It is pretty obvious that fever is useful. Work by Kluger and others has shown that increased temperatures decrease mortality during infection. Even for lizards! (When infected they crawl to warmer places.)

The mystery has been how fever works. Can higher body temperature alone inhibit pathogen growth? It seems unlikely that changing temperature by just a degree or so would have a major effect. Pathogens are too adaptable.

In a seminar discussion this week, Karl Sperling, from the Institute of Human Genetics, Charité – Universitätsmedizin Berlin, brought up the protective role of heat shock proteins, and how highly conserved they are. This quickly suggested that their original function might have been co-opted to cope with infection.

Sure enough, a quick search revealed a 2007 PNAS article by Varsha Singh, and Alejandro Aballay, showing

that that increased temperature results in the activation of a conserved pathway involving the heat-shock (HS) transcription factor (HSF)-1 that enhances immunity in the invertebrate Caenorhabditis elegans…HSF-1 is required for C. elegans immunity against Pseudomonas aeruginosa, Salmonella enterica, Yersinia pestis, and Enterococcus faecalis, indicating that HSF-1 is part of a multipathogen defense pathway.

So, it may be that fever itself may not be useful, but because HSPs have been co-opted to coordinate some aspects of the immune response, increased body temperature is the signal that turns on the response.

This has obvious major implications for treating infectious disease. Perhaps we can turn on these pathways without raising body temperature. Of course, we will need to be cautious. Natural selection has had a long time to adjust the system to various trade-offs. However, selection is constrained, and pathogens certainly also disrupt these systems, so finding out the details offers many possibilities.

All in all, this is a very nice example of the interesting ideas that pop up from interdisciplinary discussions among people with their evolution thinking caps on.

Now if we could just get NIH to invest in comprehensive studies on whether anti-inflammatory drugs speed or slow recovery from various kinds of infections, general physicians would have some fundamental knowledge they need, but lack.