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A National Institutes of Health grant of $ 2.25 million enables exploration of a better vaccine path

Augusta, Ja. (Jan 11, 2021) – To build better vaccines, scientists want to learn more about how our bodies produce sufficient numbers of effective and durable antibodies against the influenza virus.

They’re looking at a key pathway at how immune cells, called B cells, see the virus, and then become the plasma cells that make antibodies that could destroy it, or at least prevent it from infecting us.

This ufmylation pathway is known to alter proteins as well as cell functions, and immunologist Dr. Nagendra Singh has evidence that it is key to our primary production of antibodies.

A $ 2.25 million grant (1RO1AI155774-01) from the National Institute of Allergy and Infectious Diseases helps Singh, Associate Professor in the Department of Biochemistry and Molecular Biology at the University of Georgia’s Medical School Augusta, to explore these molecular mechanisms behind plasma protection. The cells and the longevity of the flu-specific antibodies they make.

His long-term goals include designing small molecules, drugs, and / or using gene-editing technology such as CRISPR-Cas9, to support issues that lead to a less than optimal immune response. It suggests that an upward selective modification of ufmylation in master cells may mean more effective vaccines, while rejecting it may help allergy sufferers and individuals with autoimmune diseases resulting from an overly aggressive immune response.

Our normal production of antibodies looks like this: B cells develop from stem cells in the bone marrow, then migrate to the spleen and more.

Lymph tissue, such as the lymph nodes, circulates in the blood, and monitors pathogens such as the influenza virus or the new coronavirus.

When the influenza virus is studied, the influenza virus will reach us, usually through the nose. After an infected relative sneezes or coughs, part of the virus will reach our lymphoid organs. There, through a process called VDJ recombination, B cells have the ability to quickly recognize and develop receptors that enable them to respond to more than 10 billion different antigens. When the invader binds to the specific receptor B cells, it moves the B cell into a plasma cell that produces the antibody that targets this virus. Singh says it’s not uncommon for many different B cells to each make different plasma cells, each producing a unique antibody in response to a single virus.

Once the plasma cells appear, they return to the bone marrow and target antibodies, which Singh likens to long-range missiles. A single plasma cell can make about 10,000 such rockets per second which also end up in the blood, which carries them throughout the body. If all goes well, we may never know we’ve been attacked.

Seasonal influenza vaccines as well as novel coronavirus vaccines work in different ways to primarily fool B cells into believing that they have seen specific pathogens, which start the same process.

In this complex production, the ubiquitin-fold modifier, or Ufm1, is a polypeptide that targets proteins through the ufmylation process and modifies their function. Ufm1 binds to the protein Ufbp1, which Singh’s lab showed a novel role in enabling B cells to become plasma cells and in plasma cells that increase antibody production.

Within plasma cells, Ufbp1 is upregulated to enable the expansion of the endoplasmic reticulum, which is a membranous intracellular network that functions in the state of plasma cells as an antibody plant. Singh’s lab showed that larger is better in this case because smaller plants produce fewer antibodies. It has also shown that the endoplasmic reticulum becomes smaller when even a component of the swelling pathway is missing.

Singh and his team are now deleting ufmylation components from B cells in mice and also expressing a mutated form of Ufbp1 in laboratory animals. The mice are then infected with the influenza virus, and are monitored for the development of plasma cells and neutralizing antibodies that target the virus.

“We want to see how this affects the number of influenza-specific plasma cells that develop in these mice that do not have Ufbp1 or Ufm1 or other components of the ufmylation pathway in B cells,” Singh says. They expect, and they have some evidence, that they will see far fewer anti-influenza plasma cells without some or all of these key ingredients, but they want to make sure they are correct in terms of the main role of the effect.

They also infect mice with the influenza virus, and once the plasma cells develop a response and the antibodies that produce them occur, the ufmylation components are removed from the plasma cells, and then the flu-specific antibodies and plasma cells survive.

They are also looking again at what happens to the size of the endoplasmic reticulum where antibodies are made, and how many antibodies are formed. Again, they have some evidence, but they need more, that even if one component of the ufmylation pathway is missing, the site of antibody production will be smaller as well as antibody production.

“Plasma cells have only one job in the body: making antibodies,” Singh says. If they can learn more about how long these cells survive, they can design those small molecules, drugs, or other methods to increase their longevity and antibody production.

There is huge individual variation in how long the antibodies to the virus or bacteria survive and how many. For example, exposure to the new coronavirus resulted in the production of antibodies in some individuals that lasted for a few weeks and in others that lasted several months. The vaccines that have been created also produce a wide range of time frames for effectiveness, from the measles vaccine, for example, which is considered to provide life-long protection while protection from whooping cough or whooping cough and pneumonia is expected to last from five to 10 years. The influenza vaccine is recommended

Annually, because the predominant virus strains vary from year to year and because the plasma cells that the virus inspires also live about one year, says Singh. The half-life of these antibodies is a few weeks, so antibody levels drop soon after the plasma cells expire. The hope, he adds, is that all vaccines can be effective in the long term.

Singh does not yet know whether individual differences in the course of the bulge also help explain a wide range of responses – from no symptoms to death – different people experience influenza virus infection as well as what is seen with the coronavirus, but that must be a factor. , He says.

Singh adds: “We do not yet know if there is a difference in the pathway of your swelling that determines the amount of antibody you make against the Corona virus, or how long these antibodies live in your body.” He adds that looking at the components of ufmylation in B cells and plasma cells should help provide insight.

Singh published 2019 in the magazine Nature Communications Ufbp1 suppresses PERK enzyme to help B cells differentiate into plasma cells. PERK helps correct problems with incorrectly folded proteins (proteins must be folded properly to function properly) but PERK also stops the production of the new protein in the process, so Ufbp1 stops it to enable protein folding in large quantities and production of plasma cells.

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