A new player in the game of memory in innate immune cells

Innate immune cells cache memories of previous infections, recognizing both pathogens and danger signals. A new study demonstrates that Heme, a danger molecule, can induce memory and have long-lasting effects on the immune response.

In 1921, when tuberculosis ravaged the world, the first human was inoculated with the bacille Calmette-Guérin vaccine. Tuberculosis vaccination gained momentum and as a consequence children mortality was dramatically reduced. Revisiting this century-old vaccine has recently shifted the way scientists think about immunological memory. Data from tuberculosis vaccination across the decades revealed that not only tuberculosis mortality decreased but also respiratory infections in general. The protection given by the vaccine turned out to be much less specific than expected.

Our immune system consists of two interacting components: the innate and the adaptive immunity. For a long time, only the adaptive component was thought to develop a memory of previous infections. It remembers a small part of each invader, the antigen, and produces specific antibodies against it, preparing our body for subsequent infections. Innate responses, in turn, were seen as a broader first line of defence, that acted fast and lacked memory. If only 5% of all species on earth, including humans, have this two-component response, it means that the remaining 95% have to fight with nothing but innate responses. Two decades of studies now point out that their immune system can be ‘primed’ by an initial infection, conferring protection against reinfection. As it turns out, innate cells do remember.

This type of memory, coined as trained immunity, has been widely studied from the perspective of pathogens that invade our body. It was first shown for the tuberculosis vaccine and helped explain its broad protection effects, beyond tuberculosis itself. Pathogen signals work by stimulating innate cells and inducing memory, shifting the way they read genetic information and their overall metabolism, priming them to face the next infection. “But it’s not just the molecules that come from pathogens that can provide memory to the innate immune system. Damage signals also have this capacity”, says Elisa Jentho, a postdoctoral researcher at the Instituto Gulbenkian de Ciência.

In a recent study published in the journal PNAS, Elisa and her colleagues discovered that Heme is an important new molecular player in this game. Heme is a danger molecule that exists in all our cells and is usually strictly controlled to remain inside them. But the moment our cells get damage, it can get released. The results of this study now show that Heme exposure is memorized by innate immune cells. “Heme is special when compared to other damage-associated molecules, or alarmins. It can be cleared from the cells and reused somewhere else, instead of staying there like other alarmins do. This study is the first time we can show that an alarmin is actually inducing trained immunity”, Elisa highlights.

The first evidence supporting the idea that cells might remember Heme came from the inside of cell culture flasks. According to Elisa, “the starting point is to isolate monocytes, which are a type of white blood cell from the innate immune system. Then you stimulate these cells with Heme and 24 hours later you wash it away. The cells then return to a resting state. After a few days, you restimulate the cells with an inflammation-inducing agent and monitor their responsiveness. If they respond more than the control conditions, that tells us we induced Heme-trained immunity.”

But the pressing question was: what are the consequences of this inside an actual living organism? When done in mice, Heme-training affects blood cell development (hematopoiesis), increasing the number of stem cells that give rise to cells of the innate immune system. “These changes in the hematopoiesis correspond to changes in the way the genetic information is organized within cells. When we isolated the nuclei of single blood cells, we saw that these past Heme stimuli lead to long-lasting modifications in the part of our DNA that is accessible, known as the open chromatin structure. These changes are very similar to what happens in cultured cells”, Elisa describes.

Such core cellular modifications seem to lead not only to the development of more immune cells, but also to changes in the way an organism survives sepsis, a clinical syndrome that occurs when an infection triggers a whole-body extreme response. Elisa adds that “the direction of these changes depends greatly on when sepsis occurs. When the infection was induced seven days after the Heme treatment, we find that the modifications on stem cells are in very low amount, but the mice survive better. Inversely, when we do this experiment 28 days after the Heme stimulus the mice succumb more to sepsis.”

“Heme is another molecular basis of how trained immunity may work, a new piece of the game. It may explain for example the long impact septic patients have on their health after they are cured. They are known to have more infections later on. Not only more, but infections with different dynamics. And in sepsis we have a lot of release of Heme. But where we are at the moment is only the bottom basis”, Elisa remarks.

The study was initiated at the group of Sebastian Weis at the Jena University Hospital, Germany and also a former IGC postdoc, where Elisa did her PhD. It was performed in close collaboration with, the group of Hendrik Stunnenberg at the Prinses Máxima Centrum Utrecht as well as the group led by Miguel Soares at IGC, and several others. Funding was granted by German Ministry of Education and Research (BMBF No. 01EO1502), the Deutsche Forschungsgemeinschaft (DFG) Grant GRK 1715/2, DFG under Germanýs Excellence Strategy—EXC 2051, DFG Project No. WE 4971/6-1,BMBF Project No. 01EN2001, DFG (SFB/TRR 127, Project A3), an National Health and Medical Research Council (NHMRC) (Australia) Investigator Grant (No. 1173314), DFG FOR 1738 a European Research Council Advanced Grant (No. 833247), a Spinoza Grant of the Netherlands Organization for Scientific Research, the Italian National Operational Programme on Research 2014 to 2020 (PON AIM 1859703-2): PON Ricerca e Innovazione 2014 to 2020—Azione I.2—D.D. n.407, 27.02.2018 “Attraction and International Mobility”—Line 2 (Researchers Attraction), the European Union’s Horizon 2020 Skłodowska-Curie Actions (Project AiPBAND) under Grant No. 76428, the Princess Maxima Center and a ZonMW Grant No. 91216061.


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