Immunity complexity: cells do their own thing (Introduction)

by David Turell , Monday, April 13, 2020, 23:52 (1684 days ago) @ David Turell

Cells on mucous membranes have some defenses of their own outside of the usual immune protections:

https://www.sciencedaily.com/releases/2020/04/200413165618.htm

"Cells in some of the body's most vulnerable entry routes to bacterial infection buffer themselves when the immune system detects danger by reorganizing the cholesterol on their surfaces, a new study led by UTSW scientists suggests.

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"Scientists have long known that the mucus membranes that line the intestines, lungs, and other sites play a key role in protecting the body from systemic infection. But exactly how the immune system enhances the defensive properties of so-called mucosal epithelial cells to block infectious agents, such as bacteria, is unclear...

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"Because immune cells, such as macrophages, are typically found in close proximity to mucosal epithelia, Alto and his colleagues wondered whether these cells might secrete a molecule that helps epithelial cells heighten their defenses when the immune system detects a threat, such as an infectious microbe.

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"When the researchers broadly surveyed gene activity in the macrophages, they found that one in particular, called cholesterol 25-hydroxylase (CH25H), became significantly more active when confronted with L. monocytogenes. Further tests showed that the small molecule produced by this gene was key for preventing epithelial infection.

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"Radhakrishnan explains that CH25H changes cholesterol, which normally doesn't mix at all with water, to produce a form called 25-hydroxycholesterol (25HC) that does slightly mix with water. This property of 25HC is exploited to regulate the amount of cholesterol, an essential lipid in every cell in the body. Some of 25HC's functions include turning down the activity of genes involved in cholesterol synthesis and activating an enzyme that converts cholesterol to a form that can be stored in cells.

"Surprisingly, when the researchers treated epithelial cells with 25HC, they found that total cholesterol in these cells didn't change during the time period of their experiments. However, using two different types of sensor molecules -- one that attaches to cholesterol on the cell surface that's accessible, and another that detects cholesterol on the cell surface that's inaccessible because it's bound by other lipids -- Alto, Radhakrishnan, and their colleagues discovered that 25HC depletes the accessible cell-surface cholesterol, pulling it inside the cell.

"'Within one hour of treatment, the accessible form of cholesterol was severely depleted from the cell surface," says Radhakrishnan. "By four hours, it was completely gone."

"The depletion of accessible cholesterol was essential to protect epithelial cells from L. monocytogenes, Alto says, reliably bolstering the cells' defenses. When the scientists treated the depleted cells with an enzyme that converted the inaccessible cholesterol on the cell surface to an accessible form, the cells became susceptible to infection again.

"This defense mechanism worked not only against L. monocytogenes but also Shigella flexneri, a bacterial pathogen that causes a disease called shigellosis, highlighting the broadly antimicrobial nature of this protection."

Comment: Another amazingly complex protective mechanism which had to be in place beforethese bacteria could attack. Only design fits