More than six years after the COVID-19 pandemic began, scientists have uncovered a previously unknown mechanism that may explain why some infections develop into severe, life-threatening illness.
Researchers at La Trobe University have identified a new pathway that enables SARS-CoV-2, the virus responsible for COVID-19, to infiltrate immune cells and trigger an excessive inflammatory response that can cause significant damage to lung tissue.
The findings provide fresh insight into one of the biggest unanswered questions surrounding the disease—how the virus infects immune cells that are not typically considered primary targets of infection—and could pave the way for more effective treatments for severe COVID-19 and potentially other respiratory viruses.
Virus Uses Dying Cells to Evade Immune Defences
According to the study, SARS-CoV-2 is capable of hiding inside fragments of infected cells that are naturally broken down as part of the body’s normal cellular cleanup process.
These fragments are then consumed by specialised immune cells known as macrophages, whose primary role is to remove dead cells, debris and invading pathogens.
Rather than being destroyed, however, the virus survives inside these cellular fragments and gains entry into the macrophages as they perform their routine cleaning function.
Once inside, the virus can spread to additional immune cells and activate an intense inflammatory response that contributes to lung injury and severe COVID-19.
Researchers believe this mechanism helps explain why some patients experience overwhelming inflammation despite the immune system’s efforts to eliminate the infection.
Discovery Solves Long-Standing Scientific Puzzle
The research was led by Dr. Kha Phan, an Emerging Leadership Fellow at the La Trobe Institute for Molecular Science.
Phan said the team had identified what appears to be an entirely new route through which the virus spreads inside the body.
According to him, macrophages respond by launching powerful defence mechanisms once infected, but those same responses can become excessive and harmful.
Instead of protecting the lungs, the heightened immune reaction can fuel widespread inflammation that damages healthy tissue and contributes to the severe respiratory complications seen in critically ill COVID-19 patients.
Phan described the findings as a significant advance in understanding how SARS-CoV-2 causes serious disease.
“This fundamentally shifts the way we think about viral infections and solves a long-standing puzzle about how COVID-19 infects immune cells and drives severe inflammation,” he said.
Potential to Improve COVID-19 Treatments
Researchers believe the discovery could influence future treatment strategies by allowing doctors to target the inflammatory process earlier in the course of infection.
By identifying the biological pathway responsible for triggering excessive immune responses, scientists may be able to develop therapies that reduce inflammation before it progresses to severe lung damage.
Phan said reducing the intensity of the body’s inflammatory response during the early stages of infection could also lower the risk of prolonged health complications associated with long COVID.
The findings could therefore contribute not only to improving survival in severe cases but also to reducing the long-term health burden experienced by many COVID-19 survivors.
Implications Extend Beyond COVID-19
Scientists say the newly identified pathway may not be unique to SARS-CoV-2.
Other respiratory viruses—including influenza and respiratory syncytial virus (RSV)—produce similar inflammatory responses, raising the possibility that they may exploit comparable mechanisms to infect immune cells.
If confirmed through future research, the discovery could have implications far beyond COVID-19.
According to the World Health Organization (WHO), seasonal influenza is responsible for up to 650,000 deaths globally each year, while COVID-19 has caused more than seven million reported deaths since it emerged in late 2019.
Researchers say understanding these hidden transmission pathways could lead to broader antiviral therapies capable of treating multiple respiratory infections.
Experts Highlight Importance for Future Pandemic Preparedness
Independent experts have welcomed the findings while emphasising the need for continued research into emerging respiratory viruses.
Associate Professor Stuart Turville, a molecular virologist at the Kirby Institute at the University of New South Wales (UNSW), described the research as an important contribution to understanding how coronaviruses affect the lungs.
He noted that the study examined an earlier strain of SARS-CoV-2 rather than the variants currently circulating, many of which are more likely to infect the upper respiratory tract.
Even so, Turville said the discovery remains highly relevant because it improves scientists’ understanding of coronavirus biology and could strengthen preparations for future outbreaks.
He warned against reducing scientific investment simply because the immediate crisis has subsided.
According to Turville, future respiratory viruses—whether coronaviruses or entirely different pathogens—may possess similar characteristics, making continued research essential for improving global pandemic preparedness.
The study adds another important piece to the evolving scientific understanding of COVID-19 and highlights that, years after the pandemic first emerged, researchers continue to uncover new mechanisms that could shape future treatments, improve patient outcomes and strengthen responses to future public health emergencies.
