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When the Spanish flu stalked the globe in 1918, some theorized that the death toll was so dire because of the World War I effort. Young and previously healthy soldiers and civilians alike had simply pushed themselves too hard, the theory went, running down their immune systems and leaving them vulnerable to a viral pandemic that ultimately killed worldwide.

But, in essence, the opposite was true. There is considerable evidence that during the 1918 epidemic of H1N1 flu, patients died because their immune response was so strong it triggered massive inflammation, damaging their lungs. (In fact, there was a disproportionately high mortality rate in young adults aged 15 to 34.) Runaway immune response to the invading flu virus caused a cytokine storm, leading to rapid destruction of lung tissue and death from pneumonia or acute respiratory distress syndrome (ARDS), a lung condition that prevents enough oxygen from getting into the blood. Evidence of extensive lung damage from ARDS was also found in autopsies of patients who died of H1N1 flu in 2009.

Now, scientists at the ӳ����ý and Massachusetts General Hospital have uncovered new components in a critical pathway that allows immune cells to detect viral invaders. Their research deepens the understanding of the body’s antiviral response and may one day lead to a drug that could potentially tamp down the immune system just enough to reduce damaging inflammation from such cytokine storms. The research into viral-sensing pathways, in the Nov. 11th issue of Cell, also holds promise for understanding autoimmune diseases, which can resemble this overwrought viral response.

The immune system is exquisitely tuned to help us navigate a world that is rife with microbial invaders. To mount this fight, chemical messengers known as cytokines signal immune cells to travel to the site of infection, stimulating them to produce more cytokines. A hyper-reaction, however, can prove lethal, triggering attacks of ARDS, sepsis, or graft-versus-host disease in transplant patients.

To further map the body’s viral-sensing pathways, ӳ����ý researchers Nicolas Chevrier, Ido Amit, core faculty member Aviv Regev, and senior associate member Nir Hacohen decided to focus on one particular family of sensors, known as Toll-like receptors, or TLRs. They uncovered 35 antiviral signaling regulators - including 19 that were new - involved in TLR pathways. They specifically looked for genes that were involved in signal transduction – the process by which a signal outside the cell interacts with a receptor on its membrane.

They also found something unexpected: a new arm of the viral-sensing pathway governed by proteins called Polo-like kinases (Plks). Some of these proteins were activating a signaling branch associated with inflammation and with autoimmune diseases, much as a faulty signal on a train track allows a locomotive to barrel ahead at full tilt.

“There is no easy way to describe what Plk does because we don’t yet know,” Hacohen said. “It’s a new arm of the pathway. On the other hand, when we add a small molecule called BI2536 that inhibits the Plk proteins, it blocks the viral response.” Although not ready for clinical use, BI2536 is in Phase 2 clinical trials for potential anti-cancer uses. Someday, researchers hope, it might be used to mediate the course of infectious diseases, or of autoimmune diseases such as lupus. The work involved a diverse team of scientists at the ӳ����ý across multiple disciplines, from cell circuitry to proteomics to chemistry.

“There’s a theme emerging in our work,” Hacohen said. “We do screens to find many genes in a process, then we look at the intersection with gene associations in human disease and with existing drugs. The deeper our understanding of the detailed cellular process in this network, the better we can connect it to diagnosis and therapy.”