Tag: RNA

Categories : DermatologyTags :

Sunburn Results from Damage to RNA, not DNA

On By ModernMedia
Photo by Rfstudio on Pexels

The warnings against sunburn are well known: avoid direct sunlight between 12 noon and 3pm, seek out shade and put on sunscreen and a hat. It is also taught that sunburn results from damage to DNA. But that is not the full truth, according the researchers behind a new study conducted at the University of Copenhagen and Nanyang Technological University, Singapore (NTU Singapore).

“Sunburn damages the DNA, leading to cell death and inflammation. So the textbooks say. But in this study we were surprised to learn that this is a result of damage to the RNA, not the DNA that causes the acute effects of sunburn,” says Assistant Professor Anna Constance Vind, who is one of the researchers responsible for the new study.

The study has been published in Molecular Cell.

RNA is a more transient molecule than DNA. A type of RNA, known as messenger RNA (mRNA), functions as the intermediate ‘messenger’ that carries information from DNA to make proteins – the basic building blocks of cellular components.

“DNA damage is serious as the mutations will get passed down to progenies of the cells, RNA damage happens all the time and does not cause permanent mutations. Therefore, we used to believe that the RNA is less important, as long as the DNA is intact. But in fact, damages to the RNA are the first to trigger a response to UV radiation,” Anna Constance Vind explains.

The new study was conducted on mice as well as human skin cells, and the objective was to describe the impact of UV radiation on the skin and what causes these damages. The researchers found the same skin response to UV radiation exists in both mice and human cells.

A built-in surveillance system for RNA damage

mRNA damage triggers a response in ribosomes (protein complexes that “read” the mRNA to synthesise protein), orchestrated by a protein known as ZAK-alpha – the so-called ribotoxic stress response – the new study shows. The response can be described as a surveillance system within the cells, which registers the RNA damage, leading to inflammatory signalling and recruitment of immune cells, which then leads to inflammation of the skin.

“We found that the first thing the cells respond to after being exposed to UV radiation is damage to the RNA, and that this is what triggers cell death and inflammation of the skin. In mice exposed to UV radiation we found responses such as inflammation and cell death, but when we removed the ZAK gene, these responses disappeared, which means that ZAK plays a key role in the skin’s response to UV-induced damage,” says Professor Simon Bekker-Jensen from the Department of Cellular and Molecular Medicine, who is one of the other researchers responsible for the study. He adds:

“So you could say that everything depends on this one response, which monitors all protein translations occurring. The cells respond to the RNA damage, realising that something is wrong, and this is what leads to cell death.”

Faster and more effective response

The result of the study changes our understanding of sunburn and the skin’s defence mechanisms: that RNA damage triggers a faster and more effective response, protecting the skin from further damage.

“The fact that the DNA does not control the skin’s initial response to UV radiation, but that something else does and that it does so more effectively and more quickly, is quite the paradigm shift,” says Anna Constance Vind.

We need to understand the function of RNA damage, as it may in the long term change our entire approach to prevention and treatment of sunburn.

“Many inflammatory skin diseases are worsened by sun exposure. Thus, understanding how our skin responds at the cellular level to UV damage opens the door to innovative treatments for certain chronic skin conditions,” says co-author Dr Franklin Zhong, Nanyang Assistant Professor at NTU’s Lee Kong Chian School of Medicine.

“This new knowledge turns things upside down. I think most people associate sunburn with DNA damage; it is established knowledge. But now we need to rewrite the textbooks, and it will affect future research on the effects of UV radiation on the skin,” Simon Bekker-Jensen concludes.

Source: University of Copenhagen

Categories : COVID Immune SystemTags :

Initial Immune Reaction Determines Severity of COVID

On By ModernMedia
Image source: CDC on Unsplash

Researchers have found that the course of severe COVID could be determined very early on, depending on the body’s initial reaction to the disease in the upper airway as well as inflammatory reactions.

Scientists at the Ragon Institute of MGH, MIT, and Harvard; the Broad Institute of MIT and Harvard; Boston Children’s Hospital (BCH); MIT; and the University of Mississippi Medical Center (UMMC) wondered whether COVID’s path towards severe disease could start much earlier than expected — perhaps even within the initial response created when the virus enters the nose.

To test this, they studied cells taken from nasal swabs of patients at the time of their initial COVID diagnosis, comparing patients who went on to develop mild COVID to those who progressed into more severe disease and eventually required respiratory support. Their results showed that patients who went on to develop severe COVID exhibited a much more muted antiviral response in the cells collected from those early swabs, compared to patients who had a mild course of the disease. The paper appears in Cell.

“We wanted to understand if there were pronounced differences in samples taken early in the course of disease that were associated with different severities of COVID as the disease progressed,” said co-senior author José Ordovás-Montañés, an associate member in the Klarman Cell Observatory at Broad and assistant professor at BCH and Harvard Medical School. “Our findings suggest that the course of severe COVID may be determined by the body’s intrinsic antiviral response to initial infection, opening up new avenues for early interventions that could prevent severe disease.”

To understand the early response to infection, Sarah Glover of the Division of Digestive Diseases at UMMC and her laboratory collected nasal swabs from 58 people, 35 of whom were just recently diagnosed with COVID, representing a variety of disease states from mild to severe. Seventeen swabs came from healthy volunteers and six came from patients with other causes of respiratory failure. The team  sequenced RNA from these samples to find out what kind of proteins the cells were making — a snapshot of the cell’s activity when collected.

By studying a cell’s transcriptome, which is its collection of RNA, can researchers understand how a cell is responding to environmental changes such as a viral infection. It can even be used to see if individual cells are infected by an RNA virus-like SARS-CoV-2.

“Our single-cell sequencing approaches allow us to comprehensively study the body’s response to disease at a specific moment in time,” said co-senior author Alex Shalek, who is also an associate professor at MIT in the Institute for Medical Engineering & Science, the Department of Chemistry, and the Koch Institute for Integrative Cancer Research. “This gives us the ability to systematically explore features that differentiate one course of disease from another as well as cells that are infected from those that are not. We can then leverage this information to guide the development of more effective preventions and cures for COVID and other viral infections.”

Analysing the transcriptome, the team investigated how epithelial and immune cells were responding to early COVID infection from the single-cell transcriptome data. Firstly, in patients who progressed to severe COVID, the initial interferon-driven antiviral response was muted. Second, patients with severe COVID had higher amounts of highly inflammatory macrophages, and high inflammation levels are often seen in severe or fatal COVID.

Since these samples were taken well before COVID had peaked in the patients, both these findings indicate that COVID’s course may be determined by the initial response of the nasal epithelial and immune cells to the virus. The weak initial antiviral response may allow a rapid spread of the virus, making it more likely to move from upper to lower airways, while the recruitment of inflammatory immune cells could help drive the dangerous inflammation in severe disease.

Finally, the team also identified infected host cells and pathways associated with protection against infection — cells and responses unique to patients that went on to develop mild disease. These findings may allow researchers to discover new therapeutic strategies for COVID and other respiratory viral infections.

If the early stages of infection can determine disease, it could enable the development of early interventions that can help prevent the development of severe COVID. Potential markers of severe disease were also identified, genes that were expressed in mild, but not severe COVID.

“Nearly all our severe COVID samples lacked expression of several genes we would typically expect to see in an antiviral response,” said co-first author Carly Ziegler, a graduate student in the Health Science and Technology Program, MIT and Harvard.

“If further studies support our findings, we could use the same nasal swabs we use to diagnose COVID-19 to identity potentially severe cases before severe disease develops, creating an opportunity for effective early intervention,” said Ziegler.

Source: Broad Institute of MIT and Harvard

Journal information: Ziegler, C G K., et al (2021) Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19. Cell. doi.org/10.1016/j.cell.2021.07.023.