Abstract
The aim of this study is to examine the use of an inflammasome competitor as a preventative agent. Coronaviruses have zoonotic potential due to the adaptability of their S protein to bind receptors of other species, most notably demonstrated by SARS-CoV. The binding of SARS-CoV-2 to TLR (Toll-like receptor) causes the release of pro-IL-1β, which is cleaved by caspase-1, followed by the formation and activation of the inflammasome, which is a mediator of lung inflammation, fever, and fibrosis. The NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome is implicated in a variety of human diseases including Alzheimer’s disease (AD), prion diseases, type 2 diabetes, and numerous infectious diseases. By examining the use of 4,4′-diaminodiphenyl sulfone (DDS) in the treatment of patients with Hansen’s disease, also diagnosed as Alzheimer’s disease, this study demonstrates the diverse mechanisms involved in the activation of inflammasomes. TLRs, due to genetic polymorphisms, can alter the immune response to a wide variety of microbial ligands, including viruses. In particular, TLR2Arg677Trp was reported to be exclusively present in Korean patients with lepromatous leprosy (LL). Previously, mutation of the intracellular domain of TLR2 has demonstrated its role in determining the susceptibility to LL, though LL was successfully treated using a combination of DDS with rifampicin and clofazimine. Of the three tested antibiotics, DDS was effective in the molecular regulation of NLRP3 inflammasome activators that are important in mild cognitive impairment (MCI), Parkinson’s disease (PD), and AD. The specific targeting of NLRP3 itself or up-/downstream factors of the NLRP3 inflammasome by DDS may be responsible for its observed preventive effects, functioning as a competitor.
Highlights
SARS-CoV-2 is an acute disease from which sufferers generally recover, though it can be deadly, with the fatality rate estimated at 2% [1]
The binding of SARS-CoV-2 to the Toll-like receptor (TLR) causes the release of pro-IL-1β, which is cleaved by caspase-1, followed by inflammasome activation and the production of active, mature IL-1β, which is a mediator of lung inflammation, fever, and fibrosis
We were drawn to their description of COVID-19 patients presenting with multi-organ symptoms mimicking internal, surgical, dermatological, immunological and renal diseases, a ‘diaminodiphenyl sulfone (DDS)-like clinical presentation’
Summary
SARS-CoV-2 is an acute disease from which sufferers generally recover, though it can be deadly, with the fatality rate estimated at 2% [1]. Most patients with SARS-CoV-2 have a mild disease course; approximately 20% develop severe disease, and a high mortality rate is associated with older age and immunosuppression. Coronaviruses infect a wide range of mammals and birds. Their tropism is primarily determined by the ability of the spike (S) entry protein to bind to a cell surface receptor. Coronaviruses have zoonotic potential due to the adaptability of their S protein to receptors of other species, most notably demonstrated by SARS-CoV [2]. MERS (Middle East Respiratory Syndrome) -CoV binds to dipeptidyl peptidase 4 (DPP4; known as CD26) receptors that are primarily in the lower respiratory tract and distributed in other tissues [3]
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