Deciphering TLR and JAK/STAT pathways: genetic variants and targeted therapies in COVID-19

Genetic alterations affecting the immune-related pathways can significantly disrupt the innate immune system among patients with COVID-19, contributing to disease severity. Research investigations have shown that common or rare mutations in TLR genes, mainly TLR3 and TLR7, can impair the recognition of viral RNA, leading to an altered interferon response. Moreover, the NF-κB pathway, which represents a vital regulator of inflammatory cytokine production, may also be genetically disturbed, resulting in either insufficient inflammatory signaling or, adversely, excessive cytokine release in the most severe cases. Alterations in the JAK/STAT signaling pathway that mediates the downstream effects of type I interferons and other cytokines, can further compromise the antiviral defenses. The purpose of this review is to outline recent literature describing the current understanding of immunogenetic mechanisms in response to SARS-CoV-2 infection, with an emphasis on TLR and JAK/STAT signaling pathways. We aimed to investigate important variants within the genes related to these cascades and their involvement in COVID-19 severity. We also discussed emerging therapeutic strategies, especially the JAK/STAT modulators and TLR antagonists in severe COVID-19.Despite significant advances in targeting JAK/STAT pathways for the treatment of COVID-19, these approaches can show partial efficacy in monitoring critical inflammatory responses, due to the rapid viral evolution. Moreover, JAK inhibitors, being beneficial in decreasing hyperinflammation, may present potential side effects, particularly linked to immunosuppression. Hence, by integrating genetic profiling and modulation of immunity pathways, novel precision medicine approaches may greatly optimize treatment strategies and COVID-19 patient outcomes.