ABSTRACT
COVID-19 survivors develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal samples. Mouse-adapted SARS-CoV-2 MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute disease through clinical recovery. At 15-120 days post-virus clearance, histologic evaluation identified subpleural lesions containing collagen, proliferative fibroblasts, and chronic inflammation with tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal upregulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.
Subject(s)
Acute Disease , Lung Diseases , Adenocarcinoma, Bronchiolo-Alveolar , Infections , Respiratory Distress Syndrome , Severe Acute Respiratory Syndrome , Chronic Disease , COVID-19 , InflammationABSTRACT
Introduction: The effect of SARS-CoV-2 infection on pregnant mothers, the placenta, and infants is not fully understood and sufficiently characterized. Methods: We performed a retrospective, observational cohort study in Chapel Hill, NC of 115 mothers with SARS-CoV-2 and singleton pregnancies from December 1, 2019 to May 31, 2021. We performed a chart review to document the infant weight, length, head circumference, survival, congenital abnormalities, and hearing loss, maternal complications, and placental pathology classified by the Amsterdam criteria. Results: The average infant weight, length, and head circumference were all within the normal range for gestational age, the infants had no identifiable congenital abnormalities, and all infants and mothers survived. Only one infant (0.870%) became infected with SARS-CoV-2. Moderate and severe maternal COVID-19 were associated with increased caesarean section, premature delivery, infant NICU admission, and maternal respiratory failure, and were more likely in Type 1 (p=0.0055) and Type 2 (p=0.0285) diabetic mothers. Most placentas (n=63, 54.8%) showed normal or non-specific findings, while a subset had mild maternal vascular malperfusion (n=26, 22.6%) and/or mild microscopic ascending intrauterine infection (n=28, 24.3%). Discussion: Most mothers with SARS-CoV-2 and their infants had a routine clinical course. Maternal SARS-CoV-2 infection was not associated with intrauterine fetal demise, infant death, congenital abnormalities, or hearing loss. Infant infection with SARS-CoV-2 was rare and not via the placenta. Most placentas had non-specific findings and a subset showed mild maternal vascular malperfusion and/or mild microscopic ascending intrauterine infection, which were not associated with maternal COVID-19 severity.
Subject(s)
Fetal Death , Diabetes Mellitus , Congenital Abnormalities , Death , COVID-19 , Fetal Growth Retardation , Respiratory Insufficiency , Hearing LossABSTRACT
Despite signs of infection, the involvement of the oral cavity in COVID-19 is poorly understood. To address this, single-cell RNA sequencing datasets were integrated from human minor salivary glands and gingiva to identify 11 epithelial, 7 mesenchymal, and 15 immune cell clusters. Analysis of SARS-CoV-2 viral entry factor expression showed enrichment in epithelia including the ducts and acini of the salivary glands and the suprabasal cells of the mucosae. COVID-19 autopsy tissues confirmed in vivo SARS CoV-2 infection in the salivary glands and mucosa. Saliva from SARS-CoV-2-infected individuals harbored epithelial cells exhibiting ACE2 expression and SARS-CoV-2 RNA. Matched nasopharyngeal and saliva samples found distinct viral shedding dynamics and viral burden in saliva correlated with COVID-19 symptoms including taste loss. Upon recovery, this cohort exhibited salivary antibodies against SARS-CoV-2 proteins. Collectively, the oral cavity represents a robust site for COVID-19 infection andimplicates saliva in viral transmission.