A Growing Threat: New Insight Into Deadly Fungal Invasion of the Lungs

The discovery reveals a new target for combating the deadly invader.

Aspergillus and other fungi are so ubiquitous in our environment that we inhale hundreds to thousands of spores daily. Usually, they do not pose a danger to healthy individuals, but can prove fatal to those with weakened immune systems. However, it is becoming increasingly understood that viral infections like influenza or SARS-CoV-2Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the official name of the virus strain that causes coronavirus disease (COVID-19). Previous to this name being adopted, it was commonly referred to as the 2019 novel coronavirus (2019-nCoV), the Wuhan coronavirus, or the Wuhan virus.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>SARS-CoV-2 can even raise the risk of invasive Aspergillus infections even in healthy people.

The World Health Organization (WHO) has warned of the growing danger posed by invasive fungal infections and stressed the need for further research. Until recently, little was understood about the mechanisms behind Aspergillus infections and how to effectively eliminate them. However, a collaboration between researchers at the University of Calgary and McGill University has shed new light on why the immune system fails to fend off the fungus.

“We discovered that influenza and COVID-19First identified in 2019 in Wuhan, China, COVID-19, or Coronavirus disease 2019, (which was originally called "2019 novel coronavirus" or 2019-nCoV) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has spread globally, resulting in the 2019–22 coronavirus pandemic.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>COVID-19 destroy a previously unknown natural immunity that we need to resist invasive fungal infections,” says Nicole Sarden, a Ph.D. candidate at the University of Calgary and first author on the study.

The findings published in Science Translational Medicine show that two types of white blood cells (neutrophils and a unique type of B cells) normally work together to fight fungal infection. However, viruses like SARS-CoV-2 and influenza impede the special B cells from doing their job. Working with mice and human blood and tissue samples, the researchers were able to see that following a viral infection, neutrophils sensed a fungal infection and were gathering nearby, but weren’t acting to destroy the invader as expected. The scientists delved further and learned that viral molecules were rendering these B cells apathetic, preventing them from cooperating with neutrophils as they normally would, and thus protecting the fungi from destruction. Understanding this process led to the next discovery.

“We also found that current therapies exist that could be repurposed in a realistic and meaningful way to replace the natural antibodies not being produced by the virally-damaged B cells and re-establish the neutrophils’ ability to fight these infections,” says Sarden.

“This research was sparked by a young man I cared for in the ICU on life support who died of influenza-associated aspergillosis, where every therapy we tried failed,” says Dr. Bryan Yipp, MD, clinician-researcher at the Cumming School of Medicine and senior author on the study. “Our findings are very timely given the high numbers of patients affected by multiple respiratory viruses including influenza.”

Sarden and Yipp believe these findings will lay the groundwork for new diagnostic tests, based on natural antibody levels to predict who is at the highest risk for invasive fungal infections, and that currently available antibody replacement strategies could be tested to treat Aspergillus infections in future clinical trials.

“These discoveries provide a new understanding of how we can best support the body to fight off deadly fungal infections,” says Yipp.

Reference: “A B1a–natural IgG–neutrophil axis is impaired in viral- and steroid-associated aspergillosis” by Nicole Sarden, Sarthak Sinha, Kyle G. Potts, Erwan Pernet, Carlos H. Hiroki, Mortaza F. Hassanabad, Angela P. Nguyen, Yuefei Lou, Raquel Farias, Brent W. Winston, Amy Bromley, Brendan D. Snarr, Amanda Z. Zucoloto, Graciela Andonegui, Daniel A. Muruve, Braedon McDonald, Donald C. Sheppard, Douglas J. Mahoney, Maziar Divangahi, Nicole Rosin, Jeff Biernaskie and Bryan G. Yipp, 7 December 2022, Science Translational Medicine.
DOI: 10.1126/scitranslmed.abq6682

The study was funded by the Canadian Institutes of Health Research.