Important new flu paper in Cell: part I

The cells of your body don't just sit there, unmindful of what is going on around them. They have to respond to things, even cooperate with other cells to get things done for the common good. Humans do the same thing. We've developed a system of signaling to each other using an intricate vocal system, a complex grammar, ears, eyes and smell detecting systems. It's a very complicated package with a lot of moving parts. It's not so surprising, then, that cells also have complex signaling systems with a lot of parts that they use to respond to their environment. Just as we sometimes make a coordinated response to something in our lives (I touch a hot stove or I have a fight or flight response to a threatening situation), so do cells respond to their environment (there is a virus touching my cell surface). Communication in cells is tied up with almost everything, including tissue repair, development, cancer and a lot more. Now a new paper in the journal Cell describes how a particular cell signaling pathway might be involved in the catastrophic response of lungs when infected by certain viruses or bacterial toxins. Because of the potential importance of this paper we are going to take some time to explain it.

The central actor in the paper by Imai et al. ("Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury", Cell, Vol 133, 235-249, 18 April 2008 is a cell signaling receptor called TLR4, which stands for Toll-Like Receptor 4. The Toll-like receptors are a family of molecules, some, like TLR4, found on the surface of certain cells that are part of the innate immune system. The adaptive immune system produces antibodies and requires some previous exposure but the innate immune system sounds a non-specific alarm. It says, "Danger here, mobilize defenses." The TLRs get their name because they bear similarity to a gene on fruitflies that had the name Toll. Toll means "weird" in German:

Christiane Nüsslein-Volhard of the Max Planck Institute in Tübingen analyzed mutations in fruit flies. In 1985, she saw a weird-looking fly larva in which the ventral portion of the body was underdeveloped. Her spontaneous comment was "Das war ja toll!" meaning "That was weird!" and she coined the name Toll for the mutated gene. (Hansson GK, Edfeldt K, Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1085)

Not so weird that it prevented Nüsslein-Volhard from receiving the 1995 Nobel Prize for her work. But the story did get weirder. In 1995 it was found that this gene was not only associated with differentiating back to front in the developing fruitfly but also was somehow involved in its resistance to fungal infection. By the early 1990s other genes similar to the toll gene in fruitflies had been found in humans. While the initial thought was the gene was probably related to development as in the fruitfly, there was soon evidence that one of them, now called TLR4, was the button pushed by lipopolysaccharide (LPS), a component of the cell wall of gram negative bacteria and the endotoxin involved in "gram negative sepsis," the devastating multi-organ system collapse seen in some bacterial infections. Gram-negative sepsis in turn was also similar to the cytokine storm of Acute Lung Injury (ALI) seen in SARS, H5N1, 1918 H1N1, inhalation anthrax and some cases of Monkeypox. TLR4 is now part of a whole family (13 at last count) of Toll-like genes that produce generalized pattern recognition receptors for broad classes of pathogen components. As such they are part of the innate immune system that begins to act before there is any antibody selection or response. Our knowledge of the TLR system is very recent since their discovery is barely ten years old. But already the original TLR gene, TLR4, is becoming part of the bird flu story.

Unfortunately the story is still hazy and it isn't possible to draw any straight line conclusions from Imai et al.'s very interesting paper. But it feels like we're getting somewhere. This is only a piece of the puzzle but I'm guessing it will later be seen as a major piece. We'll have to see. Meanwhile, what did they show? We'll pick this up in the next post.