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.

Keywords: biomarker; coronavirus disease 2019; drug target identification; immunology; mitochondrial DNA; pathophysiology; severe acute respiratory syndrome coronavirus 2; toll-like receptor 9.

FIGURE 1

TLR9-Covid-19 hypothesis. Set of circumstances suggested to drive COVID-19 poor outcome via TLR9 encompass; (A) viral load and levels of viral RNA; (B) presence of other TLR9 triggers, and; (C) TLR9 expression levels. (D) Individuals with high accumulated levels of A, B and C are proposed to be at risk for developing severe COVID-19 pathology. It is suggested that CpG motifs from SARS-CoV-2 reach TLR9 via ACE mediated viral uptake in the cell followed by RNA translation and transfer of viral CpG-motifs to the endosome. Circulating CpG motifs from virus and other sources could reach TLR9 via endocytosis or directly bind to cell surface at an inflamed site. Dashed line indicates that activation of platelets and neutrophils can increase TLR9 expression levels at cell surface which is suggested to drive a vicious circle of inflammation. Activated TLR9 induces downstream cascades via MyD88, leading to gene transcription, cytokine production and activation of lymphocytes, neutrophils and platelets. The Uncontrolled prolonged activation of TLR9 is suggested to contribute to severe COVID-19 pathophysiology.

FIGURE 2

Clues pointing toward drug target TLR9 for COVID-19. Unravelling the mechanism by which SARS-CoV-2 is causing disease is needed for identification of vulnerable patients and for drug target identification. Pieces of the complex puzzle are being filled in by insight from various disciplines including virology, genomics, immunology, clinical pathophysiology, epidemiology and pharmacology. It is proposed that TLR9 could fill in a blank spot worthwhile for further investigation. The bullet points summarize the wide spectrum of observations that can be explained via the TLR9 COVID-19 hypothesis.

FIGURE 3

SARS-CoV-2 respiratory deposition and multi-organ complications. Health effects of inhaled substances, including inhaled viruses are influenced by the effectiveness of clearance capability and the routes of elimination. Depicted is a flow chart (adapted from Bezemer, 2009) of body compartments that can be reached via the airways. SARS-CoV-2 is not hazardous for people that are able to avoid exposure or that are able to effectively eliminate the virus from their system. However people that are not able to eliminate the virus or that are vulnerable may develop complications. Organs for which TLR9 mediated pathology is described in literature in non-COVID-19 settings are indicated in red. Regional build-up of SARS-CoV-2 and/or viral RNA, due to inefficient clearance capability in those organs, is proposed to contribute to the typical multi-organ pathology in patients susceptible for TLR9 pathway activation.

FIGURE 4

therapeutic implications of the TLR9 COVID-19 hypothesis: Patients that develop severe symptoms of COVID-19 are tend to go through different stages of disease with different characteristics. Graph (A) depicts a simplified fictional scenario explaining how an inefficient viral specific immune response at start of infection (stage 1) can result in a high peak of viral load and eventually an exaggerated inflammatory response causing symptomatic infection (stage 2). When the virus remains active and/or the host immune system remains active over prolonged period of time severe complications can occur requiring ICU (stage 3) and in worst case result in death. Based on the TLR9 COVID-19 hypothesis, 3 therapeutic strategies are worthwhile investigating for following desired actions: (B) shape adaptive immunity against SARS-Cov-2 so that viral load remains low; (C) Provide a short targeted immune boost to help clearing the virus efficiently, and (D) Inhibit TLR9 pathway in vulnerable patients to prevent or dampen hyperinflammation and multi-organ complications.