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Infectious dose is a possible explanation but I don’t think it’s a very likely one, for a couple reasons.
The most important being that identical twins are not genetically identical! https://twitter.com/drzoehyde/status/1343118149072244736
The most important being that identical twins are not genetically identical! https://twitter.com/drzoehyde/status/1343118149072244736
You read that right. Identical twins are genetically identical in most cells except for two types of cells that are pretty relevant to determining outcome of a viral infection: B and T cells.
B cells, which make antibodies, and T cells, which coordinate immune responses (CD4/helper)and kill infected cells (CD8/killer), are specific to the pathogen. How do they develop this specificity, you ask? A crazy little thing called recombination.
The genes for business end of antibodies or the T cell receptors recombine at random during development, giving rise to a huge repertoire of cells with unique genomes at these sites. This diversity is what enables our immune systems to target the diverse pathogens we encounter.
Importantly this diversity arises within individuals, so the B and T cells even in otherwise genetically identical twins is specific to the individual. Meaning these twins’ immune repertoires are NOT identical.
Furthermore, even in the cells containing identical genomes, the epigenomes are different. This refers to modifications of the DNA or the proteins the DNA is wrapped around in the nucleus (histones), which determine how genes are expressed.
The epigenome can have a substantial impact on how global host responses are induced. Timing of host antiviral response is important in determining disease progression. Different epigenomes could explain different host responses to infection leading to different outcomes.
These twins presumably have had different infections over the years, as well. That means they will have different immune memory cells and may have different latent viral infections. Herpesviruses like CMV and EBV can also influence immune responses to other viral infections
Finally, I keep seeing this infectious dose argument coming up but I don’t see a lot of data to support it. Data in animals does not. Clinical data doesn’t either. You can’t measure infectious dose by looking at viral load, which is what this argument relies heavily on.
Infectious dose arguments effectively take the host out of the equation. I’m biased because the host response is what I study but...it’s really important. Given the genetic differences in identical twins are in critical immune effector cells (B/T cells)...
...and given that the epigenome is likely to uniquely determine global host responses for each individual, and we don’t know much about their prior infections/exposure, the infectious dose hypothesis seems unlikely to me. It doesn’t address these other complex variables.
Sometimes Occam’s razor cuts true and the simplest explanation is the best, but just as often the simplest explanation is too simple. That’s what I think about this infectious dose hypothesis. It’s also being presented in a dangerous way to the public.
People are getting the message that if you get COVID, getting a lower dose will result in better outcomes. A perspective in NEJM argued that this could even substitute for vaccination! Again the data does not support a direct correlation between infectious dose & disease severity
I try to refrain from speculating about a single hypothesis such as “infectious dose probably explains this” from a single case study, especially when there are many possible alternate explanations. Sometimes it’s hard to distinguish untested hypotheses from settled science.
