1/7
TLR7 loss-of-functions mutations can lead to an immunodeficiency with a strong predisposition to develop a severe form of COVID-19 in young male patients. jamanetwork.com/journals/jama/…
TLR7 loss-of-functions mutations can lead to an immunodeficiency with a strong predisposition to develop a severe form of COVID-19 in young male patients. jamanetwork.com/journals/jama/…
2/7 As such, this is the first description of a monogenic risk factor related to COVID-19 and a first risk factor next to the known general risk factors (age, male sex, cardiovascular disease, chronic disease, obesity).
3/7 Likely a rare immunodeficiency; estimate on TLR7 population data from gnomAD individuals: rare, highly conserved missense (~1:1000) and nonsense variants (~1:25,000).
4/7
The TLR7 pathway is part of the innate immune system & leads to the production of type I INF, which mediates the antiviral host response; important for defense mechanism against SARS-CoV-2, as illustrated by a low TLR7 expression & type I INF response in pts severe COVID-19.
The TLR7 pathway is part of the innate immune system & leads to the production of type I INF, which mediates the antiviral host response; important for defense mechanism against SARS-CoV-2, as illustrated by a low TLR7 expression & type I INF response in pts severe COVID-19.
5/7 In TLR7 deficiency there is a defect in both type I and by extension type II inteferon responses, which renders these patients vulnerable to severe SARS-CoV-2 infection. This may offer opportunities for treatment; eg early interferon administration; as currently trialed.
6/7 The TLR7 gene is located on the X-chromosome and displays strong constraints against damaging variants. In addition, the gene is highly conserved across species. So far no primary immunodeficiences have been linked to TLR7 deficiency.
7/7 From an evolutionary point of view it can be considered that there may have been previous outbrakes of coronavirus infections that may explain the observed constraint.
8/7 The TLR7 gene has been shown to escape X-inactivation, meaning that women carry two active copies of TLR7. This differences in dosage between males and females may be relevant to the host response; women are well-equipped due to double dose;
9/7 men with one intact TLR7 copy have intact TLR7 signaling but mount a lower antiviral host response; men with defective TLR7 as shown here present with a significantly impaired antiviral host response with an elevated risk to develop severe COVID-19 symptoms upon infection.
10/7 It is therefore tempting to speculate that other, for example regulatory variants that impact TLR7 dose may also confer a slightly increased risk to more severe COVID-19; and the TLR7 dosage effect may in part explain the general male sex-bias observed for severe COVID-19.
11/7 These findings provide insights into the pathogenesis of COVID-19 and highlight the importance of intact TLR7 signaling.
Final note: we are most grateful to the families that agreed to participate in this study; we sincerely hope this may help others. Also, I am very grateful to our wonderful interdisciplinary team at the Radboudumc that made this possible in particular the most talented.
