Researchers have shown that mice lacking a certain immune signaling molecule known as interleukin-1B, are more resistant to Salmonella than mice with interleukin-1B. This observation led researchers to further investigate how Salmonella manipulates the immune system.
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Salmonella is a bacterial infection that results in gastrointestinal symptoms ranging from diarrhea, cramps, and fever. In its worst form it can result in typhoid fever. Luckily, in most healthy humans it most commonly results in uncomplicated gastrointestinal discomfort (Giannella 1996).
Most people get Salmonella from contaminated food. After ingesting said food, the bacteria makes its way into the intestines where it releases toxins. As toxins are released, the body reacts by inducing an immune response. The immune response results in inflammation thus leading to the disagreeable symptoms discussed above.
One hallmark of the body’s immune response to Salmonella infection is the release of an inflammatory molecule known as cytokine interleukin 1B (IL-1B). Our bodies produces many types of interleukins as part of its immune response to various viral and bacterial infections. Typically interleukins like IL-1B play a vital role in defending the body from such invaders, however, in the case of Salmonella these defenders are tricked into attacking the host it is meant to protect.
This conclusion was made by Mor Zigdon and colleagues who investigated the previously unknown role of IL-B1 in Salmonella infected mice. Throughout their research they made several discoveries – all pointing to one conclusion – IL-B1 is “detrimental” during Salmonella infection (Zigdon et al. 2024).
At first I found their conclusion confusing. As far as I know, the immune response is a good thing that is responsible for fighting off infection. If the immune system plays a role in harming you, or in this case – making an infection worse – what is the point?
The first discovery that researchers made was that mice who were genetically altered to not produce IL-B1 showed lower Salmonella infection – 100-fold so. In addition to infection, mice without IL-B1 also showed less mortality and tissue damage in the colon when compared to mice with IL-B1. This illustrated for the first time that the immune response is responsible for driving Salmonella infection via interleukin-B1. While this discovery could seem niche and unrelated to anyone outside of the field of immunology – like myself – it poses exciting potential for the development of new treatments that target this pathway.
In order to further understand the role of IL-B1 in Salmonella infection Zigdon performed a technique known as RNA sequencing. RNA sequencing measures gene expression through laboratory and computational based techniques. Here researchers measured gene expression in IL-B1 lacking mice as compared to normal mice. By comparing gene expression in the two, researchers identified a list of genes that are “differentially expressed” – meaning there is a big difference in expression between the two kinds of mice. This helps researchers uncover certain genes and pathways that play a role in Salmonella infection.
Through this process the researchers were able to identify genes relating to neutrophils as those involved with IL-B1. Interleukins act as signaling molecules that “draw in” or recruit other cells that attack foreign particles in the body such as a virus or bacteria. Neutrophils are an example of these types of cells.
The RNA sequencing data illustrated that mice without IL-B1 had decreased levels of neutrophils, which seems backwards since neutrophils are meant to attack harmful bacteria like Salmonella. However, the researchers observed what they termed “defective neutrophil function.” This is when the neutrophils attack the host cells or beneficial bacteria leading to colon damage and allowing Salmonella to thrive.
Thus researchers determined something counterintuitive – mice without IL-B1 were successful in overcoming Salmonella infection not because of an increased immune response but a decreased one. Essentially, defective neutrophils that are typically meant to help destroy bacteria were turning on host tissue to actually reduce the body’s ability to fight off Salmonella.
In addition, the failure of IL-B1 deficient mice to recruit neutrophils leads to a decrease in oxygen availability in the colon. These low-oxygen conditions favor a specific beneficial bacteria present in your microbiome known as SCFA-producing Clostridia. The presence of these beneficial bacterias inhibit Salmonella growth by outcompeting the Salmonella for food sources and oxygen.
Now you may be wondering if any of this applies to humans, since all of the above research was done in mice. In order to determine how IL-B1 acts during human infection, the researchers performed RNA sequencing on sepsis patients to analyze IL-B1 levels. While they found higher levels of IL-B1 in sepsis patients I hesitate to read too much into this since there is not yet any experimental evidence. Likewise, while sepsis is a similar bacterial infection too Salmonella, it is not the same. It seems like a big jump to make when all of the mice experiments were performed using Salmonella.
With everything the researchers found, we are now one step closer to understanding what contributes to Salmonella infection. From their results it is clear that many processes are at play – I can only assume there are many more yet to be uncovered. I also wonder if potential treatments modeled to target this immune pathway would be realistic given that the immune system is so vital for protecting the body against other kinds of infections?
Sources
Ralph A. Giannella, 1996 Salmonella. Medical Microbiology. 4th edition. Chapter 21. https://www.ncbi.nlm.nih.gov/books/NBK8435/
Zigdon M, Sawaed J, Zelik L, Binyamin D, Ben-Simon S, Asulin N, et al., 2024 Salmonella manipulates the host to drive pathogenicity via induction of interleukin 1β. PLoS Biol 22(1): e3002486. https://doi.org/10.1371/journal.pbio.3002486
Written by: Susannah Armstrong, suarmstrong@davidson.edu
© Copyright 2022 Department of Biology , Davidson College, Davidson, NC 28036
Susannah, it was fascinating to read about the way that salmonella can essentially hijack our body’s immune response. I agree with your opinion that the relationship between salmonella, IL-B, and mice seems like it wouldn’t really inform us of the relationship between sepsis, IL-B, and humans. Yet I confess that immunology is not my forte, so perhaps these two organisms are more related than we think. Additionally, I would be interested in learning more about the these defective neutrophils that are attacking the host body. How are they different from “normal” neutrophils, and what precisely is happening to them – is it a structural change, a change in signaling, or something else?
Great job telling the story of a great research question. Their discovery that in mice lacking the interleukin IL-B1 saw a whole 100 fold decrease in bacterial infection is very interesting! I think further research into discreet ways certain more fatal infections, like sepsis, “highjack” our immune system. I would like to see additional research using RNA-seq on these so called defective neutrophils to hopefully deduce their mechanisms of turning against the host.