TLRs, PAMPs, and Alley Oop

I hear that some Eurasians  – probably more than some – have Neanderthal or Denisovan versions of TLRs.  Not surprising: we’ve already seen this happen with other immune system genes – HLA variants , OAS1, STAT2  all have adaptive variants that originated with archaic humans.

TLRs   (Toll-Like Receptors) are just plain interesting, but I don’t think many people are familiar with them.  They’re part of the innate immune system:  they don’t learn from experience, as happens with the adaptive immune system (recombination,  clonal selection and all that): they just know.  Born that way.

They sense pathogens by detecting molecular patterns characteristic of major classes of pathogens that we just don’t have.  These are called PAMPs (pathogen-associated molecular patterns). They can detect  lipopolysaccharide (LPS), characteristic of gram-negative bacteria. and peptidoglycan, characteristic of gram-positive bacteria. Some detect viral-double-stranded RNA.

There are ten TLRs in humans.   Generally, they react with molecular patterns  that we don’t even have. TLR-1 recognizes bacterial lipoprotein and peptidoglycans (strep and staph), TLR-2  recognizes bacterial peptidoglycans( gram-positive bacteria)  and zymosan (fungi), TLR-3 double stranded RNA (viruses) ,  TLR-4 lipopolysaccharides (salmonella) , TLR-5 bacterial flagella (listeria) , TLR-6 bacterial lipoprotein, TLR-7 single-stranded RNA (viruses) , TLR-8 single-stranded RNA(viruses) , TLR-9 CpG DNA (bacteria) .  TLR-10 appears to play an inhibitory role, down-regulating TLR-2 .

Back in the days when vaccine development was cutting-edge, I think that people knew that the body automatically reacted to some pathogens, but it has taken a long time to discover the complex details, not that we’re quite done yet.

P.S. according to some, one factor inducing Pygmyization was the high pathogen load in dense tropical jungles.  I don’t know if that was the case, but if so, considering  that it looks as if African Pygmies (also Bushmen) admixed a bit  with a very divergent hominid population (more divergent than Neanderthals) , it wouldn’t be surprising if they picked up some immune system gene variants that helped deal with that jungle environment.

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33 Responses to TLRs, PAMPs, and Alley Oop

  1. Do apes have TLRs that are like ours?

  2. Anonymous says:

    nice summary

    typo: PAMP is pathogen-associated molecular pattern

    TLRs also play a role in development

  3. benespen says:

    That is really interesting. TLR-4 recognizes lipopolysaccharides, otherwise known as endotoxins. That receptor is exquisitely sensitive, about 2 nanograms of lipopolysaccharide on a medical device or in a drug formulation is the standard limit. Unfortunately, it is really easy to get that much, since it leaks out of the cell walls of gram negative bacteria when you kill them. TLR-4 can’t tell the difference between LPS that is left behind by accident, and LPS that represents an infection. The most visible sign of this is fever, but there are other consequences that can be more severe depending on dose.

  4. TWS says:

    Does this identify folks who otherwise have unknown Denisovan or Neandertal heritage or do they match those we know. In other words does this add to the people with known Denisovan or Neandertal heritage?

  5. ohwilleke says:

    One of more of the three TLRs found in mice but not in humans (particularly TLR 11) seem like obvious low hanging fruit for genetically modifying humans to have greater immunity to a large class of pathogens. Once it was in the genome of one generation, all subsequent generations would benefit.

    • minoritymagnet says:

      You would have to genetically engineer the associated signaling and regulation systems in addition to TLR11. What immune cells are activated in response to it? How long? How many? Locally or systemically? With our current understanding, that’s impossible to modulate.

    • TWS says:

      Yes but what about the sudden overpowering urge for cheese?

    • Boris Bartlog says:

      Considering the issues that we currently have with autoimmune disorders, I’d really want to identify some problem disease that this was intended to address before just adding it without specific reason.

  6. Picking up immune system gene variants from archaic populations from which we picked up little else sounds not just possible but probable to me. I remember John Hawks talking about seven gene variants that have been discovered so far giving increased resistance to malaria. I wonder if any of them have been passed to us by Denisovans or other long gone archaic populations.

    • minoritymagnet says:

      Malaria has only become a huge problem very recently with the advent of agriculture. Population size was too small before probably. Hunter-gatherer lifestyle prevented much exposure to mosquitos. I doubt archaic populations had significant selection for malaria resistence.

      • peppermint says:

        sickle cell disease is caused by a mutation in hemoglobin that changes its shape to disrupt the malaria parasite. Unfortunately, if you have two sickle cell genes, you end up with sickle cells, which get stuck in your capillaries.

        Malaria is a tropical disease because civilized men will drain the swamp instead of putting up with it.

        • Jim says:

          The mutated site on the hemoglobin-S binds to another site on another hemoglobin molecule causing the hemoglobin-S molecules to form long rigid rods which stretch the walls of the red blood corpuscles and eventually cause them to break up. The stretching of the corpuscle walls causes potassium to leak out of the corpuscle which in turn leads to the death of the malaria parasite living in the corpuscle. I read this on p. 240-242 of Biochemistry – 2nd Ed – Mathews\van Holde. Biology is weird.

          • Jim says:

            Houston where I live was a big swamp not so long ago and nature keeps trying to turn it back into a swamp. We have a big mosquito problem with the mosquitoes carrying both Nile fever and encephalitis also heartworm which infects dogs and cats but not people. A person I know at work got Nile fever. He recovered with no aftereffects but in some people the result can be severe neurolgical impairment.

      • You could be right that malaria has only become a huge problem recently, this certainly seems to be the case with the most devastating form of malaria, Plasmodium Falciparum. But we should all caution ourselves from stating anything with certainty about the distant past about which we know so little.

        What I can say with more certainty is this. A huge driver of hominid evolution has always been gene variants that give even a slight advantage to disease. We know that individual genes can spread to a modern population from an archaic population, see This hasn’t happened once but many many times.

        Once upon a time there were archaic populations of humans scattered hither and yon, hanging on to their turf, in large part because they had genetic advantages to diseases prevalent to their particular area. A new population would hang on the edges, not able to replace the existing population until they picked up those advantageous gene variants, but when they did, the old population went the way of the dodo.

        So what did these archaic people leave us with? I dunno, but what I do know is if I keep reading westhunter I will be one of the first to know.

  7. DKlondt says:

    Hunter-gatherer lifestyle prevented much exposure to mosquitos.

    How is that? Go to any wet forest to find out that the opposite is true.

    • minoritymagnet says:

      Agriculture increased population density near waterbodies and in addition provided new mosquito breeding grounds e.g. in form of wells and irrigation channels. Several mosquito populations have adapted to this new niche, primarily targeting humans for blood e.g. Aedes aegypti aegypti.

    • RCB says:

      I doubt that mosquito bites were rare prior to agriculture, but they appear to have gotten worse after agriculture. What we ultimately care about is how agriculture affected human evolution with regard to vector-borne diseases. Here’s a fascinating factoid from :

      “…what geneticists would like to know is the timepoint at which the unusually virulent species P. falciparum began to expand in human populations. This has been addressed by a variety of approaches, with conflicting results (reviewed by Conway [2003] and Hartl [2004]), but the most persuasive evidence comes from a detailed analysis of 100 mtDNA sequences sampled from around the world (Joy et al. 2003). This suggests that some forms of P. falciparum may have existed 100,000 years ago, but that the African malaria parasite population suddenly increased ∼10,000 years ago and subsequently spread to other regions. This observation, together with analysis of the speciation of human malaria vectors by polytene chromosome analysis (Coluzzi 1999; Coluzzi et al. 2002), is consistent with the hypothesis that the emergence of P. falciparum as a major human pathogen coincides with the beginnings of agriculture, when human populations started to form resident communities that allowed the establishment of a substantial reservoir of infection.”

      From this paper and others (e.g.,, it looks like a lot of the alleles that confer resistance to malaria have indeed arisen only in the last 10k years. Given that malaria has been called the greatest selective pressure in human history, that’s pretty spectacular!

  8. Fourth doorman of the apocalypse says:

    Wikipedia says:

    In 1997, Charles Janeway and Ruslan Medzhitov showed that a toll-like receptor now known as TLR4 could, when artificially ligated using antibodies, induce the activation of certain genes necessary for initiating an adaptive immune response.

    Does the innate immune system only deal with bacterial pathogens?

    Is the adaptive immune system required to deal with viruses or is there no clear dividing line?

  9. TWS says:

    So do we know what archaic species that bushmen and pygmies are hybridized with and is it also a ‘pygmy’ sized population?

  10. Mr. Tumnis says:


    Do you have any ideas on drug development (repurposed or novel therapeutics) for diseases and disorders?

  11. JC says:

    This paper may be of interest. ‘The Importance of Dietary Carbohydrate in Human Evolution’.

    • TWS says:

      If I recall correctly, John Hawks mentioned that even wild animals preferred the taste of cooked food.

    • Fourth doorman of the apocalypse says:

      The paper is very interesting, but I noticed this in it:

      Cultural adaptation is more rapid, and in many cases more flexible, than biological adaptation (Richerson and Boyd 2008). It is our contention that changes in starch consumption—driven in part by the cultural transition to controlled fire use and cooking—is likely to have either activated positive selection on standing variation in AMY1 (and possibly AMY2) CNV, or favored de novo AMY1 CNV after cooking was adopted.

      This presupposes, I imagine, that Homo had already substantially adopted the use of fire for other reasons?

      It doesn’t seem that there are any wild animals that are comfortable with fire. Maybe I am wrong here but it seems like only domesticated animals are comfortable with fire.

      Further, if fire was initially only for cooking meat, what is the likelihood that it became ‘culturally’ adopted widely?

      • Beyond Anon says:

        Perhaps they were already used to sitting around camp fires and using the camp fires to scare off predators at night.

  12. TWS says:

    There are birds (egrets I think) that actively follow the line of a grass fire and eat the disturbed and cooked critters.

  13. TWS says:

    Most park rangers can tell you about a weird phenomenon. Bears will begin copying other bears in their methods for getting food. One bear learns to fold back the window on a little car. Pretty soon bears a hundred miles away are using the exact same method. No one knows really how it happens.

    Bears are about as far from social as you can get but learning is going on somehow. Something similar might have been going on with Ugh and Alley Oop, Alley sees Ugh sitting around a fire tossing a turtle on it. Alley tries the same thing then Zug from one tribe over gives it a shot.

  14. Pingback: So Why do Native Americans have so much Neanderthal DNA? | evolutionistx

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