Submandibular Gland Pathogenesis Following SARS-CoV-2 Infection and Implications for Xerostomia

Author(s)

Sasso-Cerri, Estela ; Martinelli, Vitor Dallacqua ; de Oliveira, Salmo Azambuja ; da Silva, Andre Acacio Souza ; de Moraes, Juliana Cerini Grassi ; Cerri, Paulo Sergio

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 25, n. 13, p. 28-pg., 2024-07-01.

Abstract

Although SARS-CoV-2 induces mucin hypersecretion in the respiratory tract, hyposalivation/xerostomia has been reported by COVID-19 patients. We evaluate the submandibular gland (SMGs) pathogenesis in SARS-CoV-2-infected K18-hACE2 mice, focusing on the impact of infection on the mucin production and structural integrity of acini, ductal system, myoepithelial cells (MECs) and telocytes. The spike protein, the nucleocapsid protein, hACE2, actin, EGF, TNF-alpha and IL-1 beta were detected by immunofluorescence, and the Egfr and Muc5b expression was evaluated. In the infected animals, significant acinar hypertrophy was observed in contrast to ductal atrophy. Nucleocapsid proteins and/or viral particles were detected in the SMG cells, mainly in the nuclear membrane-derived vesicles, confirming the nuclear role in the viral formation. The acinar cells showed intense TNF-alpha and IL-1 beta immunoexpression, and the EGF-EGFR signaling increased, together with Muc5b upregulation. This finding explains mucin hypersecretion and acinar hypertrophy, which compress the ducts. Dying MECs and actin reduction were also observed, indicating failure of contraction and acinar support, favoring acinar hypertrophy. Viral assembly was found in the dying telocytes, pointing to these intercommunicating cells as viral transmitters in SMGs. Therefore, EGF-EGFR-induced mucin hypersecretion was triggered by SARS-CoV-2 in acinar cells, likely mediated by cytokines. The damage to telocytes and MECs may have favored the acinar hypertrophy, leading to ductal obstruction, explaining xerostomia in COVID-19 patients. Thus, acinar cells, telocytes and MECs may be viral targets, which favor replication and cell-to-cell viral transmission in the SMG, corroborating the high viral load in saliva of infected individuals. (AU)

• FAPESP's process: 21/12045-5 - Effect of venlafaxine on the mast cells number and immunoexpression of structural and functional proteins in submandibular gland of adults rats
• Grantee: Juliana Cerini Grassi de Moraes
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 21/06271-2 - Histopathological analysis of submandibular gland of SARS-CoV-2-infected k18-hACE2 mice
• Grantee: Vitor Dallacqua Martinelli
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 21/09328-5 - Evaluation of immunological profile, spermatogenesis and steroidogenesis in SARS-CoV-2-infected K18-hACE2 mice
• Grantee: Salmo Azambuja de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 22/10560-2 - Immunological response of epididymis of K18-hACE2 transgenic mice infected with SARS-CoV-2, with emphasis on the clear cell
• Grantee: André Acácio Souza da Silva
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 21/07207-6 - Histopathological evaluation of testis, epididymis and submandibular gland of SARS-CoV-2-infected K18-hACE2 mice
• Grantee: Estela Sasso Cerri
• Support Opportunities: Regular Research Grants