The Astute White Blood Cell Defense

Neutrophils, the most prevalent kind of white blood cell, are able to block Candida albicans toxin, according to study from Umeå University. EMBO Reports has published the findings.

The Astute White Blood Cell Defense
Constantin Urban, Professor at the Department of Clinical Microbiology and Umeå Centre of Microbiology at Umeå university. Enhet: Immunologi, Avdelningen för infektion och immunologi. Image Credit: Mattias Pettersson, Simon Jönsson, Lizette Gunnesson, simon ohman jonsson inhousebyran

We were very surprised to see that neutrophils remained functional in the presence of candidalysin for such a long time. We found that when exposed to the toxin of the fungal pathogen, neutrophils trigger processes to release a chromatin meshwork which entangles and restrains Candida albicans hyphae.

Constantin Urban, Study Supervising Investigator and Professor, Immunology, Department of Clinical Microbiology, Umeå university

Systemic infections produced by bacterial and fungal species commonly result in sepsis, a significant cause of death in critically ill patients and hence considered a worldwide problem.

According to the World Health Organization, sepsis affects more than 30 million people globally each year, with an estimated six million fatal cases. C. albicans is the most prevalent human fungal infection and the leading cause of invasive candidiasis, which can lead to sepsis.

The ability of C. albicans to transition reversibly from yeast forms to filamentous forms, hyphae, is a defining feature of its pathogenicity. The organism employs the yeast form to quickly grow biomass and the hyphae form to penetrate and destroy tissue.

While C. albicans colonizes a huge part of the world's population from birth, people with a compromised immune system due to disease or medical intervention are in danger of developing serious or even life-threatening infections, including sepsis, caused by this fungus pathogen. Neutrophils, the most prevalent white blood cell, play a critical role in the defense against fungal infections.

The new study gives information on how neutrophils react to Candida albicans hyphae, which emit a peptide toxin called candidalysin. Notably, candidalysin is only released when Candida albicans develops as a hypha, and hence during invasive growth.

The scientists discovered that neutrophils activated cellular pathways that resulted in the release of neutrophil extracellular traps (NETs). These chromatin fibers are powerful anti-hyphae weapons.

With the aid of an enormous amount of sticky and antibacterial proteins found inside the structures, NETs can entrap and suppress the fungus. NET proteins’ sticky nature readily binds microorganisms such as fungal cells. The accompanying antimicrobial NET proteins then assault the entangled fungus.

Urban stated, “We were very surprised to see that neutrophils remained functional in the presence of candidalysin for such a long time. The immune cells continued to produce antimicrobial oxidants and continued to engulf fungal cells.

NET production was essentially nonexistent when neutrophils were infected with transgenic strains of Candida albicans lacking candidalysin.

Interestingly, candidalysin alone was not a sufficient stimulus to induce NET formation. It resulted in a more compact, less fibrous chromatin meshwork released by neutrophils, so-called NET-like structures, whereas only the combination of candidalysin exposure to and pattern recognition of C. albicans cells by neutrophils resulted in release of fibrous NETs.

Lucas Unger, Lead Experimental Researcher and Research Assistant, Department of Clinical Microbiology, Umeå University

According to the findings, candidalysin primarily contributes to chromatin swelling - an early stage in the release of extracellular DNA structures—via calcium-dependent activation. Calcium ions are permitted to enter cells via effects on neutrophil membranes, allowing these activation steps to begin.

When neutrophil receptor molecules recognize fungal cells, they activate kinases and produce antimicrobial oxidants. Calcium influx, kinase activation, and oxidant generation all work together to cause the release of huge numbers of NETs.

This study would not have been feasible without the active participation of international partners in Gothenburg, Sweden, Bristol and London, United Kingdom, and Jena and Berlin, Germany.

Urban concluded, “We are particularly grateful to clinicians from the Charité hospital in Berlin that allowed us access to neutrophils from patients with chronic granulomatous disease. The immunodeficiency renders neutrophils unable to produce antimicrobial oxidants and with the help of these we could thoroughly address the involvement of oxidants in candidalysin-triggered processes.

Source:
Journal reference:

Unger, L., et al. (2023). Candida albicans induces neutrophil extracellular traps and leucotoxic hypercitrullination via candidalysin. EMBO Reports. doi.org/10.15252/embr.202357571

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