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Researchers receive NIH grants to develop more effective flu vaccines

To make a better vaccine, scientists want to know more about how our body makes enough effective and durable antibodies against the flu virus.

They see an important pathway for how immune cells, called B cells, look at the virus and become plasma cells that destroy it or at least make antibodies that keep it from infecting us.

This ufmylation pathway is known to alter protein and cell function, and immunologist Dr. Nagendra Singh has evidence that it is the key to the essential production of antibodies.

A $ 2.25 million grant from the National Institute of Allergic Infectious Diseases (1RO1AI155774-01) was provided by Shin, an associate professor of biochemistry and molecular biology at Augusta University’s Medical College of Georgia, for these molecules behind protection. It helps to further investigate the mechanism. Lifespan of plasma cells and the influenza-specific antibodies they produce.

His long-term goals include designing small molecules and drugs, and / or using gene editing techniques such as CRISPR-Cas9 to solve problems that do not result in an optimal immune response.

Selective up-regulation of ufmylation in critical cells may mean a more effective vaccine, lowering it in allergic patients and individuals with autoimmune diseases resulting from an overly aggressive immune response He states that it may help.

Our normal antibody production is as follows. B cells originate from bone marrow stem cells and migrate to the spleen and other areas.

Lymphoid tissues, such as lymph nodes, circulate in the blood and pay attention to pathogens such as influenza virus and novel coronavirus.

When the flu virus Shin is studying, part of the virus reaches the lymphoid organs, usually after a nearby infected person sneezes or coughs and becomes accessible through the nose. There, through a process called VDJ recombination, B cells rapidly recognize and develop their receptors, enabling them to respond to over 10 billion different antigens.

When an intruder binds to a particular receptor B cell that has been created, the B cell begins to move into a plasma cell that produces antibodies that target the virus. According to Singh, it is common for several different B cells to produce different plasma cells, each producing its own antibody in response to a single virus.

When plasma cells emerge, they return to the bone marrow and Shin targets them with antibodies that compare to long-range missiles. A single plasma cell can make about 10,000 of these missiles per second, which also ends up in the blood that carries them throughout the body. If all goes well, we may never know that we were attacked.

Seasonal flu vaccines and new coronavirus vaccines work in different ways to trick B cells into thinking they have seen a particular pathogen that initiates the same process.

In this complex production, the ubiquitin fold modifier (Ufm1) is a polypeptide that targets proteins and modifies their function through the ufmylation process. Ufm1 attaches to the protein Ufbp1. This shows that Singh’s lab has a new role in allowing B cells to become plasma cells, which promote antibody production.

Inside the plasma cell, Ufbp1 is upregulated, allowing the expansion of the endoplasmic reticulum, which is an intracellular membrane network that functions as an antibody production plant in the case of plasma cells.

Singh’s lab has shown that in this case, smaller plants produce less antibody, so larger ones are better. He also showed that the endoplasmic reticulum becomes smaller if even one of the components of the endoplasmic reticulum is missing.

Currently, Singh and his team have removed the ufmylation component from mouse B cells and expressed a variant of Ufbp1 in laboratory animals. The mice are then infected with the influenza virus and monitored for plasma cell development and neutralizing antibodies that target the virus.

We would like to see how it affects the number of influenza-specific plasma cells that occur in these mice that do not have Ufbp1, Ufm1, or other components of the ufmylation pathway of B cells. “

Dr. Nagendra Singh, Immunologist and Associate Professor, Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University

They have some evidence, hoping that without some or all of these key factors, there will be much less plasma cells for influenza, but confirm that they are correct about the important role of ufmylation. I want to

They also infect mice with the influenza virus, and when plasma cells develop in response and produce antibodies they produce, they remove the ufmylation component from the plasma cells, which are influenza-specific plasma cells and antibodies. Observe how long you survive.

They are also looking again at what the size of the endoplasmic reticulum from which antibodies are produced and how many antibodies are produced. Again, they have some evidence, but even if a single component of the ufmylation pathway is missing, more evidence is needed that antibody production sites are smaller and antibody production is also smaller. ..

“Plasma cells have only one job in the body, they are making antibodies,” says Shin. Knowing more about how long these cells survive, they can design their small molecules, drugs, or other methods to maximize their longevity and antibody production.

He points out the large individual differences in how long antibodies against viruses and bacteria live and how many we have. For example, exposure to a new coronavirus can last for weeks while others for months.

Established vaccines are also effective from measles vaccines, which are believed to provide lifelong protection, for example, while protection from whooping cough, whooping cough, and pneumonia is expected to last 5 to 10 years. Creates a wide range of time frames for.Influenza vaccine is recommended

Every year, the strains in which the virus is prevalent vary from year to year, and the plasma cells that the virus stimulates live for only about a year, Shin says. The half-life of these antibodies is several weeks, so antibody levels drop as soon as the plasma cells expire. The hope is to allow all vaccines to have long-term efficacy, he says.

Shin does not yet know if individual differences in the ufmylation pathway can help explain the wide range of reactions that people, from asymptomatic to death, experience from being infected with the influenza virus or seen with the coronavirus. But that must be a factor, he says.

“We still don’t know if there are any differences in the ufmylation pathway that determines how much antibodies are made against coronaviruses and how long they remain in the body,” Singh adds. Examining the ufmylation components of B cells and plasma cells should ultimately help provide insights, he adds.

Shin was published in the journal in 2019 Nature Communications Ufbp1 suppresses the enzyme PERK and helps B cells differentiate into plasma cells. PERK helps fix problems with improperly folded proteins (the proteins must fold correctly to function properly), but PERK also stops the production of new proteins during the process, so Ufbp1 stops it, allowing sufficient protein folding and plasma cell production.

Source:

Augusta University Medical College of Georgia

Researchers receive NIH grants to develop more effective flu vaccines

Source link Researchers receive NIH grants to develop more effective flu vaccines

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