Surprising Cells Rein In Killer Flu

Potentially lethal strains of influenza wreak havoc indirectly – by overstimulating the immune system to produce a cytokine storm. Such cytokine storms arise from a positive feedback loop in the immune system that gets out of control. Excessive levels of cytokine signaling molecules are produced, causing immune cells such as macrophages and natural killer cells to swarm into the site of infection (the lungs in the case of influenza), producing even more cytokines, and so on.

The immune system has mechanisms that normally control this process, but somehow certain strains of influenza – such as the Spanish Influenza of 1918 – apparently interfere with the controls. Now a way has been found that seems to quiet the storm, and it involves cells that aren’t even part of the immune system.

Sphingosine-1-phosphate, a signaling molecule that is active in some immune system cells, is triggered by a cell surface receptor, S1P1. It was found that a chemical that binds this receptor (an “agonist“) could prevent cytokine storms in mice infected with influenza. The S1P1 receptor exists on the surface of immune system lymphocytes – but also on the surface of endothelial cells occurring on the inner lining of lymphatic and blood vessels in the lung. Surprisingly enough, it seems that binding S1P1 on the endothelial cells is what calms the cytokine storm, since the S1P1 agonist was effective even in mice that lacked lymphocytes.

Surprising Cells Rein In Killer Flu – ScienceNOW

When the researchers went looking for the cells in the lungs that carry the S1P1 receptor, they found that it occurs on endothelial cells, which line lymphatic and blood vessels, and on the white blood cells known as lymphocytes. That was unexpected because “they are not the cells that are infected by the virus,” Oldstone says. To determine which of these two cell types controls the cytokine surge, the researchers tested the S1P1 receptor activator in mice that lack lymphocytes. The compound also prevented the storms in these animals, suggesting that endothelial cells, not lymphocytes, orchestrate cytokine release.

For mice at least, the S1P1 receptor can be a lifesaver. After infecting the rodents with a flu virus isolated from a patient who fell ill during the 2009 swine flu outbreak, Rosen and colleagues dosed some of the animals with a compound that stimulates the receptor. The death rate was 80% in untreated animals buy only 20% in the mice that received the molecule.

Further reading:

Cytokine storms

Blocking Flu Death

Endothelial Cells Are Central Orchestrators of Cytokine Amplification during Influenza Virus Infection


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