I think more studies need to be done in humans as it seems likely that antipyretics do more harm than good in some situations. Lowering body temperature could be neutralising a powerful antiviral defence.

Thanks for reading this thread.

Interestingly, the 1918, 1957 and 1968 pandemic viruses all had an avian-origin PB1 that enabled efficient replication at febrile temperatures.

I think this is one reason these pandemics caused so much severe disease.

An increase of just ~2 degrees C (a regular fever) was enough to convert a severe or lethal challenge into a mild disease.

Because these viruses are essentially identical apart from their ability to replicate at different temperatures, this indicates that temperature itself protected the mice in this model (not thermally stimulated immune responses).

Simulated fever protected against severe disease from the parental virus, but the mutant virus still caused severe disease despite the elevated temperature.

We genetically isolated temperature sensitive replication by making point mutants in PB1. This allowed us to test 2 nearly identical viruses (one temp sensitive and the other temp resistant) in mice with a simulated fever (note that the mock traces are duplicated for clarity).

When mice are housed in hot cages, their body temperature increases, which simulates febrile body temperature. Mice with a simulated fever are known to be protected against many viruses.

It is known that avian influenza A viruses replicate more effectively at fever-range temperatures than mammalian-adapted viruses. We found that avian-origin PB1 proteins predominantly confer fever-resistant replication.

Firstly thanks to all the authors who contributed to this project. A special shout out to Matt Turnbull who led this study and Yingxue Wang who took it over in Cambridge).

(Origami from Zhuonan Li)

Hey Nick! Hope all is well.