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

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 25, n. 13, p. 28-pg., 2024-07-01.

Resumo

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)

• Processo FAPESP: 21/12045-5 - Efeito da venlafaxina no número de mastócitos e na imunoexpressão de proteínas estruturais e funcionais de glândula submandibular de ratos adultos
• Beneficiário: Juliana Cerini Grassi de Moraes
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 21/06271-2 - Análise histopatológica de glândula submandibular de camundongos K18-hACE2 infectados por SARS-CoV-2
• Beneficiário: Vitor Dallacqua Martinelli
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 21/09328-5 - Avaliação do perfil imunológico, da espermatogênese e esteroidogênese em camundongos K18-hACE2 infectados por SARS-CoV-2
• Beneficiário: Salmo Azambuja de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 22/10560-2 - RESPOSTA IMUNOLÓGICA DO EPIDÍDIMO DE CAMUNDONGOS TRANSGÊNICOS K18-hACE2 INFECTADOS COM SARS-COV-2, COM ÊNFASE NA CÉLULA CLARA
• Beneficiário: André Acácio Souza da Silva
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 21/07207-6 - Avaliação histopatológica de testículo, epidídimo e glândula submandibular de camundongos K18-hace2 infectados por SARS-CoV-2
• Beneficiário: Estela Sasso Cerri
• Modalidade de apoio: Auxílio à Pesquisa - Regular