Blocking Flu Death
Researchers have identified the cellular regulators of cytokine storms in influenza, which cause serious illness and death.
By Tia Ghose | September 15, 2011
http://the-scientist.com/2011/09/15/blocking-flu-death/
Researchers have identified a receptor that can block the flooding of immune cells into infected tissue that causes deadly bouts of the flu. The findings, published today (September 15) in Cell, could one day be used to develop treatments for people who are vulnerable to getting very sick from the flu.
“This was a hugely complex and very complete study,” said Herbert “Skip” Virgin, a viral immunologist at Washington University Medical School in St. Louis, who was not involved in the study. What’s exciting is that “there’s a specific pharmacologic inhibitor molecule that can be targeted to improve clinical outcome in influenza.” The new approach is unique, he added, because it targets the reaction of the host, rather than characteristics of the virus, which can easily evolve to evade most therapies.
When a person gets the flu, the body sends immune signaling molecules called cytokines to kill the infection. Normally, cytokines direct immune cells to infiltrate infected tissue, such as lung tissue, and cause a few days of cough, fever, and achy joints. But occasionally, the body whips up a cytokine storm and a massive amount of the immune molecules flood the system, causing inflammation and sometimes severe illness and death. Cytokine storms are thought to have played a role in the unusually high mortality rate amongst the young and healthy in the Spanish Influenza of 1918, as well as the higher death rate seen in swine flu.
Michael Oldstone, an experimental biologist at the Scripps Research Institute in La Jolla, California, was trying to untangle the pathways that led to cytokine storms in influenza, while his colleague Hugh Rosen, a chemical biologist at the same institution, was studying a receptor called sphingosine-1-phosphate (S1P1) known to modulate immune cell trafficking. Putting their research together, they found the answer Oldstone had been looking for.
The group created mice that expressed fluorescent versions of the S1P1 receptor and pinpointed them to endothelial cells that line blood vessels in the lungs. Administering a molecule that binds the S1P1 receptor quieted cytokine storms in mice, but did not affect the immune system’s ability to fight the infection. Finally, they infected mice with the swine flu and showed that binding the S1P1 receptor muted the cytokine response and reduced mortality. The approach could “differentially affect the collateral damage caused by the immune system while still allowing the host to eradicate the virus,” Rosen said.
The findings suggest that people could one day be treated with an S1P1 agonist and an anti-viral agent to blunt the severity of the flu, Oldstone added.
The new research could also help discover genetic markers that may predict who will fare worst with the flu. “One of the things we need to focus on going forward is defining precisely, in genetic terms, people who are susceptible to cytokine storms,” Rosen said.
J. Teijaro, et. al, “Endothelial Cells Are Central Orchestrators of Cytokine Amplification during Influenza Virus Infection”Cell, doi:10.1016/j.cell.2011.08.015, 2011
[The Cell article]
Volume 146, Issue 6, 16 September 2011, Pages 980-991
Endothelial Cells Are Central Orchestrators of Cytokine Amplification during Influenza Virus Infection
John R. Teijaro1, 5, Kevin B. Walsh1, 5, Stuart Cahalan2, Daniel M. Fremgen1, Edward Roberts3, Fiona Scott4, Esther Martinborough4, Robert Peach4, Michael B.A. Oldstone1, , , Hugh Rosen2, ,
1 Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
2 Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
3 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA
4 Receptos, Inc., La Jolla, CA 92037, USA
Received 23 February 2011; revised 27 March 2011; Accepted 13 August 2011. Published: September 15, 2011. Available online 15 September 2011.
Summary
Cytokine storm during viral infection is a prospective predictor of morbidity and mortality, yet the cellular sources remain undefined. Here, using genetic and chemical tools to probe functions of the S1P1 receptor, we elucidate cellular and signaling mechanisms that are important in initiating cytokine storm. Whereas S1P1 receptor is expressed on endothelial cells and lymphocytes within lung tissue, S1P1 agonism suppresses cytokines and innate immune cell recruitment in wild-type and lymphocyte-deficient mice, identifying endothelial cells as central regulators of cytokine storm. Furthermore, our data reveal immune cell infiltration and cytokine production as distinct events that are both orchestrated by endothelial cells. Moreover, we demonstrate that suppression of early innate immune responses through S1P1 signaling results in reduced mortality during infection with a human pathogenic strain of influenza virus. Modulation of endothelium with a specific agonist suggests that diseases in which amplification of cytokine storm is a significant pathological component could be chemically tractable.
Graphical Abstract
Highlights
- S1P1 signaling inhibits cytokine storms, potentially fatal immune responses
- S1P1 signaling in the endothelium protects mice from pathogenic human influenza
- In cytokine storms, cytokine production and leukocyte recruitment are separate events
- S1P1 signaling suppresses chemokine production by pulmonary endothelial cells
[Link to the article]
http://www.sciencedirect.com/science/article/pii/S009286741100941X |
