epithelial and endothelial damage in the lung parenchyma, leading to severe respiratory disorders such as ARDS and acute lung injury (ALI), possibly resulting in severe pneumonia.11

Figure 2
Figure 2
Pathophysiology of ARDS. The initial inflammatory stimulus activates alveolar macrophages through TLR and NLRP signalling. Activated alveolar macrophages release proinflammatory cytokines and recruit circulating macrophages and neutrophils to injury sites. This influx of persistently activated neutrophils and macrophages causes extensive damage to epithelial and endothelial lung tissue, resulting in an impaired alveolar-capillary barrier.
ENaC: Epithelial sodium channel; Na: Sodium; NETs: Neutrophil Extracellular Traps; TLR: Toll-like receptor; U: Ubiquitination.
Source: version adapted from the original by Seung Hye Han. et al. Scientific illustrator: Miguel Soto.

It is likely that COVID-19 infection can trigger a violent immune response and in turn activate the NLRP3 inflammasome in alveolar macrophages, causing a potentially fatal “storm” of cytokines, notably IL-1β.

We currently have a drug called anakinra, which neutralises the biological activity of interleukin-1 alpha and ß by competitively inhibiting their binding to the interleukin-1 type I receptor. Another available molecule is canakinumab, which binds with high affinity specifically to IL-1β and neutralises its biological activity by blocking interaction with IL-1 receptors, thus preventing IL-1β induced gene activation and the production of inflammatory mediators.

These drugs that can block IL-1β activity have shown efficacy in the treatment of autoinflammatory diseases such as neonatal-onset multisystem inflammatory disease (CINCA), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), Still’s disease and cryopyrin-associated diseases, a rare genetic disease caused by an autosomal dominant mutation in the NLRP3 gene.12, 13

The link between the presence of an NLRP3 inflammasome and the origin of the inflammatory cascade in ARDS has been confirmed in the medical literature.11, 12 The initiating pathway of IL-1β makes it a specific and central target for controlling the pro-inflammatory picture generated in the pulmonary alveolus. It is thus a potential therapeutic target in patients who may progress to ARDS after COVID-19 infection. The use of anakinra (anti IL 1β R) or canakinumab (anti IL 1β) is a therapeutic option to control alveolar inflammation secondary to COVID-19 infection.14, 15

However, these are different drugs with equally different pharmacokinetics and pharmacodynamics. The peak serum concentration (Cmax) of canakinumab occurs approximately 7 days after a single subcutaneous dose of 150 mg administered to patients with cryopyrin-associated periodic syndrome (adult CAPS). The mean terminal half-life is 26 days and mean peak plasma concentration (Cmax) after a single subcutaneous dose of 150 mg in a typical adult CAPS patient (70 kg) is 15.9 μg /ml and an absolute bioavailability after subcutaneous administration of 66%.15

Anakinra, in contrast, has an absolute bioavailability of 95% for healthy adults after a 70 mg subcutaneous bolus injection. The Cmax of anakinra is generally 3 h to 7 h after subcutaneous administration of clinically relevant doses (1-2 mg/kg/day) and the terminal half-life ranges from 4 h to 6 h. It is therefore a drug with a shorter half-life than canakinumab and thus with great potential for use in a clinical emergency such as ARDS due to COVID-19.14

It is likely that using the immunosuppressive biologic therapies is a way to control ARDS due to COVID-19. However, other scenarios must be considered beyond the individual potential of each molecule where even 2 or more of these lines of treatment can be added. While we need randomised clinical trials to advance the safety and efficacy of anakinra in ARDS due to COVID-19, this option should be considered when current treatments are ineffective or unavailable.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041148/


More information: Johannes C. Melms et al, A molecular single-cell lung atlas of lethal COVID-19, Nature (2021). DOI: 10.1038/s41586-021-03569-1

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