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This pandemic means we've learned so much (it would have been preferable, of course, to learn these things almost any other way) but we now know fascinating pieces of viral within-host dynamics @Grahammunology and Bryan Grenfell in @PLOSPathogens https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009105
...we started thinking about how you might frame this in the context of four classic pieces of ecology: the SIR model, predator-prey dynamics, collective action, and alternative stable states.
1st, just as spread of the infection from person to person is described using R0 (# of new infections per infected individual) + generation time (avg time separating somone being infected to infecting others), we can describe spread of the virus between cells in the same way...
...with R0~2 and generation time ~ a week, cases double every week. For viral spread between cells in our respiratory tract, R0 seems to >3 (or >8!) + generation time < 1 day. This means # of infected cells in an infected person grows incredibly fast, see: https://www.medrxiv.org/content/10.1101/2020.09.25.20201772v1
... just as early actions in a population outbreak improve prospects of virus containment, greater immune capacity for early detection + response (via youth, or female immmunity - lovely review by @sabraklein1998 here https://www.sciencedirect.com/science/article/pii/S0966842X20302638) might contribute to better outcomes.
2nd, it seems natural to cast immune cells and the virus into another ecological role-play: predator (immune system as fox) vs prey (viral infected cells as rabbit). This metaphor breaks down lots of ways (the 'predatory' immune system doesn't need 'prey' to survive, etc)...
but if 'predator' numbers grow with increasing numbers of 'prey' this might explain why better early control (the young, females) doesn't seem to translate into lower viral peaks. Perhaps older/male 'predator' population grow faster in response to early large numbers of 'prey' ?
....there also isn't much relationship between peak viral load and symptoms - (though time to clearance may be longer, e.g. @mugecevik's https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3677918). The worst symptoms seem to occur after viral loads are at low levels hinting at a role for immune dysfunction...
...and thus a 3rd piece of ecology enters...a predator/prey role-play ignores exquisite coordination across a wide diversity of immune cells. Theory around collective action tells us that very simple rules at the scale of individuals can lead to complex emergent behavior.
For example, simply by drawing close to, and broadly aligning with each other, and moving faster when they reach patches of light, fish can end up schooling in the shade [let @icouzin dazzle you: , this feature at around minute 22].
Immune cells might coordinate similarly (see https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1008051) - with viral disruption of signalling potentially particularly damaging....
4th, and finally, one of the things that first got us thinking about this was the fact that it seemed that if two apparently very similar individuals got infected, one might be asymptomatic and one might end up in ICU, and it wasn't really clear why.
This made us think of @stavercarla's work on alternative stable states. Identical climate conditions can harbour either forests OR savannahs, and can flip . To understand why, you have to unpack the trajectory - the outcome is 'path dependent'.
The alternative stable states for SARS-CoV-2 might be 'asymptomatic' or 'in the ICU'. The trajectory we might need to unpack might be a marker for inflammation.
This chimes with evidence that though IL-6 (inflammatory cytokine) correlates with bad outcomes, it is nowhere near as elevated in severe COVID-19 cases as in severe flu (as I learned via @onisillos retweet of this https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2767939). Magnitude might matter less than path.
Is any of this useful? I think so - thinking dynamically about cell interactions, and trajectories occurring within individuals through time, even simply plotting the data in different ways - might help us think through the knotty tangles of the intricate mechanisms of immunity.
(a complementary approach to the intricate and lovely 'systems immunology' approaches, e.g., https://science.sciencemag.org/content/369/6508/1210)
.... finally, this paper exist because I said something vague about alternative stable states and health outcomes to @edyong209 and he said "That sounds interesting. What do you mean?" and I realized I had no idea. #overlyhonestmethods
... oh and, @michaelmina_lab drew that lung for me - he thought my effort (for Figure in this https://www.sciencedirect.com/science/article/pii/S1755436514000723#fig0005) was not terribly convincing (he was right) - and he is always wonderfully generous with his time.
