key: cord-303022-9hqoq7tf
authors: Madapusi Balaji, Thodur; Varadarajan, Saranya; Vishal Rao, U.S.; Thirumal Raj, A.; Patil, Shankaragouda; Arakeri, Gururaj; Brennan, Peter A
title: Oral cancer and periodontal disease increase the risk of COVID 19? A mechanism mediated through furin and cathepsin overexpression
date: 2020-06-01
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2020.109936
sha: 
doc_id: 303022
cord_uid: 9hqoq7tf

nan

COVID-19 was first reported in Wuhan, China in December 2019 [1] . The infectious disease has spread rapidly and was upgraded by WHO to be a pandemic. It commonly presents as fever, dry cough, and dyspnea. In a minor proportion of patients as the disease progresses, it may lead to severe alveolar damage-causing respiratory distress, which can culminate in mortality [2] . The main route of human to human transmission has been suggested to occur by respiratory droplets released by the infected [3] , which has necessitated social distancing. Despite numerous measures by health agencies the disease continues to afflict the human race. Understandably, the past couple of months have seen a surge in the number of articles published on SARS-corona virus-2. These articles largely consist of clinical case reports, molecular profiling of the virus, bio-informatic analysis, and hypothesis. Among the hypothesis, the focus has largely been on identifying highrisk group, decoding pathogenic pathways, and in formulating therapeutic strategies.

We present a hypothesis to recognize a potentially high-risk group and to strategize a prophylactic measure to reduce the risk of virus infection in the specific group.

Studies including bio-informatic analysis have shown the presence of angiotensin-converting enzyme 2 (ACE2) receptors in oral mucosa, including the tongue, buccal mucosa, and gingiva [4] .

Similar to SARS-corona virus-1, even the SARS-corona virus-2 exhibits affinity towards ACE2 receptors [2] . Thus, oral mucosa could be a possible route for SARS-corona virus-2 infection. Oral mucosa in pathological states such as chronic periodontitis/oral cancer has shown to exhibit higher levels of osteopontin, which in turn can activate the p38 mitogen-activated protein kinase, stimulating nuclear factor-kappa B signaling and elevating the level of the protease furin [5] [6] [7] . In addition to furin, another protease cathepsin L is also elevated in chronic periodontitis and oral cancer, which in turn could be a result of the interleukin 6 mediated activation of the caveolin -1 mediated JNK-AP-1 signaling pathway [8] [9] [10] . Both furin and cathepsin play a major role in enabling the SARS-corona virus-2 to infect the host cells as elaborated in the following steps: 1) Furin pre-cleaves the S glycoprotein of the SARS-corona virus-2 into S1 and S2 subunits [11, 12] .

2) Following the pre-cleavage of the S glycoprotein, the receptor-binding domain (RBD) of the S1 subunit attaches itself to the angiotensin-converting enzyme 2 (ACE2) present in the host cells [13] .

3) Following binding of the S1 subunit to the ACE-2 receptors, the virus fuses with the host cell in two mechanisms: (a) endosomal fusion which is mediated by cysteine proteases cathepsin B/L and (b) plasma membrane fusion mediated by the serine protease TMPRSS2.

The heptad repeat (HR) 1 and the HR2 of the S2 subunit form a six-helix bundle (6-HB) fusion core. The formation of this core brings the cell membrane of the virus and the host close allowing cell fusion and infection [12, 13] .

Based on the above-mentioned data, it can be hypothesized that the increased protease levels in chronic periodontitis and oral cancer could potentially increase the risk of an oral mucosa mediated SARS-corona virus-2 infection (figure 1). In addition to increasing proteases, chronic periodontitis, and oral cancer patients have also reported having a low melatonin level [14, 15] .

Melatonin possesses anti-inflammatory, anti-oxidant properties. 13 Also, melatonin has shown to inhibit cathepsin L [16] . Thus, exogenous supplementation of the melatonin could aid in reducing the virus-induced inflammation, oxidative stress, and disrupting the cathepsin mediated fusion of virus and host cell.

A novel coronavirus outbreak of global health concern

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Surface Environmental, and Personal Protective Equipment Contamination by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) from a Symptomatic Patient

High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa

Plasma and crevicular fluid osteopontin levels in periodontal health and disease

Immunohistochemical analysis of osteopontin expression in oral squamous cell carcinoma

p38 Kinase Is Crucial for Osteopontin-Induced Furin Expression That Supports Cervical Cancer Progression

Expression of proteolytic cathepsins B, D, and L in periodontal gingival fibroblasts and tissues

Quantitative analysis of cathepsin L mRNA and protein expression during oral cancer progression

Enhances Cathepsin Pathway in Human Gingival Caveolin-1-Mediated JNK-AP-1 B and L Production Via Fibroblasts

Significant expression of FURIN and ACE2 on oral epithelial cells may facilitate the efficiency of 2019-nCov entry

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

Salivary and gingival crevicular fluid melatonin in periodontal health and disease

Clinical significance of serum melatonin in predicting the severity of oral squamous cell carcinoma

Effect of melatonin administration on activities of some lysosomal enzymes in the mouse


