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
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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.
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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
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