Posted by If you had a prowler at your house you’d call the police. You’d want them to come. But what if they sent a SWAT Team, surrounded the house and blasted it from all sides. Not good. That seems to be something like the scenario for a response to a class of virulent influenza viruses. They trip the alarm and the army descends and levels the house. The prowler is taken care of. So are you. The phenomenon has acquired the name “cytokine storm,” although a better description might be immune system dysregulation. Your immune system has a lot of powerful weapons to protect you, but like a police force you want them used lawfully and appropriately. This week scientists at the St. Judes flu group in Memphis published an intriguing paper in the Proceedings of the National Academy of Sciences with the unintriguing title, “TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection” (Aldridge et al., PNAS; hat tip to Dave Fedson, with whom I enjoyed a long and informative lunch yesterday).
It is becoming increasingly clear that some of the nastiest effects of virulent flu strains like the 1918 H1N1 or the bird flu H5N1 are related to the violent and uncontrolled immediate response of the immune system, a response which destroys lung tissue by runaway inflammation. Helpless clinicians have tried to damp down the immune response in bird flu patients by using steroids which depress all parts of the immune system. It hasn’t worked. The immune system is a very complex apparatus with many moving parts. Those parts have to be coordinated and regulated. Using steroids is like laying off the police force. It isn’t going to protect people from attacks from pathogens like the flu virus. The intricate choreography of the immune system, like the cruder one of a police response, is based on signaling and communication between its different parts. Most of that signaling is done by chemical messengers called chemokines. When one kind of immune cell is ready to recruit others to help, it releases a chemical signal. When that signal is received (by another chemical, called a receptor), it activates a new set of biological events. And so on. I’d love to lay out the whole intricate system for you, but I can’t. No one can. At the moment it’s like a giant jig saw puzzle where we know some of the pieces and how they fit together, but not always where they sit in the Big Picture and there are lots of pieces still lying in the puzzle box. But we are making progress and the PNAS paper by Aldridge et al. is a step to putting some more in place.
The paper is quite technical, but the main ideas aren’t too difficult. The immune system operates on two different time scales. There is an immediate response that is generic in character. Sound the alarm, there is a microbial intruder on the premises. Strike at it with generic weapons. That’s called the innate response. But then there is a second, later response. The immune system has figured out what kind of intruder it is. Send in the specialized units designed for just that person. That’s the adaptive response. Some of the adaptive response is via proteins made by immune cells that circulate in the blood. These antibodies are what vaccines are designed to elicit. Once you are familiar with different kinds of intruders you can react to them more quickly. The immune system learns how to react by seeing specific examples and training antibody making cells to respond quickly. The immune system also has its own Special Forces cells that go out to kill virally infected cells. These are a kind of T-cell, another one of the cells of the immune system. So what kinds of response do we see in the lung when its cells are infected with influenza virus? That’s one of the important questions scientists are trying to puzzle out.
The Aldridge paper identifies a particular kind of immune cell, called a dendritic cell, as being centrally involved in the process. When a flu virus infects a lung cell it sounds an immune system alarm. One of the first things that happens is a generic immune cell called a macrophage, like a cop on the lung beat, sounds an alarm by making a protein, MCP-1 (monocyte chemotactic protein-1). MCP-1 combines with CCR=2 (chemotactic chemokine receptor-2) which calls to the area another cell called a monocyte. CCR-2 also induces the monocyte to perform a more special function: produce two more proteins, Tumor Necrosis Factor-alpha (TNFalpha) and inducible nitric oxide synthase (iNOS). This may sound complicated, but I’m simplifying a great deal. It’s much more complicated than I’m letting on.
The monocytes have now changed into a cell called a dendritic cell (DC), or more precisely a special subset of dendritic cells called Tip-DCs (TNF-iNOS-producing DCs). There are many other kinds of immune cells in the mix: natural killer (NK) cells, neutrophils, other kinds of DCs, macrophages. Aldridge et al. found, however, that when a mouse is infected with the kind of virulent flu virus causing a runaway inflammatory response, the only kind of immune cell that ramps up compared to others is the Tip-DC. When a mouse was infected with a less virulent flu virus, there was no unusual increase in Tip-DC but with highly virulent strains, Tip-DC accumulated in the lungs. The Tip-DCs were also making a lot of TNFalpha and nitric oxide, damaging the lungs. The SWAT Team had arrived and was firing at will. This suggested the obvious thing: get rid of the Tip-DC response and you would protect against the runaway immune response.
Unfortunately there is nothing obvious about how the immune system operates. When Aldridge et al. repeated the experiments with mutant mice that couldn’t make CCR-2, they also did badly, dying at the same rate as the mice that had an intact CCR-2 response. As expected, there wasn’t an accumulation of Tip-DC in the lungs, but the mice died anyway. So more is involved. The “more” involves, at least in part, further activities of the Tip-DC cells. Dendritic cells also function in the later phase of the immune response. They are “antigen presenting” cells, essentially cells that take the pathogen and broadcast its description to other cells in the immune system, cells like the killer T cells. These T cells are like the specialized sniper team that comes in after the culprit is identified. Only the ones trained for that flu virus are called up. But if there are no Tip-DC cells to perform the description and broadcast function, there is a weak or ineffective T cell response. Aldridge et al. first established that the Tip-DCs were actually functioning as the flu virus antigen presenting cell (their method was technically clever, but the details would take us too far from the main story). Then they showed that the Tip-CD were necessary for the killer T cells to function properly in clearing virus. Here is their summary for where they had arrived at this point (APC means “antigen presenting cell,” a cell that functions as the describer/broadcaster of the invader):
So far we have shown that the number of tipDCs is significantly elevated in mice infected with HP [highly pathogenic] influenza A viruses, that these tipDCs function locally in the respiratory tract as APCs, and that they are required for the full realization of protective CD8+ T cell-mediated immunity [i.e., functioning killer T cells]. In addition, their complete absence from the lungs of CCR2−/− mice is associated with severe disease, indicating that tipDC ablation [elimination] is not a viable therapeutic option. (Aldridge et al., PNAS)
In other words, when it comes to Tip-DC, you can’t live with them and you can’t live without them (in terms of infection with virulent flu virus). What to do? The Goldilocks Principle: Not too much, not too little. Just right.
They reasoned that this was yet another example of the balance needed in any complicated system. You want the police to come, but you don’t want them to send the army. By searching the literature, they found a drug that affects CCR-2 but doesn’t completely knock it out. The drug belongs to an interesting class of compounds called peroxisome proliferator-activated receptors (PPARs), of which there are three (alpha, beta and gamma). They were interested in the gamma subtype, one of which is a compound called pioglitazone. Another compound of this class is rosiglitazone, marketed under the tradename Avandia, as a treatment for type II diabetes. PPARs have many interesting biological effects and we have been studying them from the environmental angle and this connection with dendritic cells was new to me and extremely interesting. But back to the flu story. By pre-treating the mice with pioglitazone Aldridge et al. were able to reduce significantly the lethality and weight loss related to infection with the virulent strains of flu virus. The mice weren’t completely protected, but the mortality went from 90% to 50%. There was also a reduction in the inflammatory response, with the most evident reason being a reduction in accumulation of Tip-DCs in the lungs of the mice.
Before you run out and buy Avandia, you should know that there are some significant questions about risk of heart attack for those taking it long term for diabetes. On the other hand, balancing that risk against death from a pandemic flu virus suggests it is worthwhile to consider as part of our arsenal should a pandemic develop. Unfortunately, I fear it will be put on the shelf with other possibly effective and low cost approaches, like statins. Antivirals and vaccines seem to be the only weapons that the infectious disease folks can imagine. Of course there is much to learn yet before this would make sense as a policy. But if a pandemic arrives before we’ve figured out how to handle it, statins and PPARs are something people would (or should) try in the urgency of the moment. Right now there is no effective treatment for a runaway response to flu.
Admittedly this is well out of the conventional approach to flu. The infectious disease community has been very slow to look in new directions. Maybe this paper by one of the premier flu groups in the world will change that. But it will also require the people at St. Judes to push their new findings. I hope they will.
It’s not the only thing I wish they’d do. While they’re at it, maybe they could release the flu sequences they’re sitting on until they can publish papers. In that respect they are no different than the nutcase Indonesian Health Minister everyone likes to rant about (including us). They’re not alone. I’ll include CDC and Mt. Sinai and probably other elite flu groups as well. Just to be fair.
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