Scientists from A*STAR’s Singapore Immunology Network (SIgN) and the Institute of Medical Biology (IMB) say they may have discovered a unique way to help protect us against infections by using evolved fungal pathogens.

The research team led by SIgN’s principal investigator, Norman Pavelka, Ph.D., found that the immune system of an animal subject was boosted when an evolved version of the fungal pathogen Candida albicans was introduced into its gut. The results of the study (“Experimental evolution of a fungal pathogen into a gut symbiont“) were published in Science and a series of patents have been filed for the method of evolving microbes within the gut of animals.

“Gut microbes live in symbiosis with their hosts, but how mutualistic animal-microbe interactions emerge is not understood. By adaptively evolving the fungal pathogen Candida albicans in the mouse gastrointestinal tract, we selected strains that not only had lost their main virulence program but also protected their new hosts against a variety of systemic infections. This protection was independent of adaptive immunity, arose as early as a single day postpriming, was dependent on increased innate cytokine responses, and was thus reminiscent of “trained immunity,” write the investigators.

“Because both the microbe and its new host gain some advantages from their interaction, this experimental system might allow direct study of the evolutionary forces that govern the emergence of mutualism between a mammal and a fungus.

C. albicans
Left: Unevolved C. albicans strains with the ability to transform into hyphae and become infectious
Right: Gut evolved C. albicans strains that have lost the ability to transform into hyphae. [Agency for Science, Technology and Research (A*STAR)]
The study aimed to discover how microbes, which are naturally found within the gastrointestinal tract, interact with the body to form the gut ecosystem. The study also sought to discover if the body’s natural defenses play a part in selecting microbes that are beneficial to it.

The method developed by the researchers for evolving microbes within the gut of animals involves introducing a fungus, in this case, C. albicans, into the gut of laboratory animals such as mice. The fungal pathogen’s evolution is then facilitated through a series of fecal transplants from host to host. Using this method, researchers studied how C. albicans evolved in dozens of parallel experiments. This would ensure that the results were reliable and could be replicated.

When the evolved C. albicans strains were studied, researchers found that all the different evolution experiments yielded strains that were hardier in the gut ecosystem in comparison to the starter cultures. This proved that the evolved C. albicans strains gained a fitness advantage over the original strain. Moreover, all gut-evolved strains were also found to have lost their ability to cause infections to laboratory mice.

Thus, evolution in the animals’ gut selected for C. albicans strains that no longer caused harm to their host, like well-behaved gut commensals.

The scientists then sought to test if animals colonized in their gut by evolved C. albicans strains gained any benefit from the fungus. To do so, researchers introduced one of several bacterial or fungal infections to laboratory mice.

When mice were previously colonized in their gut (or systemically vaccinated) with one of the gut-evolved C. albicans strains, they survived subsequent infections much better than mice colonized or vaccinated with either control or no C. albicans strains. When tested, it was found that the innate immune systems of the mice treated with the evolved C. albicans were stronger and showed signs of “trained immunity,” which means that the body’s immune system responds more vigorously to situations such as infections because it has previously encountered a “training” stimulus.

“The results clearly show a mutually beneficial relationship between the host and the evolved C. albicans strains,” said Dr. Pavelka. “This is extremely exciting as it shows that introducing these mutually beneficial microbes to the body possibly boosts the body’s resistance to infectious diseases. This opens up many new avenues regarding how we could potentially fight and control these diseases.”

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