Human neutrophils release extracellular RNA that modulates Aspergillus fumigatus gene expression across kingdoms.
This study demonstrates that human neutrophils release a diverse repertoire of extracellular RNAs, including specific miRNAs and tRNA-derived fragments, which can cross kingdoms to directly modulate gene expression in the fungal pathogen *Aspergillus fumigatus* as part of an intrinsic antifungal defense mechanism.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer
The human body is constantly under siege by microscopic invaders, from bacteria to fungi, yet a healthy immune system usually keeps them at bay. Among the immune system's most rapid responders are neutrophils, a type of white blood cell that acts as a first line of defense. When these cells encounter a threat, they do not just engulf and destroy it; they also release a complex soup of molecules into the surrounding space to coordinate a broader attack. For decades, scientists have known that cells can communicate using chemical signals, but a more recent and surprising discovery has revealed that they also use genetic instructions carried by tiny RNA molecules. These RNA fragments can travel between different species, acting as a form of cross-kingdom messaging where a host cell might send a genetic command to a pathogen to shut down its ability to cause harm. This concept challenges the old view that RNA is strictly an internal cellular tool, suggesting instead that it can function as a weapon or a signal that travels outside the cell to influence the behavior of entirely different organisms.
In a new study, researchers investigated whether human neutrophils use this RNA messaging system to fight Aspergillus fumigatus, a common mold that can cause severe, life-threatening infections in people with weakened immune systems. The team started by collecting blood from healthy volunteers and isolating their neutrophils. They then exposed these cells to the fungal spores in a laboratory setting to see what the immune cells released in response. Using advanced sequencing techniques, they analyzed the genetic material floating in the liquid surrounding the cells. They found a diverse mixture of RNA, including fragments derived from transfer RNA and ribosomal RNA, but they noticed a particularly strong presence of a specific family of small RNA molecules known as the Let-7 family. These molecules are known to be effective at silencing genes, and the researchers suspected that the neutrophils were releasing them to target the fungus directly.
To test this idea, the scientists took the liquid containing these released RNA molecules and applied it to growing fungal hyphae in a dish. They focused on a specific gene in the fungus called metE, which they had predicted would be a target for the human Let-7 RNA based on its genetic sequence. When the fungus was exposed to the neutrophil secretions, the levels of the metE message dropped significantly, suggesting that the human RNA was successfully entering the fungal cells and blocking the production of that specific protein. The researchers then checked if the fungus needed its own internal machinery to receive this message. They used a strain of the fungus that lacked its own RNA-silencing proteins, expecting that without these internal tools, the human RNA would have no effect. Surprisingly, the human RNA still silenced the fungal gene even in the absence of the fungus's own machinery, indicating that the human molecules might be acting directly or using a different, unknown pathway to get the job done.
To confirm that the effect was truly due to the specific match between the human RNA and the fungal gene, the team created a version of the fungus where the target site for the human RNA was slightly altered. When they treated this modified fungus with the same neutrophil secretions, the silencing effect disappeared. The fungal gene remained active, proving that the human RNA was indeed targeting that specific sequence to shut it down. The study also revealed that the neutrophils maintained this antimicrobial RNA environment regardless of whether they were currently fighting an infection or not, suggesting a constant state of readiness. While the researchers noted that the effect varied slightly between different human donors, the core finding remained consistent: human immune cells release RNA that can cross the species barrier and directly alter the gene expression of a dangerous fungal pathogen. This discovery opens a new window into how our bodies defend themselves, showing that the battle against infection involves a sophisticated exchange of genetic information that goes far beyond simple physical attacks.
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