The “oral” history of COVID‐19: Primary infection, salivary transmission, and post‐acute implications

Abstract

Severe acute respiratorysyndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has led to more than 3.25 million recorded deaths worldwide as of May 2021. COVID-19 is known to be clinically heterogeneous, and whether the reported oral signs and symptoms in COVID-19 are related to the direct infection of oral tissues has remained unknown. Here, we review and summarize the evidence for the primary infection of the glands, oral mucosae, and saliva by SARS-CoV-2. Not only were the entry factors for SARS-CoV-2 found in all oral tissues, but these were also sites of SARS-CoV-2 infection and replication. Furthermore, saliva from asymptomatic individuals contained free virus and SARS-CoV-2-infected oral epithelial cells, both of which were found to transmit the virus. Collectively, these studies support an active role of the oral cavity in the spread and transmission of SARS-CoV-2 infection. In addition to maintaining the appropriate use of personal protective equipment and regimens to limit microbial spread via aerosol or droplet generation, the dental community will also be involved in co-managing COVID-19 "long haulers"-now termed Post-Acute COVID-19 Syndrome. Consequently, we propose that, as SARS-CoV-2 continues to spread and as new clinical challenges related to COVID-19 are documented, oral symptoms should be included in diagnostic and prognostic classifications as well as plans for multidisciplinary care.

Morphological and tissue-based molecular characterization of oral lesions in patients with COVID-19: A living systematic review

“…Recent studies suggest that sex hormones may influence the viral infectivity process ( Mohamed, Moulin, & Schiöth, 2021 ). However, the pathophysiology of this difference has not yet been established and it was observed that genes encoding entry factors for SARS-CoV-2 appeared similar in epithelial cells from males and females (Huang, P é rez, Kato, Mikami, Okuda & Gilmore, 2021; Marchesan, Warner, & Byrd, 2021 ).…”

“…For example, based on the included studies in this LSR, the oral lesions were negative for HHV-1, HHV-2, HHV-3, CMV, and Treponema pallidum. Nevertheless, in this sense, it is important to mention recent robust evidence that demonstrates the rich expression of SARS-CoV-2 viral entry factors in the salivary glands and epithelia of the oral mucosa, which are also sites for SARS-CoV-2 infection and replication, suggesting that the oral cavity is a hot spot for COVID-19 infection ( Huang et a., 2020 ; Huang, P é rez, Kato, Mikami, Okuda & Gilmore, 2021 ; Marchesan et al, 2021 ).…”

Visible blue light inactivates SARS-CoV-2 variants and inhibits Delta replication in differentiated human airway epithelia

“…SARS-CoV-2 infects the oral cavity, upper respiratory tract, and large airway (Hou et al, 2020; Huang et al, 2021) prior to spread to the lower respiratory tract and the late-stage development of acute respiratory distress. Sustained replication in the oral and nasal cavities is likely a key contributor to the increased transmissibility of SARS-CoV-2 compared to other coronaviruses (Hou et al, 2020; Huang et al, 2021; Marchesan et al, 2021). For these reasons, a targeted approach for acute SARS-CoV-2 infection of the upper airway epithelia to halt progression via the oral-lung transmission axis is an attractive aim.…”

Imaging viral infection in vivo to gain unique perspectives on cellular antiviral immunity*

“…Iannacone's group demonstrated that inflammatory monocytes recruited to LCMV-infected LNs interacted with virus-specific B cells, confining B cell motility and decreasing B cell survival. 47 During pathogenic CHIKV-infection 56 To explore antiviral immunity in the oral mucosa, our laboratory recently adapted our skin VACV infection model to the murine labial mucosa (inner lip), which can be imaged almost noninvasively using IVM. 9,10,34 Many poxviruses replicate in the oral mucosa-the first lesions during human smallpox infection appeared in the oral mucosa rather than the skin, and smallpox patients were most infectious during the first week after the onset of symptoms as ulcerated oral mucosal lesions shed copious amounts of virus.…”

“…Although many medically significant viruses, including SARS‐CoV‐2, replicate in the human oropharyngeal mucosa and can be shed into the saliva, few animal models exist of acute oral mucosal viral infection, and little is known about antiviral immunity in this barrier tissue 56 . To explore antiviral immunity in the oral mucosa, our laboratory recently adapted our skin VACV infection model to the murine labial mucosa (inner lip), which can be imaged almost non‐invasively using IVM 9,10,34 .…”