TLR7 signaling is induced by endocytosed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) single-stranded RNA (ssRNA) motifs. Downstream effects are transduced by the adapter MyD88, associating kinases IRAK1 and IRAK4, and ubiquitin ligases TRAF3 and TRAF6. This is followed by activation ofinterferon regulatory factor 7 (encoded by IRF7, OMIM 605047), which translocates to the nucleus to induce transcription of type I interferon (including interferon beta 1 [IFNB1, OMIM 147640] and interferon-stimulated genes [ISGs],
including ISG15 [OMIM 147571]). In parallel, the endosomal TLR3 receptor sensesSARS-CoV-2 ssRNA and consequently activates adapter protein TRIF, which then recruits associating kinases TBK1 and IKKε and the ubiquitin ligases TRAF3 and TRAF6. TLR3 signaling continues via stimulation of IFN regulatory factor 3 (encoded by IRF3, OMIM 300365), which transfers to the nucleus to induce transcription of type I IFN genes. In TLR7 deficiency due to loss-of-function variants (as indicated by the red cross), transcription of downstream effector
genes IRF7, IFNB1, and ISG15 are downregulated (as indicated by downward pointing arrows). In addition, the production of IFN-γ is impaired. The expression of IRF3 remains unaltered (as indicated by the equal sign).

Rare genetic alterations in the TLR7 gene may have predisposed two sets of brothers to falling severely ill with COVID-19, a new research has found.

People infected with SARS-CoV-2 exhibit a range of symptoms, and while age, sex, and comorbidities such as diabetes and obesity may predispose patients to more severe disease, there is emerging evidence that genetic factors may influence disease severity, as well. 

Severe COVID-19 is less common among younger patients, but in a new case series appearing in the Journal of the American Medical Association on Friday, Dutch researchers examined the exomes of two pairs of otherwise healthy brothers under the age of 32 who became severely ill with COVID-19 and required ventilation, with one of them dying.

“In such a case, you immediately wonder whether genetic factors could play a role,” senior author Alexander Hoischen from Radboud University Medical Center said in a statement. “Getting sick from an infection is always an interplay between — in this case — the virus and the human immune system. It may be a mere coincidence that two brothers from the same family become so severely ill. But it is also possible that an inborn error of the immune system has played an important role.”

By analyzing whole-exome sequencing data from the two sets of brothers, he and his colleagues found all four had variants affecting the TLR7 gene, which is involved in pathogen recognition and immune system activation.

The researchers were particularly interested in whether there were any alterations on the X chromosome that could have predisposed the men to severe COVID-19. Men, they noted, have in general fared worse than women when infected with SARS-CoV-2, which could implicate immune-related genes that are encoded on the X chromosome.

By analyzing the patients’ exomes, the researchers uncovered two different rare variants in the TLR7 gene, which is located on the X chromosome. In a series of calculations, they estimated that the probability of encountering rare, loss-of-function TLR7 variants in unrelated individuals in gnomAD was very low, as there is little variation in this gene in population databases. TLR7 encodes the toll-like receptor 7, which has a role in the activation of interferons and triggers an immune response.

One set of brothers had a four-nucleotide deletion in TLR7, while the other pair had a missense variant. Both alterations are predicted to be deleterious and appear to impair host viral response. When the researchers examined primary peripheral blood mononuclear cells obtained from the patients that were stimulated with the TLR7 agonist imiquimod, they noted decreased expression of the type I IFN genes IRF7, IFNB1, and ISG15, compared to cells from unaffected family members and controls. Additionally, production of IFN-γ, a type II interferon, was low in patients following imiquimod stimulation.

“These tests make it clear that [SARS-CoV-2] appears to have free rein in people without properly functioning TLR7 because it is not recognized by the immune system,” first author Cas van der Made from Radboud said in a statement. It also suggests that TLR7 is needed for protection from SARS-CoV-2 and points to a possible treatment approach, he and his colleagues noted.

“This discovery not only provides us with more insight into the fundamental workings of the immune system, but it may also have important consequences for the treatment of severely ill COVID-19 patients,” co-author Frank van de Veerdonk, immunologist and infectologist at Radboud, added. He noted that interferon is currently being explored as a COVID-19 treatment.

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