Viruses do not encounter a blank biological landscape when they infect humans. They meet an immune system shaped by thousands of generations of exposure to bacteria, parasites and other viruses, with genetic differences that can influence whether infection remains mild or progresses to life-threatening disease. A study led by researchers at the University of Southern California Dornsife College of Letters, Arts and Sciences and Howard University has traced evolutionary signatures in four immune-related genes and identified rare variants in one of them that were associated with severe COVID-19.
The findings, published in BMC Biology, connect population genetics with clinical infectious-disease research. The investigators examined the evolutionary history of IL-4, TLR2, CCL2 and SLC11A1, genes involved in regulating inflammation and the detection or control of invading pathogens. They then compared genetic variation in these genes with clinical outcomes among nearly 4,000 people in Italy who had tested positive for SARS-CoV-2 through the Italian GEN-COVID study.
The evolutionary analysis used genetic data from more than 2,000 individuals representing African, European and Asian populations. The researchers searched for patterns consistent with natural selection, including differences in allele frequencies between populations and other signatures indicating that particular genetic variants had been favored or removed over time. All four genes showed evidence of evolutionary change, although the patterns differed across regions. That variation suggests that infectious diseases and other environmental pressures have shaped immune responses along distinct population histories.
Natural selection can act on immune genes in complex ways. A variant that improves resistance to one pathogen may increase the risk of excessive inflammation or another disease under different conditions. Immune genes are therefore often subject to balancing pressures rather than a single, universally beneficial genetic solution. The study’s results indicate that the versions of these genes common today may reflect long-term compromises between pathogen defense, inflammatory damage and changing environments.
The researchers also compared modern human sequences with genetic material from Neanderthals and Denisovans, extinct relatives of modern humans. Some shared variants may have been inherited from a common ancestor, while others could reflect interbreeding between ancient modern humans and these archaic populations. Such exchanges introduced genetic material into ancestral human populations tens of thousands of years ago, potentially including immune-related variants that influenced how later generations responded to infectious organisms.
These evolutionary signatures were established long before SARS-CoV-2 appeared. The coronavirus did not create the ancient patterns detected in the four genes; instead, it encountered immune systems already shaped by earlier infectious threats. “SARS-CoV-2, the coronavirus that causes COVID-19, may be new, but the immune system it encountered isn’t,” said Michael Campbell, an associate professor of biological sciences at USC Dornsife and the study’s senior author. The distinction is important because it frames COVID-19 susceptibility as a possible consequence of pre-existing biological variation rather than a response that evolved during the pandemic.
The clinical analysis produced a more recent and specific finding involving TLR2, which encodes Toll-like receptor 2. TLR2 is part of the innate immune system, the body’s rapid first line of defense against infection. It recognizes molecular patterns associated with microbes and activates signaling pathways that stimulate inflammatory responses. Two rare TLR2 variants were identified in the Italian COVID-19 dataset. One occurred more frequently among patients who had previously received organ transplants, while the other was associated with more severe COVID-19.
The transplant-related observation is notable because organ-transplant recipients already face elevated risks from COVID-19. Immunosuppressive medications used to prevent rejection can weaken antiviral defenses, while the underlying medical conditions of recipients may further increase vulnerability. A rare alteration in TLR2 could potentially add another layer of risk by changing pathogen recognition or downstream inflammatory signaling. However, the study does not establish that either variant causes severe disease, and the observed associations may be influenced by sample size, population structure or other clinical factors.
The researchers emphasize that the TLR2 results require replication in larger and more genetically diverse groups. Rare variants are particularly difficult to evaluate because they occur infrequently, meaning that even a study involving thousands of participants may contain only a small number of carriers. Independent cohorts, functional laboratory experiments and mechanistic studies will be needed to determine whether the variants alter TLR2 expression, protein activity or immune signaling during SARS-CoV-2 infection. Broader sampling will also help clarify whether the associations apply beyond the Italian population.
By combining evolutionary genomics with patient data, the study illustrates how ancient genetic history can guide investigations of modern viral disease. Genes shaped by past pathogens may contain clues to why individuals respond differently to the same infection, while rare mutations can reveal additional vulnerabilities that are invisible when researchers focus only on common variation. The authors say that this approach could eventually identify biological pathways useful for predicting disease risk or developing new preventive and therapeutic strategies, although such applications remain a future possibility rather than an immediate clinical outcome.
Subject of Research: People
Article Title: The evolutionary landscape of host immunity genes involved in respiratory and other immune-related diseases, and the identification of TLR2 variation associated with severe COVID-19
News Publication Date: 29-May-2026
Web References: https://doi.org/10.1186/s12915-026-02623-6
References: BMC Biology, DOI: 10.1186/s12915-026-02623-6
Keywords: COVID-19, SARS-CoV-2, TLR2, immune genes, evolutionary genetics, natural selection, rare genetic variants, severe disease, organ transplantation, infectious diseases
Tags: CCL2COVID-19 severitycross-population genetic differences in COVID-19evolutionary signatures in immune genesgenetic basis of immune defense against virusesgenetic factors influencing immune responsegenetic variation and COVID-19 outcomesIL-4immune system geneticsnatural selection in immune-related genespopulation genetics and infectious diseasesrare genetic variants and disease severitySLC11A1 gene analysisTLR2
