By Naomi Chege
Edited by Emily DeMichele
Reincarnation? Sounds religious, right?! When you die and get reborn. Yes, that’s what I am talking about! If you don’t believe in reincarnation, parasites may change your mind. In my weirdest daydreams, science and non-science-based ideas come together to try to make sense of the world. It is during these moments that I have linked host-parasite interactions to reincarnation.
Humans and other vertebrates have evolved different defenses against pathogens. With a considerable number of encounters with different pathogens, it is only fair that we develop the thick skin required for survival. However, the evolution is not only restricted to the host side, the pathogens also have evolved diverse and effective ways to hide from these sharpened host defenses. A key focus has been on how pathogens evade immune mechanisms, which is no surprise since it is the sole central operating system affecting the fight against infectious agents. Some key immune evasion strategies include mimicking or changing their surface coat to become indifferent or unrecognizable by the host and degrading host immune factors. New insights into immune evasion have shown that intestinal parasitic worms can cause intestinal stem cell reprogramming. The mastery of these camouflaging and weaponry techniques by pathogens significantly limits efforts to develop new vaccines and innovative treatments.
Parasitic worms/helminths constitute a very successful group of pathogens that have evolved several unique host adaptations. Like other parasitic organisms, they can subvert host immune responses by altering immune alarms and subsequently suppress the immune system despite infection persistence. Some parasitic worms whose favorite niche is the intestinal epithelium are known to interfere with nutrient absorption [1], intestinal permeability [2][3], and the enteric nervous system [4]. Recently, they have been reported to induce intestinal epithelial “reincarnation” to promote survival. Their gigantic size compared to bacteria and viruses does not limit their immunomodulatory mechanisms as most of their impact on the host is induced by their excretory-secretory products.
The intestinal epithelium forms the dynamic lining of the digestive system. It regulates nutrient uptake from the interface between internal tissues and the outside environment. As a consequence, it is subjected to a myriad of pathogens, including bacteria, viruses, protozoa (single-celled parasites), and helminths (roundworms and flatworms) which can negatively impact epithelial function [2]. Their dynamic nature however allows them to withstand continuous mechanical, chemical, and biological assault. The different cell subsets of the intestinal epithelium assist in keeping it healthy. These cells are continuously being replenished from intestinal stem cells (ISCs). ISCs sit at the bottom of intestinal crypts and differentiate into all the different epithelial lineages [5][6]. Briefly, the stem cells proliferate and give rise to intermediate cells called transit amplifying cells (TA) from which multiple epithelial subsets emerge, including the absorptive (enterocytes) and secretory (goblet, paneth, tuft) cells which migrate up the crypt-villus before dying to make room for other cells [7](Figure 1). Think of the crypt-villus structure as an escalator, continually in motion. This intestinal epithelium regeneration is a highly coordinated process, and uncontrolled/unrestricted ISC proliferation or impaired differentiation can lead to significant medical problems, including cancers. The ISCs are indispensable, generating intestinal epithelial cells regardless of being delicate and getting destroyed easily following injury.
Figure 1: Intestinal epithelium regeneration under homeostasis. The stem cells divide and give rise to transit amplifying cells (TA) from which multiple epithelial subsets emerge, the absorptive (Enterocytes) and secretory lineages (goblet, paneth, tuft cells) and migrate up from the crypt to the villi.
Why reincarnation? So far, this all sounds like basic biology: a stem cell proliferates and differentiates into different cell types. What’s new here? This is where it gets interesting. For example, if intestinal stem cells get damaged because of an infection, there are several backup strategies to ensure their functions remain afloat. For instance, there are standby backup stem cells that are not only damage resistant but under homeostasis, they divide very slowly and can revert back to rapid division to fulfill the function of ISCs. The already differentiated cells of the villi can revert back to become stem cells and fulfill this function, a strategy that is subject to lots of debate [5]. What is more exciting is that experimentally, when the gut is irradiated, ISCs are destroyed and the intestinal epithelium undergoes a fetal reversion! Fetal reversion means, the adult gut expresses markers that are only seen in a growing fetus epithelium. The intestinal epithelium becomes young again to facilitate healing! I call this “reincarnation”! If these young cells would speak for themselves, they would say they are carrying the soul of the destroyed adult ISCs! This is where I want you to focus!
Figure 2: Fetal reprogramming of ISCs following infection with H. polygyrus. Studies done both in vivo and in vitro report that upon infection or treatment of organoids with H. polygyrus excretory-secretory products, the markers for adult stem cells are lost and instead are replaced with other stem cells expressing markers only seen in fetal epithelium, reincarnation. The red star signifies inhibition.
Intestinal epithelium infections with Heligmosomoides bakeri (Previously H. polygyrus), have been shown to cause fetal reversion/reincarnation! You may be wondering who is H. bakeri and why should we care?! Heligmosomoides bakeri is a parasitic worm that naturally infects rodents and is the most extensively studied model of helminth infection in humans/livestock. It is the model parasite for human hookworms! Following infection through the fecal-oral route, it occupies a niche in the small intestine where it survives for weeks. It has been associated with fetal reversion phenotype/“reincarnation” [8][9] (Figure 2). But why should we care? Interestingly, the “reincarnation” reprograms the differentiation process of ISCs in favor of the fetal genes, which in turn, display a reduced capacity to generate secretory cell lineages (Figure 3) with direct anti-helminth activity. It was also reported that Type-2 cytokines, important in host clearance of intestinal worms, and excretory-secretory products from H. bakeri counter-regulate the ISCs in vitro using organoids [8][10]. Specifically, Type-2 cytokines prevented H. bakeri-induced “reincarnation” in vivo which subsequently translates to effective clearance of the pathogen. This confirmed that H. bakeri-induced reincarnation is a strategy to evade host immune mechanisms. This particular parasite-induced phenotype is therefore important for the host and parasite to co-survive for long periods since it promotes healing for the host, while also promoting parasite survival.
Figure 3: Intestinal epithelium regeneration under reincarnation: The fetal genes expressing stem cells are capable of giving rise to all the cells of the intestinal epithelium, but there is a suppression in differentiation towards the secretory lineage. The red star signifies inhibition.
If I haven’t convinced you to believe in reincarnation, I believe that we both understand that parasites are evolving interestingly yet peculiar mechanisms to fight the host’s defenses. And who knows in the future, we might seek solace from a parasite to beat aging!
References
[1] S. Koehler et al., “Ascaris suum nutrient uptake and metabolic release, and modulation of host intestinal nutrient transport by excretory-secretory and cuticle antigens in vitro,” Pathogens, vol. 10, no. 11, 2021, doi: 10.3390/pathogens10111419.
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[6] C. Booth, C. S. Potten, C. Booth, and C. S. Potten, “Gut instincts : thoughts on intestinal epithelial stem cells Find the latest version : Gut instincts : thoughts on intestinal epithelial stem cells,” vol. 105, no. 11, pp. 1493–1499, 2000.
[7] N. Barker, “Adult intestinal stem cells: Critical drivers of epithelial homeostasis and regeneration,” Nat. Rev. Mol. Cell Biol., vol. 15, no. 1, pp. 19–33, 2014, doi: 10.1038/nrm3721.
[8] D. Karo-Atar et al., “Helminth-induced reprogramming of the stem cell compartment inhibits type 2 immunity,” J. Exp. Med., vol. 219, no. 9, 2022, doi: 10.1084/jem.20212311.
[9] Y. M. Nusse et al., “Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche,” Nature, vol. 559, no. 7712, pp. 109–113, 2018, doi: 10.1038/s41586-018-0257-1.
[10] C. Drurey et al., “Intestinal epithelial tuft cell induction is negated by a murine helminth and its secreted products,” J. expemental Med., vol. 219, no. 1, 2021.
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