Many people do not become infected despite close contact with respiratory viruses, including SARS-CoV-2. This resistance can be attributed to the activation of innate immunity, which provides early protection against infection. However, the exact mechanisms of innate immune defense are not fully understood, as they are difficult to isolate due to the influence of adaptive immunity. To study these mechanisms, researchers need to examine individuals who had close contact with the virus but did not become infected, as confirmed by PCR and antibody tests.
Researchers from Imperial College London conducted such a study involving unvaccinated individuals living with SARS-CoV-2-infected persons. Blood samples and nasal swabs were collected from participants on days 4, 7, 14, and 28 post-exposure to examine their immune responses. The study revealed that early activation of IFN-related genes correlates with protection against infection. The early innate immune response may play a key role in preventing disease.
Research in Three Independent Cohorts
The scientists analyzed gene activity in individuals infected with COVID-19 and healthy controls. They identified 66 of the most active genes in the early days of infection, along with one suppressed gene, PI3. After a week, only 20 genes remained active, with key pathways linked to type I interferon and antiviral responses.
Through an additional analysis (CTV) and data integration, researchers identified 96 genes characteristic of early COVID-19. These genes help distinguish early stages of infection from later stages or the absence of disease. Genes associated with early COVID-19 were linked to antiviral defense and viral replication suppression, with a predominance of type I IFN-related genes. The expression of these genes correlated with viral load.
Next, the researchers compared gene activity between healthy controls and those exposed to infected individuals who did not contract COVID-19. Initially, no significant differences in gene expression were observed. After a week, increased expression was detected in only one gene—IFI27—in those who had contact with infected persons but did not contract the virus.
CTV analysis revealed an additional 111 genes with increased activity in uninfected patients. Some of these genes were associated with suppressing viral replication. Five were linked to early SARS-CoV-2 infection. A small group of uninfected individuals showed increased gene activity related to innate immune activation.
Uninfected individuals exhibited high expression of 96 early-infection genes. These participants demonstrated a similar antiviral response to infected individuals, potentially explaining their resistance to infection despite close contact with the virus.
Researchers confirmed that the short-term activation of early-infection genes in PCR-negative participants reflects their ability to contain viral infections effectively. This part of the study analyzed data from healthcare workers and volunteers experimentally exposed to SARS-CoV-2. Of the 96 early-infection genes, 89 were available for analysis. Among these, 81 genes showed elevated expression in PCR-positive healthcare workers compared to PCR-negative ones. Similarly, 81 genes exhibited higher expression in experimentally infected volunteers in PCR-positive individuals. The PI3 gene was significantly elevated in all PCR-negative participants.
The findings confirmed that IFN-related gene activation characterizes resistance to infection. Unlike PCR-negative participants, PCR-positive individuals did not exhibit increased gene activity within 6 hours to 3 days post-infection. Only after 3 days did the genes become active, with sustained expression levels thereafter. Early-infection gene expression in PCR-positive individuals was significantly higher than in early samples from PCR-negative individuals.
The diagram illustrates the dynamics of viral load and early-infection gene expression. The blue line represents those who remained uninfected, while the red line represents those who became infected. Solid lines denote typical gene expression, and dashed lines indicate viral load. The horizontal dashed line marks the detection limit for measuring viral load. Rapid increases in IFN-related gene expression are sufficient to limit viral load to undetectable levels. Conversely, slower gene expression fails to suppress viral replication quickly, resulting in exponential increases in both expression and viral load.
Source of the Diagram: https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(24)00511-5/fulltext
Conclusion
Newly infected individuals exhibit increased activity of IFN-related genes, confirmed across three independent cohorts: household contacts, healthcare workers, and SARS-CoV-2-infected volunteers. Early-infection genes activate less intensely among PCR-negative contacts at high risk of infection than in PCR-positive individuals.
Short-term increases in IFN-related gene expression within 6 hours post-infection may suppress viral replication and prevent infection. In PCR-positive participants, gene activation occurs only after 3 days, when viral load is already high.
This discovery could be used to develop prophylactic and therapeutic strategies that stimulate innate antiviral pathways in individuals at high risk of SARS-CoV-2 infection and other respiratory viruses.