Influenza and Candida albicans: the same interleukin antagonist implicated in both infections

The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that play a central role in the regulation of immune and inflammatory responses. They are involved in infection and immune-mediated diseases such as arthritis, asthma, inflammatory bowel disease, multiple sclerosis, and psoriasis. The IL-1 family members IL-1α and IL-1β are the most studied ones because they were discovered first and they have strong pro-inflammatory effects. These molecules have a natural antagonist IL-1Ra (IL-1 receptor antagonist). The two following studies focused on this molecule, the endogenous inhibitor that competes for occupancy of the IL-1 receptor but does not trigger downstream signalling. Several isoforms exist, intracellular IL-1Ra is constitutively expressed in epithelial cells whereas secreted and intracellular isoforms may be induced in diverse leukocyte subsets in response to pro-inflammatory cytokines, microbial products, or tissue injury. In the following two studies, this molecule was shown to be key during the immune response to respiratory influenza infection and candidiasis.

The Influenza study at Harvard Medical School:

Pathogenic respiratory viruses, such as influenza, remain a major global health problem due to lung injury and respiratory failure. The immune response that fights respiratory viruses can also cause lung damage. Thus, the innate immune response to influenza has both positive and negative effects; it helps control the virus at first, but can also lead to severe illness and death later on. Regulatory T cells suppress immune and inflammatory responses and are very sensitive to respiratory viral infection. However, the influence of regulatory T-cell functions on the outcome of respiratory viral infection remains unclear. This study, conducted at Harvard Medical School, investigates how regulatory T cells modulate adaptive and innate immunity during the early immune response to influenza. Conditional KO mice for IL-1Ra, generated in the laboratory of GCIR member Professor Cem Gabay at the Geneva Faculty of Medicine, were infected with influenza. The authors showed that total genetic deletion of IL-1Ra dramatically increases influenza mortality, while selective deletion of IL-1Ra in regulatory T cells improves survival. The results show that the timing, location and cellular source of IL-1Ra are important in modulating the host response to flu infection. 

Article: Griffith, J.W., Faustino, L.D., Cottrell, V.I. et al. Regulatory T cell-derived IL-1Ra suppresses the innate response to respiratory viral infection. Nat Immunol (2023). https://doi.org/10.1038/s41590-023-01655-2

The Candida albicans study at the University of Bern:

The fungus Candida albicans is part of the human microbiome. In most individuals, C. albicans resides as a harmless, lifelong commensal. However, under certain circumstances, C. albicans can cause infections ranging from superficial skin to life-threatening systemic infections. This is the case for people with immunosuppression due to haematological malignancies, organ transplantation, AIDS, or prolonged hospitalisation in intensive care.

To study the susceptibility to invasive candidiasis, Stefan Freigang's group at the University of Bern investigated IL-1Ra levels produced by specific cell types involved in antifungal immunity. Furthermore, his group showed that IL-1Ra secreted by macrophages prevented effective pathogen clearance. Instead, when they selectively removed it, there was protection from lethal C. albicans sepsis. In addition, they found that IL-1Ra secreted by macrophages was positively regulated by type I interferon, reflecting the association between secondary invasive candidiasis and preceding viral infections. Their results provide a mechanistic explanation for the elevated susceptibility to Candida infection in the bloodstream and suggest IL-1Ra-targeted therapies as a novel therapeutic approach.

Article: Gander-Bui et al., 2023, Immunity 56, 1743–1760 https://doi.org/10.1016/j.immuni.2023.06.023

Summary in French: https://www.unige.ch/medecine/faculteetcite/media/grippe-candida-albicans-un-meme-mecanisme-inflammatoire-identifie

News