After cells die, they leave a residue that sends messages to other cells in ways that are valuable to the immune system. But this process can also be hijacked by viruses such as influenza, according to new research published in Nature Communications.

Cells are known to signal to immune cells to clean up their remains after death, but the current findings open a new window on the process of cell death and renewal, with eventual implications for viral transmission and potential drug development, researchers noted. 

A team of researchers at La Trobe University, Melbourne, Australia, identified what they called the “footprint of death” when performing time-lapse confocal microscopy of cell death (apoptosis).

“Cells can continue to have impacts on our health even after they die,” lead author Stephanie F. Rutter said in an interview. “Every day, billions of cells die via apoptosis, so understanding what happens to them after death is a key way we can better fight disease and keep our bodies healthy,” said Rutter, a PhD candidate at La Trobe University.

The footprint of death (also referred to as FOOD in the study) may help guide the immune cells to the exact spot to clear away cell remains, she said.

Apoptotic cell-derived extracellular vesicles (ApoEVs) can host DNA, RNA, proteins, and pathogens, the researchers noted. The release of ApoEVs by dying cells has been shown to aid in cell clearance and tissue regeneration, but this same mechanism could facilitate the spread of a virus, thanks to the footprint of death, the researchers found. Their study of cell death included a model examination of cells infected with influenza A to see whether the vesicles generated by the FOOD would contribute to viral spread.

The footprints contain adhesive proteins, including F-actin, and the researchers found that when immune cells (macrophages) absorbed the footprints and their proteins from influenza A-infected cells, they were able to hijack complete viral particles and spread the infection more easily.

“We discovered that viruses could hide within the membranes of this footprint, and when our immune cells try to clear it away, the virus is capable of infecting those cells that are trying to protect us,” Rutter explained.

Looking ahead, the researchers want to explore how viruses hijack the disassembly of apoptotic cells to see what else they might be manipulating and how cell activity can affect health during viral infections. “If we can get a better picture of the changes they are making, then we can start developing therapies to fight back,” Rutter said.

Ultimate Implications for Wound Healing and Treatment Response

The current study provides a deeper understanding of the role of phagocytes in the process of apoptosis, said Shirin Mazumder, MD, an infectious diseases specialist and an associate professor at The University of Tennessee Health Science Center, Memphis, Tennessee, in an interview.

“Since apoptosis results in more than 200 billion cells dying on a daily basis, the understanding of how cell clearance occurs is critical on the cellular level,” said Mazumder, who was not involved in the research. “Substrate-bound extracellular vesicles, or the ‘footprint of death,’ contribute to this process by producing signals to flag the site of cell death to aid in efferocytosis,” Mazumder said.

This research has the potential for clinical applications in several areas of medicine, notably wound healing and immune signaling, said Mazumder. “The extracellular vesicles have the potential to serve as biomarkers, which may be used for tissue damage and possibly to assess the response to cancer treatment,” she said.

However, the study of the “footprint of death” is still in the very early stages, Mazumder told Medscape Medical News. More research is needed to understand the functional impact and how this will translate to clinical medicine, she said.

The study was supported by a La Trobe University Postgraduate scholarship to Rutter and by grants to coauthors from the National Health and Medical Research Council, the Australian Research Council, the Jack Brockhoff Foundation, and the L’Oreal-UNESCO For Women in Science. The researchers disclosed having no financial conflicts of interest.

Mazumder disclosed having no financial conflicts of interest.