Lipids and Viral Infections

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

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 cell^18-20, 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.