TLR9 and COVID-19: A Multidisciplinary Theory of a Multifaceted Therapeutic Target

Abstract

By mapping the clinical pathophysiology of the novel coronavirus disease 2019 (COVID-19) against insights from virology, immunology, genomics, epidemiology and pharmacology, it is here proposed that the pathogen recognition receptor called toll like receptor 9 (TLR9) might have a pivotal role in the pathogenesis of COVID-19. Severe Acute Respiratory Syndrome Coronavirus 2, is causing the greatest global social and economic disruption since world war II. Lack of a vaccine, lack of successful treatment and limitations of the healthcare workforce and resources needed to safeguard patients with severe COVID-19 on the edge of life, demands radical preventive measures. It is urgently needed to identify biomarkers and drug candidates so that vulnerable individuals can be recognized early and severe multi-organ complications can be prevented or dampened. The TLR9 COVID-19 hypothesis describes a mechanism of action that could explain a wide spectrum of manifestations observed in patients with severe COVID-19. The introduced hypothesis proposes biomarkers for identification of vulnerable individuals and positions TLR9 as a promising multifaceted intervention target for prevention and/or treatment of COVID-19. TLR9 agonists might have value as prophylactic vaccine adjuvants and therapeutic immune stimulators at the early onset of disease. Additionally, in this current manuscript it is proposed for the first time that TLR9 could be considered as a target of “inhibition” aimed to dampen hyperinflammation and thrombotic complications in vulnerable patients that are at risk of developing late stages of COVID-19. The readily availability of TLR9 modulating drug candidates that have reached clinical testing for other disorders could favor a fast track development scenario, an important advantage under the current high unmet medical need circumstances regarding COVID-19.

Nutritional Impact and Its Potential Consequences on COVID-19 Severity

“…This, in turn, may trigger other inflammatory signalling pathways and the production of proinflammatory mediators ( 41 , 43 ). The expression levels of TLR9 and levels of endogenous triggers for TLR9 activation are also influenced by diet which has been proposed to contribute to a severe outcome of COVID-19 in vulnerable patients ( 44 ).…”

SARS-CoV-2: Current trends in emerging variants, pathogenesis, immune responses, potential therapeutic, and vaccine development strategies

“…NK cells and TLR activity must be inhibited to decrease hyper inflammation and prevent multi-organ complications in the hyper inflammation stage. [242] , [243] , [244] Toll-lik receptor (TLR) activator (PUL-042 CpG) Oxygen therapy mechanical ventilation A ventilator's early employment for mild COVID-19 patients could prevent progressing to more severe lung injury. Mechanical ventilation is lifesaving in severe respiratory failure.…”

“…Studies have shown that the use of umbilical cord blood-derived or isolated NK cell from healthy donor PBMCs may be helpful to the treatment of COVID-19 in the early of infection. Meanwhile, the activation of pathogen recognition receptors, including toll-like receptors 2, 6, and 9 (TLR2/6/9) by PUL-042 CpG oligodeoxynucleotides (CpG ODNs) in the early stage of COVID-19 infection, particularly on DCs and B cells, leading to innate immune stimulation can be employed as prophylactic or therapeutic [244] . In the hyperinflammation level of COVID-19 infection in vulnerable patients in which the host immune system remains active over a prolonged period, the inhibition of TLR and NK cell pathway can help to prevent or dampen hyperinflammation and multi-organ complications [244] ( Table 2 ).…”

Through DNA sensors and hidden mitochondrial effects of SARS-CoV-2

“…In array analysis, the level of TLR9 was upregulated in response to SARS-CoV infection, even more than other TLRs such as TLR2 and TLR4 [ 105 ]. TLR9 can in fact explain a huge variety of the symptoms observed in COVID-19, and in specific cases be hypothesized as the leading cause of the hyperinflammatory process [ 106 ]. AIM2 can be activated in monocytes infected with SARS-CoV-2 in an antibody mediated manner, causing pyroptotic cell death [ 107 ] and in pangolins, carriers of coronaviruses and together with bats, focus of studies of the SARS-CoV-2 zoonotic transmission to humans, lack the ZBP1 protein [ 108 ].…”