“One can compare it to the cruise control of a car that maintains a constant speed but allows a temporary increase or decrease in velocity and then revert to the original speed”, says Ylva Engström, professor in the Department of Molecular Biosciences at Stockholm University and responsible for the new study.

Without an efficient immune defense humans and animals would not survive for long in a world full of pathogens like bacteria, viruses and parasites. However, the immune system is such a powerful weapon that it can damage our own cells and tissues if turned too active. The immune system must therefore be in balance, neither overreacting nor staying too passive. This is of special importance in the gut because of its natural flora of bacteria that should not be attacked by the immune system. At the same time, through our diet, we are exposed to pathogenic bacteria that the immune system must combat.

“If this balance between an active and passive immune system fails, it might lead to serious infections, inflammations, autoimmune diseases and even cancer. Associated autoimmune diseases and inflammatory bowel diseases are major endemic diseases today, and we need to better understand how the immune system works and what goes wrong when it leads to illness”, says Ylva Engström.

The upper left panel shows fruit flies fed with fluorescent bacteria. If the immune response does not function properly, the bacteria can breach the intestinal barrier and spread throughout the fly. The upper right panel highlights the production of Nub-PB (green) and Nub-PD (red) in the fruit fly gut. These act as “gas” and “brake” for the immune system to ensure that pathogens are swiftly cleared while avoiding excessive damage to the fruit fly itself.

Two proteins from the same gene have antagonistic effects on the immune system

By studying the immune system in the intestine of the fruit fly Drosophila melanogaster the researchers discovered a new mechanism used by gut cells to increase or decrease the activation. They found that two variants of the same regulatory protein, Nub-PB and Nub-PD, have opposite effects on the immune system and that the relative level of these two proteins regulates the activity. When the researchers fed fruit flies with pathogenic bacteria, Nub-PB activated the immune system by turning on genes producing agents that recognize and kill microbes. After a period of immune system activation the researchers discovered elevated levels of Nub-PD, inhibiting the effect of Nub-PB. The immune system was shut off and could return to a default state. The ratio between Nub-PB and Nub-PD therefore works as a molecular regulator balancing the activity of the immune system in such a way that it is adapted to the level of infection without giving rise to lethal side effects.

“What makes this system unique is that both Nub-PB and Nub-PD are produced from the same gene. In other words the gene codes for the “gas and brake function” simultaneously, which is used to regulate the power of the immune system” says Ylva Engström.

In an earlier study, the Engström group showed that the immune system was constantly turned on in fruit flies lacking Nub-PD (the “brake function”). This leads to a drastic change in the intestinal flora and shorter life span of these flies. In the current study the researchers used flies with boosted “gas-function” by genetically increasing the level of Nub-PB. These flies got severe gut inflammation. Moreover, the flies were extremely sensitive towards infections and were killed when fed with relatively harmless bacteria. This was not due to the fact that the bacteria multiplied, on contrary the bacteria were killed efficiently by the activated immune defense. However, the hyper-activation led to extremely elevated levels of toxic substances which had a drastic effect on the whole organism, which collapsed and died within 24 hours.

“This indicates how potent and lethal a hyper-activated immune system can be and how essential the balancing mechanisms are”, says Ylva Engström.

The gene is also present in humans

The gene for Nub-PB and Nub-PD can also be found in mice and humans where it is called Oct1 (or POU2F1). It regulates many functions, including protection against cellular stress reactions. Like its counterpart in fruit flies, the human Oct1 gene produces several different protein variants. However, it is unknown whether these variants have the same balancing effects on stress and immune reactions in man. Further studies on human Oct1 and its variants are an important task for the future.

“The fact that molecular regulators with gas and brake functions directs essential processes gives us new insight into how evolution have solved an important problem, namely how such processes can be balanced and fine-tuned by single genes. It gives us new opportunities to look for similar regulators balancing other types of cellular processes and allows us to use new ways to tackle disorders where the balance is not working properly”, says Ylva Engström.

From left: Priya Gohel, Bo Lindberg, Xiongzhuo Tang, Ylva Engström, Shiva Seyedoleslami Esfahani, Yunpo Zhao Missing: Widad Dantoft, Jessica Lindvall


“Nubbin isoform antagonism governs Drosophila intestinal immune homeostasis”
Bo G Lindberg, Xiongzhuo Tang, Widad Dantoft, Priya Gohel, Shiva Seyedoleslami Esfahani, Jessica M Lindvall, Ylva Engström PLOS Pathogens. Published online March 2nd,  2018


Ylva Engström, PhD, Professor
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University
SE-106 91 Stockholm
Phone: +46 8 16 41 66
E-mail: ylva.engstrom@su.se