Winter Is Coming and the COVID-19 Pandemic Is About To Get Worse

By University of Illinois College of Agricultural, Consumer and Environmental Sciences Dec 10, 2021

Protein region on COVID viral peak detects temperature, drives seasonal mutation patterns.

Not to pile on, but winter is coming and the COVID-19 pandemic is about to get worse. Not necessarily because of ommicron — scientists are still working it out — but because there is more evidence than ever that COVID-19 is a seasonal disease.

We know this intuitively. It’s no surprise that moving in and closing windows stops transmission. But new analyzes from University of Illinois researchers show that, among all variants and waves, the disease has been circulating seasonally around the world for nearly two years.

More importantly, the researchers identify a molecular culprit for the seasonal nature of the virus. The finding could help predict future mutations and potentially pave the way for new therapies or vaccines.

“Our proposal is the first proposal of a viral sensor that responds to external seasonal patterns of environment and physiology,” said Gustavo Caetano-Anollés, professor in the Department of Crop Sciences and the CR Woese Institute for Genomic Biology at the University of Illinois, and senior author of the Methods in Microbiology study. “The structure should now become a focus for prediction, mitigation and informed decision-making about public health.”

The structure, embedded in the N-terminal domain of the viral peak, falls into a broad category of proteins known as lectins. All organisms make lectins; the proteins recognize and bind to carbohydrates and form adaptive and innate immune responses. They are also known to help viruses and other microbes attach to their host cells. But only recently did scientists discover that some lectins play a role in sensing temperature changes in the environment.

This is where coral reefs and COVID-19 come together.

University of Illinois researchers, including Gustavo Caetano-Anollés (pictured), draw on a discovery in coral reef bleaching to identify the protein on the COVID peak that causes seasonal mutation patterns. Credit: Photo by L. Brian Stauffer

In 2019, scientists in China discovered that a type of lectin — galectin — was involved in the recognition between photosynthetic dinoflagellates and coral polyps. But this recognition mechanism didn’t work as well when the water temperature fell outside a narrow thermal band: 25-30 degrees Celsius. It was a first hint that galectins sense external temperatures and an explanation for coral bleaching, the devastating demise of coral reefs in warming waters.

Learning about this discovery, Caetano-Anollés and his collaborators analyzed tens of thousands of SARS-CoV-2 genomes and discovered a galectin-like structure on the spike protein. The researchers think that galectin protein structures detect external conditions and, if not too hot or humid, cause a conformational change in the virus’s spike protein, allowing viral RNA to enter host cells.

“Think of the spike as a small jar with flaps on top to keep it closed. When the temperature is high, the jar stays completely closed and the infectious contents cannot be spilled. But when the flaps recognize the host cell in the lung – under cool and dry conditions – the jar opens, releasing a fusion peptide that helps the virus and host membranes join together, allowing the virus to enter the cell and make more of its kind,” says Caetano-Anollés.

Viruses are constantly changing. When a certain part of the genome starts to change faster, that’s a signal that the virus is exploring new and better ways to survive and spread within its host. In other words, rapid mutation is the virus that throws spaghetti at the wall to see what sticks.

Scientists expect these rapid mutations to occur in regions responsible for transmission, infectivity and immune escape, as they are most useful to the virus. Since sensing the environment is so important to the virus, it made sense that the peak’s galectin-like structure would also be one of those regions, and that its role would be related to virus infection.

“Remarkably, we find that the galectin-like structure is a frequent target of mutations because it helps the virus evade or modulate the host’s physiological responses to promote spread and survival,” says Caetano-Anollés.

Tracking mutations in the galectin protein region led the researchers to identify a seasonal pattern around the world. By focusing on genomic changes around the world, they found bursts of rapid mutations that happened in 2020, often leading to new variants of concern. The eruptions were fired in parts of the world that experienced winter or in high-altitude locations where the weather remains cool year round. As for eruptions in the summer, or in low-lying tropical areas? They just didn’t happen.

Significantly, most seasonal bursts occurred in the N-terminal region of the spike protein. That’s where the galectin structure is located; more evidence of its importance to the virus.

“Tracking the prevalence of mutations in this structure past the beginning of the pandemic resulted in the identification of a hemisphere-dependent seasonal pattern driven by mutation bursts. These bursts are now responsible for the emergence of the Variant of Concern Delta and new viral variants in the works,” says Caetano-Anollés. “Understanding how these processes of viral diversification occur is crucial for mitigation.”

Caetano-Anollés’ lab is now examining the millions of viral sequences obtained worldwide to determine how genomic makeup changes the virus’s behavior. They hope to further unravel the molecular underpinnings of seasonality as COVID-19 becomes endemic.

Reference: “The seasonal behavior of COVID-19 and the galectin-like culprit of the viral spike” by Kelsey Caetano-Anollés, Nicolas Hernandez, Fizza Mughal, Tre Tomaszewski and Gustavo Caetano-Anollés, November 15, 2021, Methods in Microbiology.
DOI: 10.116/bs.m.2021.10.002

The research was supported by the Office of Research and Office of International Programs of the College of Agricultural, Consumer and Environmental Sciences at the University of Illinois at Urbana-Champaign.