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. 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