ACE2 and TMPRSS2 immunolocalization and oral manifestations of COVID‐19

Abstract

Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into the host cells depends on the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). We investigated the distribution of ACE2-and TMPRSS2-expressing cells in various oral tissues to identify the underlying mechanism of oral manifestations in patients with coronavirus disease 2019. Subjects:We analyzed the expression patterns of ACE2 and TMPRSS2 in the oral mucosa (tongue, palate, and buccal mucosa), trigeminal ganglion, vessels, and salivary glands of 9 Sprague-Dawley rats using immunohistochemistry and immunofluorescence.Results: ACE2 and TMPRSS2 were strongly expressed in the intermediate layer of the squamous epithelia of tongue papillae and buccal mucosa. ACE2-and TMPRSS2positive cells were observed in the taste buds of the tongue. Additionally, ACE2 and TMPRSS2 were co-expressed in the ductal epithelium and acinar cells of salivary glands. Furthermore, both ACE2 and TMPRSS2 were stained in the neuronal cell body of trigeminal ganglia, but not in Schwann cells. Moreover, ACE2 and TMPRSS2 were expressed in capillaries, but not in venules/arterioles. Conclusions: SARS-CoV-2 can spread the suprabasal area of squamous epithelia of the oral mucosa, invades taste bud, trigeminal nerve, parotid gland, and microvessel, resulting in oral manifestations.

An update on oral clinical courses among patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: A clinical follow-up (a prospective prevalent cohort) study

“…Accordingly, salivary glands could be the invasive target of SARS-CoV-2 (33). Moreover, the salivary gland cells with ACE2 receptors may become host cells for the virus and cause inflammatory reactions in related organs and tissues, such as the tongue, the periodontal tissues, and oral mucosa (30) (34). Furthermore, scholars have revealed oral clinical courses such as dysgeusia, petechiae, gingivitis, candidiasis, traumatic ulcers, geographical tongue, and thrush-like ulcers among patients with SARS-CoV-2 infection (35) (36).…”

Investigating the possible mechanisms of autonomic dysfunction post-COVID-19

“… Route of entry Anatomical site of entry Findings suggesting entry through the route Reference Suggested pathway to ANS invasion Neuronal Olfactory nerve Autopsy of patients with COVID-19 showed viral RNA of SARS-CoV-2 in the olfactory mucosa and olfactory bulb. Spike protein was colocalized with neuronal cells In macaques, SARS-CoV-2 was detected in the olfactory cortex preferentially in neurons Meinhardt et al, 2021 Beckman et al, 2022 Olfactory epithelium → olfactory nerve → olfactory cortex → MFB → brainstem Ocular nerve In patients with COVID-19, SARS-CoV-2 was detected in the retina Patients with COVID-19 had increased retinal nerve fiber layer thickness Casagrande et al, 2020 Burgos-Blasco et al, 2021 Retina → ocular nerve → retinohypothalamic tract → suprachiasmatic nucleus of the hypothalamus Trigeminal nerve Oral mucosa, taste buds, salivary gland, and trigeminal ganglion express ACE-2 receptors and TMPRSS2 Park et al, 2022 Nociceptors in the oral cavity → trigeminal nerve → trigeminal ganglia → trigeminal spinal nucleus caudalis in the medulla Glossopharyngeal and vagus, nerves High expression of ACE-2, NRP1, and TMPRSS2, in the vagus and the glossopharyngeal nerves Vitale-Cross et al, 2022 Taste sensory fibers in oral cavity → glossopharyngeal and vagus nerves → NTS Respiratory tract epithelium → vagus nerve → vagal ganglia → NTS and the nucleus ambiguous Hematogenous BBB Postmortem examination of a COVID-19 patient showed viral-like particles in the capillary endothelium of the frontal lobe Paniz-Mondolfi et al, 2020 Viral hijacked leukocytes or transcellular/paracellular migration across BBB → hypothalamus and brainstem CVOs High expression of ACE-2 in CVOs and PVN Ong et al, 2022 Subfornical zone, organum vasculosum, median eminence, and area postrema → PVN of hypothalamus

Fig. 1 Direct invasion of the hypothalamus or the medulla by SARS-CoV-2 through the neuronal or hematogenous routes can induce autonomic dysfunction.

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“…The oral mucosa, taste buds, salivary gland, and trigeminal ganglion express ACE-2 receptors and TMPRSS2 ( Park et al, 2022 ). The trigeminal ganglia transmit oral facial nociception to the trigeminal spinal nucleus caudalis in the medulla ( Bista and Imlach, 2019 ).…”

An update on oral clinical courses among patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: A clinical follow-up (a prospective prevalent cohort) study

“…Accordingly, salivary glands could be the invasive target of SARS-CoV-2 [36]. Moreover, the salivary gland cells with ACE2 receptors may become host cells for the virus and cause inflammatory reactions in related organs and tissues, such as the tongue, the periodontal tissues, and oral mucosa [33,37]. Furthermore, scholars have revealed oral clinical courses such as dysgeusia, petechiae, gingivitis, candidiasis, traumatic ulcers, geographical tongue, and thrush-like ulcers among patients with SARS-CoV-2 infection [38,39].…”