The Immunopathology of COVID-19 and the Cannabis Paradigm

Abstract

Coronavirus disease-19 caused by the novel RNA betacoronavirus SARS-CoV2 has first emerged in Wuhan, China in December 2019, and since then developed into a worldwide pandemic with >99 million people afflicted and >2.1 million fatal outcomes as of 24th January 2021. SARS-CoV2 targets the lower respiratory tract system leading to pneumonia with fever, cough, and dyspnea. Most patients develop only mild symptoms. However, a certain percentage develop severe symptoms with dyspnea, hypoxia, and lung involvement which can further progress to a critical stage where respiratory support due to respiratory failure is required. Most of the COVID-19 symptoms are related to hyperinflammation as seen in cytokine release syndrome and it is believed that fatalities are due to a COVID-19 related cytokine storm. Treatments with anti-inflammatory or anti-viral drugs are still in clinical trials or could not reduce mortality. This makes it necessary to develop novel anti-inflammatory therapies. Recently, the therapeutic potential of phytocannabinoids, the unique active compounds of the cannabis plant, has been discovered in the area of immunology. Phytocannabinoids are a group of terpenophenolic compounds which biological functions are conveyed by their interactions with the endocannabinoid system in humans. Here, we explore the anti-inflammatory function of cannabinoids in relation to inflammatory events that happen during severe COVID-19 disease, and how cannabinoids might help to prevent the progression from mild to severe disease.

Keywords: COVID-19; SARS-CoV2; cannabinoid receptors; cannabinoids; cannabis; cytokine release syndrome; cytokine storm; inflammation.

Figure 1

Distribution of ACE2 in the human body. ACE2 is expressed in different cells of the eye, the upper airway, the lung, the liver, the gut, the central nervous system, the heart, the vasculature system, and of the kidneys.

Figure 2

Inflammatory responses in COVID-19 patients. Inflammatory responses to SARS-CoV2 comprise a “core” inflammatory response, which all COVID-19 patients experience. In patients with mild disease, the inflammatory response resolves on the way to convalescence. The appearance of additional inflammatory clusters is observed during progression to severe disease. This includes the release of a higher number of systemic pro-inflammatory cytokines, low numbers but over-reactive T cells, and infiltration of monocytes/macrophages to the sites of infection.

Figure 3

Cannabinoids in Cannabis sativa spp. Depicted is the number of the compounds of the cannabis plant, which are >400 non-cannabinoids and ≈150 cannabinoids that are listed including their abbreviations.

Figure 4

Impact of cannabinoids on inflammatory responses during a SARS-CoV2 infection. The entry of the virus via ACE2 can be inhibited by CBD, reducing the virus load inside the cells. Infection with the virus triggers a cascade of inflammatory responses of the innate and adaptive immunity. Monocytes and macrophages secrete cytokines and chemokines. Activated macrophages secrete CXCL2 and CXCL8 which attract neutrophils, which release NETs to the site of infection. Infiltrating FCN1+ macrophages secrete IL-6, IL-10, and TNFα in the lung, which leads to T cell apoptosis. CD8⁺ T cells secrete IFNγ and TNFα. T helper cells Th1 and Th17 stimulate CD14+ and CD16+ monocytes to secrete IL-6, IL-1β, and CSF1 and CSF2. This leads to the development of the cytokine storm, which might culminate in ARDS or multi-organ failure. Cannabinoids have the potential to inhibit the secretion of several pro-inflammatory cytokines resulting in prevention of CRS.