The role of TLR7 agonists in modulating COVID-19 severity in subjects with loss-of-function TLR7 variants.

We investigate the mechanism associated with the severity of COVID-19 in men with TLR7 mutation. Men with loss-of-function (LOF) mutations in TLR7 had severe COVID-19. LOF mutations in TLR7 increased the risk of critical COVID by 16.00-fold (95% confidence interval 2.40-106.73). The deleterious mutations affect the binding of SARS-CoV2 RNA (- 328.66 ± 26.03 vs. - 354.08 ± 27.70, p = 0.03) and MYD88 (ß: 40.279, p = 0.003) to TLR7 resulting in the disruption of TLR7-MyD88-TIRAP complex. In certain hypofunctional variants and all neutral/benign variants, there is no disruption of TLR7-MyD88-TIRAP complex and four TLR7 agonists showed binding affinity comparable to that of wild protein. N-acetylcysteine (NAC) also showed a higher binding affinity for the LOF variants (p = 0.03). To conclude, TLR7 LOF mutations increase the risk of critical COVID-19 due to loss of viral RNA sensing ability and disrupted MyD88 signaling. Majority of hypofunctional and neutral variants of TLR7 are capable of carrying MyD88 signaling by binding to different TLR7 agonists and NAC.

Untangling the Role of TREM2 in Conjugation with Microglia in Neuronal Dysfunction: A Hypothesis on a Novel Pathway in the Pathophysiology of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder involving heterogenous pathophysiological characteristics, which has become a challenge to therapeutics. The major pathophysiology of AD comprises amyloid-ß (Aß), tau, oxidative stress, and apoptosis. Recent studies indicate the significance of Triggering receptor expressed on myeloid cells 2 (TREM2) and its mutant variants in AD. TREM2 are the transmembrane receptors of microglial cells that performs a broad range of physiological cell processes. Phagocytosis of Aß is one of the physiological roles of TREM2, which plays a pivotal role in AD progression. R47H, a mutant variant of TREM2, increases the risk of AD by impairing TREM2-Aß binding. Inconclusive evidence regarding the TREM2 signaling cascade mechanism of Aß phagocytosis motivates the current review to propose a new hypothesis. The review systematically assesses the cross talk between TREM2 and other AD pathological domains and the influence of TREM2 on amyloid and tau seeding. Disease associated microglia (DAM), a novel state of microglia with unique transcriptional and functional signatures reported in neurodegenerative conditions, also depend on the TREM2 pathway for its differentiation. DAM is suggested to have a neuroprotective role. We hypothesize that TREM2, along with its signaling adaptors and endogenous proteins, play a key role in ameliorating Aß clearance. We indicate that TREM2 has the potential to ameliorate the Aß burden, though with differential clearance ability and may act as a potential therapeutic target.

Corrigendum to "mTOR inhibition and p53 activation, microRNAs: The possible therapy against pandemic COVID-19" [Gene Rep. 20 (2020) 100765].

[This corrects the article DOI: 10.1016/j.genrep.2020.100765.].

mTOR inhibition and p53 activation, microRNAs: The possible therapy against pandemic COVID-19.

mTOR is a serine-threonine kinase and participates in cell proliferation, cellular metabolism was found to be activated during Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection and replication. During viral replication mTOR, downstream target genes such as ribosomal protein S6 kinase beta 1 (S6K1) and Eukaryotic translational initiation factor 4E-binding protein1 (4-E-BP1) are activated result in ribosome biosynthesis and efficient protein synthesis. In plasmacytoid dendritic cells (pDCs), mTOR plays a key role in the association of adapter protein myeloid differentiation primary response gene 88 (MyD88), Toll-like receptor 9 (TLR9) and interferon regulatory factor (IRF-7) leading to the transcriptional activation of type-I interferon (IFN) genes. Viruses also inactivate the interferon α (IFN-α) pathway by impairing the IRF-7 mediated activation of IFN-α gene transcription. Thus, mammalian target of rapamycin (mTOR) inhibitors can help in suppressing the early stages of viral infection and replication. Interestingly, the key tumor-suppressor p53 protein will undergo degradation by virus-encoded E3 ubiquitin ligase Ring-finger and CHY zinc-finger domain-containing 1 (RCHY1) leading to an increased viral survival in host cells. Thus, the mTOR inhibitors and p53 activators or microRNAs that functions as p53 and can target 3'-UTR of mTOR and RPS6KB1 might effectively inhibit viral replication in the human respiratory tract and lung cells.