Francis Crick Institute researchers learn how fungal invaders disable body's infection-fighting responses
About 20% of all deaths worldwide are due to severe sepsis, the poisoning of the blood by infectious microorganisms. Fungal-induced sepsis, particularly that caused by the yeast Candida albicans, is the most lethal form, accounting for 5% of all microbial sepsis deaths.
About 20% of all deaths worldwide are due to severe sepsis, the poisoning of the blood by infectious microorganisms. Fungal-induced sepsis, particularly that caused by the yeast Candida albicans, is the most lethal form, accounting for 5% of all microbial sepsis deaths.
Now researchers at the Francis Crick Institute in London, with German and Swiss collaboration, have uncovered the mechanisms by which the fungal invaders act on the immune system to disable its infection-fighting responses.
A report on their work appears in Nature Communications Aug. 9.
Role of the spleen
The action centers on the spleen although, as the authors note, most previous studies of invasive candida infection have focused on the kidneys.
The spleen is an important producer of macrophages, a type of large white blood cell that identifies, surrounds and digests foreign substances including microbes, as well as cellular debris produced in the body, a process known as phagocytosis.
Macrophages also play a critical role in the immune system by recruiting other immune cells, such as the lymphocytes known as T cells, to aid in warding off infection.
The macrophages produced in the spleen, especially the MZ (or marginal zone) macrophages, have a special ability to capture and surround fungal pathogens in the blood and lymph system.
Once they have captured the fungal invader, the macrophages send a signal to the T cells to come and help with the destruction of the invader.
The ‘Trojan horse’ effect
Prior to capture by the macrophage, the infecting agent usually has been subjected to a first line of immune defense, the neutrophil extracellular trap (NET). The NET is a network of fibers composed of DNA from neutrophils that binds the pathogen and also releases various antimicrobial proteins.
One of these proteins, known as myeloperoxidase (MPO), helps to reduce sepsis by suppressing the release of the histones that are a byproduct of NET formation.
One of the discoveries by the Crick Institute group and their collaborators is that the capture of large numbers of the invading fungi by the macrophages can act as a sort of Trojan horse, as the authors describe it. The phagocyte receptor on the macrophage neutralizes the infection-fighting oxidant myeloperoxidase and, thus, facilitates release of more histones.
Like the Greek soldiers hidden inside Odysseus's gift to the Trojans, the fungi manage, even in captivity, to do damage directly inside the besieged citadel.
Further, the histones and the fungal filaments, known as hyphae, induce production of cytokines (an immune-signaling protein) in adjacent macrophages, which shorten the lifespan of the mature neutrophils while favoring immature neutrophils that are unable to carry out their anti-infective activity.
Another protein known as granulocyte colony-stimulating factor (G-CSF) plays a role in this dysregulation of the neutrophils.
This newly uncovered activity may play a role in other infections.
The authors note, “Histones and G-CSF regulate this process by selectively targeting mature neutrophils and may be relevant in other conditions, given that alterations in the age of neutrophils influences neutrophil function. The ability of G-CSF to shorten the lifespan of mature neutrophils uncovers a new mechanism for the regulation neutrophil populations through the modulation of lifespan . . .”
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Ioannou, M., Hoving, D., Aramburu, I.V. et al. Microbe capture by splenic macrophages triggers sepsis via T cell-death-dependent neutrophil lifespan shortening. Nature Communications 13, 4658 (2022).
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