Ancient Immune Gene Variants May Help Explain Why Some COVID-19 Patients Get Sicker

A study published in BMC Biology starts from a simple premise: when a virus enters a person, it meets an immune system that took thousands of years to build. Researchers at the USC Dornsife College of Letters, Arts and Sciences and Howard University, working with colleagues at Yale and Columbia, set out to read that history in the DNA of people alive today, and then to ask whether it could help explain why COVID-19 hits some people harder than others.

The team focused on four genes that help regulate the body's immune response: IL-4, TLR2, CCL2 and SLC11A1. All four had previously been linked to respiratory or inflammatory diseases. Using genetic data from more than 2,000 people representing populations in Africa, Europe and Asia, the researchers looked for signs that evolution had favored particular versions of these genes, leaving lasting marks in the human genome.

They found such evidence for all four genes. But the pattern was not uniform. Different versions of the genes were more common in different populations, which suggests that infectious diseases and other environmental pressures shaped human evolution differently around the world.

Some of the variants also turned up in the DNA of Neanderthals or Denisovans, extinct human relatives that lived tens of thousands of years ago. In some cases, the overlap likely reflects DNA inherited from a shared ancestor. In others, it points to ancient interbreeding between early modern humans and these relatives.

Michael Campbell, associate professor of biological sciences at USC Dornsife and the study's senior author, stressed that none of this was a response to the coronavirus. "The signals we found weren't created by COVID-19," he said, describing them as reflections of much older pressures, probably from infectious diseases that ancestors faced over thousands of years. SARS-CoV-2 may be new, he said, but the immune system it encountered is not.

The second part of the study turned to the present. Using genetic and clinical information from nearly 4,000 people in Italy who had tested positive for COVID-19, drawn from the Italian GEN-COVID study, the researchers searched for links between these genes and severe illness. They identified two rare changes in TLR2. One appeared more often in COVID-19 patients who had previously received an organ transplant than in other patients. The other was associated with more severe forms of the disease.

Unlike the common variants shaped over millennia, these two TLR2 changes are rare and appear to be much more recent mutations. Because transplant recipients are already known to face a higher risk of severe COVID-19, the finding hints that a TLR2 variant could be one factor in that elevated risk. The researchers say more work is needed to establish whether that is so.

They are careful about the COVID-19 results overall. The associations will need to be confirmed in larger, independent populations and validated through laboratory studies. They also call for more genetically diverse populations in future research, so that disease risk can be understood worldwide, not just in one group.

Campbell argues that tracing this history could eventually point toward biological pathways that inform strategies for prevention and treatment. For now, the next steps are replication in other cohorts and experiments in the lab.