A Quick Recap
In our last post about lipids and the immune system, we focused about how lipoproteins, particularly LDL, can participate in immune responses directly during infection – both by blocking the infection of cells through multiple mechanisms, and by binding to pathogens to neutralize them. In that post, infections were being referenced generally – both viral and bacterial.
However, in this post, there will be a focus on viral infection in particular in order to highlight some key differences between infection types. This all serves to showcase the complexity of immune responses, but also the fascinating interplay between how viruses try to infect us, and how the immune system utilizes the lipid system to thwart viral infection efforts.
It’s The Differences That Make You Stronger…
When trying to find the best solution to a problem, it helps to know the details of what you’re trying to address and change your method of response to target that issue specifically. This means knowing the enemy, if there is one, knowing the tools at your disposal, and combining that knowledge accordingly for the best possible response.
This concept is wonderfully demonstrated when looking at the lipid metabolism differences between viral and bacterial infections. As mentioned in the previous post, in response to exposure to certain toxins like lipopolysaccharide (LPS; a component of some bacteria) production of lipids – like triglycerides, cholesterol, and their carrier lipoproteins, increase.1-2
However, during viral infection lipid production by cells can decrease,3 and cholesterol uptake by cells (including immune cells), via lipoprotein uptake, can increase.4 In other words, although less cholesterol is made by the cell’s own machinery, the cell takes up more cholesterol from lipoproteins during a viral infection in order to compensate. This shift in lipid metabolism in response to some viral infections may be one explanation for the acute decrease in serum cholesterol sometimes seen in response to viral infections as well.5-7
What’s The Use of Low Cholesterol?
Although this concept may seem a bit confusing at first, there are a few clues as to why cells may down-regulate cholesterol production in favor of taking it up from lipoproteins instead. For example, the step that results in this switch lowers cholesterol in a particular part of the cell’s membrane, or outer shell. This in itself results in a protein signal (called interferon) being released by the cell,4 which is used to alert to the presence of viruses.8 This interferon signaling will also signal to any cell that sees it to decrease production of cholesterol, which will loop back around to increasing interferon signaling to spread the message to even more cells in the area.
Among many other things, this interferon signaling results in the production of a protein that disrupts cholesterol rich areas in the cell membrane called lipid rafts.9-11 Many different types of viruses take advantage of lipid rafts in our cells as a point of entry, as well as exploiting them for other uses.12 Production of this protein may work to decrease the ability of the virus to infect cells by limiting their entry points.
In regards to this shift in lipid metabolism during viral infection, the authors of one paper on the topic stated the following:
[…] leading the authors to conclude that a lipid code is being detected during innate immunity, which is read out as a signal. This code will also be altered when lipid synthesis is enhanced as occurs, for example, in response to LPS.How Low Cholesterol is good for anti-viral immunity
In other words the shift in lipid metabolism from infection, and resulting cholesterol distribution in the cell, may help to provide some context as to how to react, and whether the cell should prepare to deal with a bacteria (in which case lipid synthesis would be increased) or a virus (in which case lipid synthesis would be decreased). Because this results in a signal, interferon, this message would be able to be spread in order to warn neighboring cells as to what’s going on, and enact changes that may help decrease their vulnerability against the invader. I also can’t help but point out that although they call it a lipid code, you could very well call it a cholesterol code and be just as accurate!
Hijacking Vs. Competition
This may not be the only reason, however. It turns out that some viruses, after infecting the cell, will hijack the cellular factories and increase production of cholesterol and other lipids for their own gain. Essentially using our resources to assist in their replication.13-16 Perhaps the decreased cholesterol production by uninfected cells is a way to make this hijacking a little bit more difficult, even beyond attachment and entry of the virus.
Beyond that single effect, although certain cells down-regulate cholesterol production when exposed to viruses or interferon, their intake of lipoproteins increases.4, 17 This may serve an additional purpose beyond just getting materials: some viruses will use the receptors that recognize various lipoproteins to invade the cell18-20, which might make one assume that this would be a bad thing for anti-viral immunity. But, on the other hand, in some cases, lipoproteins can compete for entry with the virus as they’re using the same “door” to get in (called direct competition or competitive clearance) which can decrease the rate of entry for the virus.
In fact, with regards to hepatitis C, a genetically inherited form of apoE, called apoE4, is thought to be more protective against infection and aide in spontaneous clearance (e.g. resolution) as it promotes higher levels of LDL which may compete with viral entry into cells via the LDL receptor.
These high levels of LDL-c [from APOE4] may compete with [infected lipoproteins] for the binding to the LDLR, thus decreasing the entry of the virus.Hepatitis C virus Clearance and less liver damage in patients with high cholesterol, low density lipoprotein cholesterol and APOE E4 Allele
Neutralized By Lipoproteins
Lipoproteins don’t only serve to be hijacked and used by viruses to sneak past defenses, however. As mentioned in the prior post, the ability of lipoproteins to bind and otherwise neutralize pathogens is certainly notable – and this applies to some viruses too. Both have been noted to occur in vitro with the herpes simplex virus21, and others.22-23 It isn’t just the lipoprotein as a whole that can neutralize viruses, however. Components of lipoproteins, like their identifying proteins, have also been found to be able to bind and inhibit viral infection of cells in some in vitro studies as well.
ApoA-I, found on HDL particles, has been shown to have antiviral activity in the herpes virus when separated from HDL24 , something that can occur during the response to infection.25 HDL also carries other proteins which have been shown to have antiviral activity including Apolipoprotein A-I Binding Protein (AIBP) 26, and Serum Amyloid A (SAA).27 This isn’t only restricted to HDL, however, as apo(a), one of the identifying proteins on lipoprotein(a), has also been shown to bind to and inactivate the hepatitis C virus in vitro.28
However, even this has a counterpoint as some viruses can also exploit some of these proteins and apolipoproteins to further their infection and replication, either by using them to access receptors, or via other methods.29-31 It seems for every exploit there is a defense, and vice versa. The result of both viruses and human immune systems trying to one-up each other in a battle that will likely never end.
An Ongoing Battle
Just by looking at the different vulnerabilities and defenses against viral infections, it becomes clear that these adaptions on both sides are the result of an ongoing battle that has been raging for time immemorial. While viruses have many tactics to invade, infect, and replicate, so too does our own immune system have special adaptions to shut down points of entry for viruses, limit materials that viruses can use, force competition between viruses and benign particles, and many others.
It’s unclear whether it may be beneficial to lower serum cholesterol, or cholesterol synthesis, during viral infections – although this question has been asked a few times in some of the papers mentioned. Although lowering cell membrane cholesterol has been shown to be protective in cell cultures, it’s unclear whether cholesterol lowering drugs do this, and if they do to what extent. Trials attempting to answer this question have likewise not shown consistent results either way.
Likewise it’s unclear whether higher baseline cholesterol may be protective, as – although in some cases this has been speculated to be protective – some viruses can likewise hijack lipoproteins, the proteins they carry, or otherwise take advantage of our lipid system for their own gain.
Nonetheless, one thing that is certain is that we have much to learn about how lipids and the immune system interact. It is sure to be endlessly fascinating the more we learn about the complexity, and elegance, of the system, as well as the ongoing war between viruses and our immune system. We here at CholesterolCode will be sure to provide updates as we continue to explore this topic over time.Citations
1 Feingold, K. R., Staprans, I., Memon, R. A., Moser, A. H., Shigenaga, J. K., Doerrler, W., Dinarello, C. A., & Grunfeld, C. (1992). Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: Low doses stimulate hepatic triglyceride production while high doses inhibit clearance. Journal of Lipid Research, 33(12), 1765–1776.
2 Harris, H. W., Gosnell, J. E., & Kumwenda, Z. L. (2000). The lipemia of sepsis: Triglyceride-rich lipoproteins as agents of innate immunity. Journal of Endotoxin Research, 6(6), 421–430.
3 Blanc, M., Hsieh, W. Y., Robertson, K. A., Watterson, S., Shui, G., Lacaze, P., Khondoker, M., Dickinson, P., Sing, G., Rodríguez-Martín, S., Phelan, P., Forster, T., Strobl, B., Müller, M., Riemersma, R., Osborne, T., Wenk, M. R., Angulo, A., & Ghazal, P. (2011). Host defense against viral infection involves interferon mediated down-regulation of sterol biosynthesis. PLoS Biology, 9(3), e1000598. https://doi.org/10.1371/journal.pbio.1000598
4 O’Neill, L. A. J. (2015). How Low Cholesterol Is Good for Anti-viral Immunity. Cell, 163(7), 1572–1574. https://doi.org/10.1016/j.cell.2015.12.004
5 Hu, X., Chen, D., Wu, L., He, G., & Ye, W. (2020). Low Serum Cholesterol Level Among Patients with COVID-19 Infection in Wenzhou, China (SSRN Scholarly Paper ID 3544826). Social Science Research Network. doi:10.2139/ssrn.3544826
6 Shor-Posner, G., Basit, A., Lu, Y., Cabrejos, C., Chang, J., Fletcher, M., Mantero-Atienza, E., & Baum, M. K. (1993). Hypocholesterolemia is associated with immune dysfunction in early human immunodeficiency virus-1 infection. The American Journal of Medicine, 94(5), 515–519. doi:10.1016/0002-9343(93)90087-6
7 Baillie, E. E., & Orr, C. W. (1979). Lowered high-density-lipoprotein cholesterol in viral illness. Clinical Chemistry, 25(5), 817–818. https://doi.org/10.1093/clinchem/25.5.817
12 Bukrinsky, M. I., Mukhamedova, N., & Sviridov, D. (2019). Lipid Rafts and Pathogens: The Art of Deception and Exploitation. Journal of Lipid Research. https://doi.org/10.1194/jlr.TR119000391
13 González-Aldaco, K., Torres-Reyes, L. A., Ojeda-Granados, C., José-Ábrego, A., Fierro, N. A., & Román, S. (2018). Immunometabolic Effect of Cholesterol in Hepatitis C Infection: Implications in Clinical Management and Antiviral Therapy. Annals of Hepatology, 17(6), 908–919. https://doi.org/10.5604/01.3001.0012.7191
14 Thaker, S. K., Ch’ng, J., & Christofk, H. R. (2019). Viral hijacking of cellular metabolism. BMC Biology, 17. https://doi.org/10.1186/s12915-019-0678-9
15 Wang, L. W., Wang, Z., Ersing, I., Nobre, L., Guo, R., Jiang, S., Trudeau, S., Zhao, B., Weekes, M. P., & Gewurz, B. E. (2019). Epstein-Barr virus subverts mevalonate and fatty acid pathways to promote infected B-cell proliferation and survival. PLoS Pathogens, 15(9). https://doi.org/10.1371/journal.ppat.1008030
16 Fritsch, S. D., & Weichhart, T. (2016). Effects of Interferons and Viruses on Metabolism. Frontiers in Immunology, 7. https://doi.org/10.3389/fimmu.2016.00630
18 Finkelshtein, D., Werman, A., Novick, D., Barak, S., & Rubinstein, M. (2013). LDL receptor and its family members serve as the cellular receptors for vesicular stomatitis virus. Proceedings of the National Academy of Sciences of the United States of America, 110(18), 7306–7311. https://doi.org/10.1073/pnas.1214441110
19 Hofer, F., Gruenberger, M., Kowalski, H., Machat, H., Huettinger, M., Kuechler, E., & Blaas, D. (1994). Members of the low density lipoprotein receptor family mediate cell entry of a minor-group common cold virus. Proceedings of the National Academy of Sciences of the United States of America, 91(5), 1839–1842. https://doi.org/10.1073/pnas.91.5.1839
20 Agnello, V., Ábel, G., Elfahal, M., Knight, G. B., & Zhang, Q.-X. (1999). Hepatitis C virus and other Flaviviridae viruses enter cells via low density lipoprotein receptor. Proceedings of the National Academy of Sciences of the United States of America, 96(22), 12766–12771.
21 Huemer, H. P., Menzel, H. J., Potratz, D., Brake, B., Falke, D., Utermann, G., & Dierich, M. P. (1988). Herpes simplex virus binds to human serum lipoprotein. Intervirology, 29(2), 68–76. https://doi.org/10.1159/000150031
22 Activity of human serum lipoproteins on the infectivity of rhabdoviruses. – Abstract—Europe PMC. (n.d.). Retrieved March 31, 2020, from https://europepmc.org/article/med/6306404
23 Singh, I. P., Chopra, A. K., Coppenhaver, D. H., Ananatharamaiah, G. M., & Baron, S. (1999). Lipoproteins account for part of the broad non-specific antiviral activity of human serum. Antiviral Research, 42(3), 211–218. https://doi.org/10.1016/s0166-3542(99)00032-7
24 Srinivas, R. V., Rui, Z., Owens, R. J., Compans, R. W., Venkatachalapathi, Y. V., Gupta, K. B., Srinivas, S. K., Anantharamaiah, G. M., & Segrest, J. P. (1991). Inhibition of virus-induced cell fusion by apolipoprotein A-I and its amphipathic peptide analogs. Journal of Cellular Biochemistry, 45(2), 224–237. https://doi.org/10.1002/jcb.240450214
25 Eklund, K. K., Niemi, K., & Kovanen, P. T. (2012). Immune functions of serum amyloid A. Critical Reviews in Immunology, 32(4), 335–348. https://doi.org/10.1615/critrevimmunol.v32.i4.40
26 Dubrovsky, L., Ward, A., Choi, S.-H., Pushkarsky, T., Brichacek, B., Vanpouille, C., Adzhubei, A. A., Mukhamedova, N., Sviridov, D., Margolis, L., Jones, R. B., Miller, Y. I., & Bukrinsky, M. (2020). Inhibition of HIV Replication by Apolipoprotein A-I Binding Protein Targeting the Lipid Rafts. MBio, 11(1). https://doi.org/10.1128/mBio.02956-19
27 Lavie, M., Voisset, C., Vu-Dac, N., Zurawski, V., Duverlie, G., Wychowski, C., & Dubuisson, J. (2006). Serum amyloid A has antiviral activity against hepatitis C virus by inhibiting virus entry in a cell culture system. Hepatology (Baltimore, Md.), 44(6), 1626–1634. https://doi.org/10.1002/hep.21406
Thanks Siobhan, really interesting and how complex!!
“Just by looking at the different vulnerabilities and defenses against viral infections, it becomes clear that these adaptions on both sides are the result of an ongoing battle that has been raging for time immemorial.“
“It’s unclear whether it may be beneficial to lower serum cholesterol, or cholesterol synthesis, during viral infections”.
“Likewise it’s unclear whether higher baseline cholesterol may be protective, as – although in some cases this has been speculated to be protective”.
So far, I feel the best bet is to maintain a high fat, low carb diet and give the body the metabolic leeway and balance to adapt as necessary. At this point, it would seem that trying to directly influence one thing may unknowingly derail multiple other things.
Glad you enjoyed! And I definitely agree it’s quite complex. I like to highlight that, because to me that’s part of what makes it so interesting – sometimes we don’t have clear cut answers yet.
I’m glad you’ve found a lifestyle that makes you feel best, and provides you good health. Cheers to that! 🙂
I made so many notes, and then I realized it all boils down to this: whether it’s a bacterial, or viral, invasion, the body will do what it needs with the cholesterol, in order to mount the best defense possible.
That being said, during a viral infection, should fatty foods be avoided?
And during a bacterial infection, should fatty foods be encouraged?
THAT being said, viral infection = “starve a fever” = avoid regular/normal full-fat foods?
bacterial infection = “feed a cold” = eat the fats! …?
Yes, certainly as far as I’ve read there are different adaptions depending on the circumstance in order to try and yield the best defense in that situation – it is pretty cool. But we still have much to learn!
With regards to fatty foods, most of what I’ve been reading is regarding cholesterol/lipid synthesis pathways (e.g. production of cholesterol, fatty acids, and resulting VLDL is lowered). If you are eating cholesterol/fat that would be via a different pathway (absorption; transported by chylomicrons). So these appear to be separate from what it is talking about in regards to cholesterol levels in the blood and production levels as well. The two pathways are also in two different areas (liver, VLDL; vs gut, chylomicrons). So I don’t know for sure, but I would suspect these are two separate things.
“Anorexia of infection” is a thing that can happen sometimes (meaning a loss of appetite/inability to keep food down in general) but I don’t know that this is specific to bacterial or viral infections. Either way, when I’ve had the flu for example I lost appetite – in which case I didn’t eat or ate something like broth. But that’s anecdotal and personal preference on my part. I’ve not really seen anything with regards to macro composition during infections and whether they’re detrimental – except for this one regarding sugar specifically. It would definitely be an interesting question to explore, though.
feed a cold=viral infection, as colds are caused by viruses
That’s what I’ve always heard and followed,feed a cold, starve a fever.lots of fluids & pull the covers over your head,3 days of bed rest ,& orange juice,& good old chicken soup,has always worked when I did get sick,&4 kids
Have you given any thought to asking individuals who have the characteristics of a “hyper responder” to post their COVID-19 experience? John
This is actually something that people have been asking others in the Lean Mass Hyper-responders and CholesterolCode facebook groups since there are a collection of those that fit the profile there! You might want to check them out 🙂
How many of the COV19 casualties were, or being medicated with Statin/or Lipid inhibitor drugs?
I’m not sure I’ve seen any information on that specifically yet.
Early in the pandemic I read that the one statistical difference between those who got it bad and those who did not, were that those who were not seriously hit by the virus were on statins. I do not have a source for this but I expect it is out there somewhere. Being a statin resister from way back with high cholesterol I took notice.
I loved this! What an interesting point of view. Thanks so much!
Glad you enjoyed!
Great article and info Siobhan. This is something I have often thought about. I have personally noticed that my immune system has been very effective since going low carb/keto/carnivore. I have not been sick at all (no colds, allergies, flu, or anything) since going low carb and my LDL of course has gone way up. I was wondering, would someone with some kind of a persistent viral infection that lasts for a long time or is ongoing (herpes, HIV, etc) who goes low carb have a better chance of becoming a hyper responder with very high LDL? What are your thoughts?
I’m not entirely sure, honestly. No one has come forward (that I’ve seen) saying that they had that sort of history in particular and what results they saw, but I would be curious to hear about it if anyone did. Considering (some) viral infections may depress serum cholesterol, it’s an interesting question for sure. Low carb being woefully understudied means I’ve not seen any publications on this particular question that may lend some insight, either. It may be worth asking in the CholesterolCode facebook group though, as there may be someone there who’s gone through exactly what you’re asking. People tend to be pretty willing to share there, if you ask.
Fan, J., Wang, H., Ye, G., Cao, X., Xu, X., Tan, W., & Zhang, Y. (2020). Low-density lipoprotein is a potential predictor of poor prognosis in patients with coronavirus disease 2019. Metabolism: clinical and experimental, 154243-154243. https://doi.org/10.1016/j.metabol.2020.154243
In this retrospective longitudinal study, we monitored the serum lipids in 17 surviving and 4 non-surviving COVID-19 cases prior to their viral infections and duration the entire disease courses.
RESULTS: In surviving cases, the low-density lipoprotein (LDL) levels decreased significantly on admission as compared with the levels before infection; the LDL levels remained constantly low during the disease progression and resumed to the original levels when patients recovered (pre-infection: 3.5 (3.0-4.4); on admission: 2.8 (2.3-3.1), p < 0.01; progression: 2.5 (2.3-3.0); discharge: 3.6 (2.7-4.1); median (IQR), in mmol/L). In non-surviving patients, LDL levels showed an irreversible and continuous decrease until death (1.1 (0.9-1.2), p = 0.02 versus the levels on admission). The ratio changes of LDL levels inversely correlated with ratio changes of high-sensitivity C-reactive protein levels. Logistic regression analysis showed increasing odds of lowered LDL levels associated with disease progression
Thanks! Don’t think I’ve seen this one before – I will have to give it a read. 🙂
My total cholesterol dropped from 240 down to 186 subsequent to me fighting off the covid 19. I had no lifestyle or dietary changes. This sounds to be in line with the research that you have been publishing correct?
Additionally, my LDL HDL ratio remained the same prior and post infection
Hi, I’m not a doctor, and can’t give medical advice, so I can’t say for sure if this is what caused the drop. But, this would fit with what they’re seeing specifically with COVID-19 cases. Typically the levels returned to normal after a while of recovery from what I read. If it were me, I’d want to keep an eye on it and confirm that’s what the cause was as there’s always a possibility the timing was a coincidence and something else caused it – but if it did end up being related to the viral infection I wouldn’t be particularly surprised.
I’m not the brightest bulb, but my cholesterol is border line , I eat healthy, but also lazy not to over weight. BUT I don’t get sick. So? I might not get sick,but die from a heart attack! Thanks for accepting my application, tired of lame advice, found article very interesting looking forward to more.
Glad you enjoyed! Hope you enjoy the other content on the site as well. 🙂
Read this preprint and thought it needed to be delivered here… Interesting high VLDL and Trigs and low HDL AND LDL and outcomes.
Wow, my head is spinning. I know of 2 people (friends of friends’ parents) in their 90’s who have survived Covid (arguably, against the odds); one is in a memory care unit (so a greater likelihood of being ApoE4), and the other has a better than 50% chance of having some degree of cognitive impairment. As DF regularly reminds us, all cause morbidity increases with lower LDL after 60. Yes, so fascinating and so much more research to do. Thank you!
No way to know if these things are related yet of course, just from anecdotes. It will be interesting to see what large population data that includes prior lipid levels shows, though. I have no doubt at some point in the future we’ll get that, given that so many countries were impacted, some of which have national health databases, etc. Until then we’re left to wonder. 🙂
Imagine if you will, a group of people that figured out they could splice different types of cholesterol/hormone lipoproteins/glycoproteins onto an animal plasmid, and could introduce these contraptions to human cellular machinery, and be able to elicit immune responses that they could tweak and sharpen in the laboratory until they figured out how to even combine insect enzymes, bacterial enzymes, etc., to create complicated multilayered, perfectly measured amino acid inserts that would correlate perfectly with natural enzymatic protease that would cleave these ligands at just the right terminal to release the next step or process, so as to thwart specific immune responses with enzymes from tick saliva, placed just right, while simultaneously increasing activity of other immune mechanisms. Then what if they even made up new medical lingo to describe the exact same processes that every cell goes through for this branch, but made the lingo sound more scary. Then primed everyone to believe that their little creations actually “evolve” to this sophistication out of the want for survival, human characteristics that these little “virus as a vaccine vector” creations just don’t possess.
When I had covid last year (August 21) I noticed that my hair and skin were amazingly greasy. I could see the grease on my pillow case, and then the first time I got my hair cut (after recovering) the barber had trouble cutting my hair with clippers (guess I hadn’t washed it that morning).
I don’t generally eat keto, but I do sometimes and I’ve ate low carb for maybe 8-10 years now.
No idea if we should view that as a caused by the infection or by the reaction from the immune system, but I’m sure there was an effect.
I suspect I’ve had it again in recent weeks (all tests -ve, but cough, tired, etc), but I haven’t noticed the same greasy hair reaction this time.