(🧵1/5, EMERGENCE): What happens to virulence after a new pathogen emerges? Popular thinking on the subject is that pathogens evolve become less virulent over time when they co-exist with their host species, based on the logic that virulent pathogens don't spread effectively.(1/)

This perception is occasionally echoed by experts as well, for example in this Science article: “𝑆𝐀𝑅𝑆-𝐂𝑂𝑉-𝟐 is going to become a common cold. At least that’s what we want.” (If wishes were horses, then zoonotic spillover would be nothing to worry about, I guess?) (2/)

The idea dates back to the "Law of Declining Virulence", propounded by medical doctor Theobald Smith in the 19thC (far from the last MD to confidently hold forth on the topic of evolution). Unfortunately, it's not supported by experimental data (see screenshots for example). (3/)

An alternative hypothesis, put forth in the 80s, says virulence improves transmissibility, up to a point. Experiments support the first part of that statement, but not necessarily the second. (see screenshot). In which case, virulence would be expected to increase over time. (4/)

Myxomatosis, often put forward as an example of virulence decreasing over time, is an interesting case study. Host(rabbit) populations quickly developed resistance to myxoma virus after it was introduced in AUS & UK in the '50s, which led to an apparent decrease in virulence.(5/)

This increased host resistance provided "headroom" for the virus, and it evolved to become more immunosuppressive. Researchers have found that modern myxoma strains are often more virulent than the original, killing with delayed kinetics. (https://t.co/9kMzWloEWE) (6/)

This is not surprising- myxoma is a pathogen, and it really doesn't care about rabbit outcomes, as long as it can find new hosts. “With myxoma, the virus has developed new tricks, which are resulting in greater rabbit mortality." (https://t.co/Dn6ViPDFyH) (7/)

This arms race between host & pathogen is described in evolutionary literature as the Red Queen's Race. In the back & forth of adaptation & counter-adaptation, apparent virulence declines come from natural selection acting on the host, providing it with a transient advantage.(8/)

So, how does the Red Queen's Race end? Usually, in extinction for one or other species (see screenshots for examples). Studies show that extinction-causing pathogens typically have rapid evolutionary rates, alternative animal reservoirs & spread independent of host density. (9/)

Running the Red Queen's Race with a pathogen can lead to evolution of host resistance, but it's a slow, bloody business. Using evolution to manage a disease is like using arson to manage wildfire risk. Unmitigated disease spread is not a controlled burn. (10/)

Every species has a lifespan- species are born, they live & they die, just like we do. The average lifespan of a mammalian species is 2-3 million yrs. Hominin species live for about 500k yrs. As we saw, infectious disease is a major cause of species "death" (extinction). (11/)

A case can be made that infectious disease caused Neanderthal (NT) extinction. When archaic modern humans (AMH) & NT first came into contact, AMH brought with them a package of diseases that NT didn't have resistance to (see screenshots), a plausible cause for extinction. (12/)

For about 100k yrs, AMH & NT coexisted (& interbred) in the Levant, after which AMH spread throughout the world. Modeling suggests NT DNA picked up through interbreeding provided AMH with -asymmetrical- resistance to NT diseases, while leaving NT vulnerable to AMH diseases.(13/)

As it happens, introgressed ("borrowed") NT DNA sequences are enriched for genes that code for resistance to - wait for it- RNA viruses. Human genome evolution after Neanderthal interbreeding was shaped by viral infections, selecting for alleles that provided resistance. (14/)

More generally, Human Virus Interacting Proteins (VIPs) are under stronger purifying selection & adapt faster than other similar proteins. Viruses are a dominant driver of protein adaptation in mammals- HLA genes undergo particularly rapid coevolution (screenshots). (15/)

Think about what that means for a minute. That old chestnut about "we have always lived with infectious diseases". No, we haven't. We have always died with infectious diseases, and that's how we've evolved resistance to those diseases that have been with us for a long time. (16/)

The price of evolved resistance is natural selection, "nature red in tooth & claw". Coevolution of humans that reduces virulence happens on human, not pathogen, life-cycle timescales. The speed of evolution is generally proportional to the strength of the selection pressure.(17/)

Put simply, the more people that are killed, the faster resistance emerges. Let's look at that with a modern example. Malaria, which emerged relatively recently (10k yrs ago), has killed a lot of people. In the 20th c alone, malaria caused 2-5% of all deaths (150- 300m) (18/)

Malaria, no surprise, is the strongest known force for positive selection on the human genome. (Positive selection sounds like a good thing, but it actually means more people dying if they don't have resistance). West African populations, e.g., are more resistant to malaria (19/)

Cape Verde Islanders evolved resistance to malaria blazingly fast (over 500yrs) as a result of introgression of West African DNA into their genomes. Took 20 generations, during an era when "50% of children died before the age of 4 years, mostly from malaria”(Brumpt, 1922) (20/)

If we let malaria spread freely and let evolution do its thing, the pathogen can be expected to evolve increased virulence, to increase transmissibility again. Countless millions will die, likely over 000s of years, before malaria is "tamed" in this way. It's a dumb plan. (21/)

Fortunately, we aren't following it. We suppress malaria spread every chance we get, we develop vaccines & new drugs (which the bug quickly evolves resistance to). We are fighting malaria, rather than surrendering to it & letting the Red Queen's Race carry us where it will. (22/)

So, the answer to the question "does virulence decrease after emergence" is "No, that's not how evolution works". Increased virulence provides a transmission advantage & host resistance leading to reduced virulence creates headroom for the pathogen to up its virulence again.(23/)

As we discussed, infectious disease is the strongest driver of evolution. Meaning that it’s the biggest threat-any given selection pressure doesn't get to leave a fingerprint on our genomes without removing lots of people from the gene pool (usually involves killing them).(24/)

By analogy, infectious disease is to species what high blood pressure is to people. High BP kills people the way infectious disease kills species. "Learning to live with" high BP means managing it actively, not throwing one's hands up and hoping for the best. (25/)

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