Tiny Model Intestines, Noroviruses and Innate Immunity
Background
A HuNoV is a human norovirus, the main worldwide cause of gastroenteritis (think vomiting and diarrhea — or maybe don’t think about that). The big problem is that there are no vaccines or antiviral drugs against them because not much is known about these viruses and how they work. There have been no good models for researching noroviruses — until now.
This paper focuses on the use of a new technology, the Human Intestinal Enteroid model (HIE for short) that has revolutionized the study of HuNoV and similar viruses. Basically, a tiny sample of stem cells is taken from intestinal biopsy or surgery samples (so, no embryos and less ethical controversy). These cells are then grown in a lab where they multiply and differentiate into almost all the cells present in the intestines and form a tiny little sphere (like a balloon). This is a perfect little model, a tiny “pocket” of the intestines that can be manipulated, infected, and observed.
Before this, there was no good ways to test viral infections outside of the body. The methods used were all “in vitro,” meaning in glass, or in a fake environment. Those just didn’t cut it — they couldn’t compare to what happens “in vivo,” which means in the living body. HIEs represent a third category, “ex vivo,” meaning outside of the body but still replicating the body in a naturally derived environment.
So, what did they find?
Summary: Using HIEs to understand intestinal immune response
Using the HIEs, researchers infected the cells with two different strains of norovirus, strains 3 and 4 (their fancy names are HII.3 and HII.4).
The first point they established was that adding interferons to the HIEs decreased replication of the virus within the cells for both strains.
Now, hold on, what is an interferon? Well, an interferon (aka IFN) is part of the body’s innate immune system. Basically, interferons are tiny little signaling molecules that can be released by almost any human cell that senses something fishy. The cells recognize a sign of viruses in the body — maybe a piece of virus RNA or DNA or a certain protein, etc. — and upregulate the interferons, stimulating expression of genes that help stop the invaders.
So, back to the paper. Normally, the intestinal cells are infected, and by the time they can sense the viruses and start to respond, the viruses are already spreading, and that gives the viruses and edge. However, when researchers dumped interferons onto the HIEs pre-infection, it helped stop the viruses by giving the cells in the HIE time to “warm up” their defenses by expressing anti-viral genes before the viruses could even get a foothold. The cool thing here was that the effect on the viruses was strain-independent. It didn’t matter if the enteroids were infected with strain 3 or 4 — the advantage over the virus was present both times. (The HIEs are super important here because they allow representation of the complete virus life cycle, giving us more details about how well the virus infects the human cells.)
So, interferons are good for cells, bad for virus. If more interferons hurts the virus, fewer IFNs should help it, right? Well, not exactly.
The second half of the experiments included messing with the genetics of the human cells in the HIEs to stop them from being able to produce interferons. These “crippled” HIEs could be infected as usual but couldn’t use a main part of their defenses to fight back. When they repeated the infection experiment described above, strain 3 acted exactly as expected: it grew faster and spread farther because it wasn’t being attacked by the interferons and the innate immune system. However, strain 4 did not grow any faster.
This means that getting rid of the interferon systems did not help strain 4 do better. That implies that strain 4 was not susceptible to those certain interferons in the first place, but instead its growth in the previous experiments is being inhibited by something else occurring in the cells. This is called a strain-specific response because the different strains react in different ways.
So, what does this all mean?
One way to summarize a paper is actually to analyze the title. Here, that is: “Human norovirus exhibits strain-specific sensitivity to host interferon pathways in human intestinal enteroids.” So, when different strains of noroviruses are used, we can see a different effect (strain-specific sensitivity) from the interferons of the innate immune system inside the HIE model. This study is groundbreaking because it demonstrates the importance of HIEs and reveals new information on the way noroviruses respond to different types of interferons.
The fact that the strains responded differently suggests that the differences in the biology of the viral strains affect their interactions with the body, and might explain epidemiological patterns. For example, since strain 4 (HII.4) may not be susceptible to the internal interferon pathway, this might explain why it is the more widespread viral strain seen in the world. The findings concerning the protective effect of adding interferons may also be an idea for developing treatments against noroviruses that cause gastroenteritis. Not only does this research reveal new and important information, it provides hope going forward.
