COVID-19 research

Gene: TLR4

Comment on list classification: Although this gene has not been associated with a phenotype in OMIM nor Gen2Phen, an animal model and two population studies indicate that deletion or the minor alleles of rs4986790 or rs4986791 are all associated with susceptibility to respiratory syncytial virus (RSV). The recently published article speculates that TLR4 could be involved in recognizing SARS‐CoV‐2 and proposes the selective targeting of TLR4‐spike protein interaction to treat COVID‐19 (PMID 32383269).

Created: 28 May 2020, 3:32 p.m. | Last Modified: 28 May 2020, 5:40 p.m.

Panel Version: 0.364

TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping).
PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina).
PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T399I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection.
PMID 17709532 also found that the same minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for p.D299G and p.T399I compared with control frequencies of 10.5% and 6.5%, respectively.
PMID 32391647 reports: Hyperactivated B cell and TLR4 signalling pathway were observed in WT HBV-carrier mice, while TLR4 ablation failed to induce B cell hyperactivation, and downstream MyD88 and NF-κB were also not altered. Taken together, TLR4 pathway plays a pivotal role in B cell hyperactivation during CHB, which might serve as a promising target for B cell function restoration.
PMID 32383269 reports that: cell surface TLR4 is most likely to be involved in recognizing molecular patterns from SARS‐CoV‐2 and speculates that selective targeting of TLR4‐spike protein interaction by designing competitive TLR4‐antagonists could pave a new way to treat COVID‐19.

Created: 28 May 2020, 3:28 p.m. | Last Modified: 28 May 2020, 5:39 p.m.

Panel Version: 0.364

Publications

• 11062499
• 17579031
• 17709532