Age-differential CD13 and interferon expression in airway epithelia affect SARS-CoV-2 infection - Effects of vitamin D.

Young age and high vitamin D plasma levels have been associated with lower SARS-CoV-2 infection risk and favourable disease outcomes. This study investigated mechanisms associated with differential responses to SARS-CoV-2 across age groups and effects of vitamin D. Nasal epithelia were collected from healthy children and adults and cultured for four weeks at the air-liquid interface with and without vitamin D. Gene expression and DNA methylation were investigated. Surface protein expression was confirmed by immunofluorescence while vitamin D receptor recruitment to the DNA was analysed through chromatin immunoprecipitation. HEp-2 cells were used for protein co-immunoprecipitation and luciferase reporter assays. Compared to children, airway epithelia from adults show higher viral RNA recovery following infection. This was associated with higher ANPEP/CD13, reduced type I interferon expression, and differential DNA methylation. In cells from adults, exposure to vitamin D reduced TTLL-12 expression, a negative regulator of the interferon response. This was mediated by vitamin D receptor recruitment to TTLL12, where it instructs DNA methylation through DNA methyltransferase 1. This study links age-dependent differential expression of CD13 and type I interferon to variable infection of upper airway epithelia. Furthermore, it provides molecular evidence for vitamin D reducing viral replication by inhibiting TTLL-12.

Remdesivir-ivermectin combination displays synergistic interaction with improved in vitro activity against SARS-CoV-2.

A key element for the prevention and management of coronavirus disease 2019 is the development of effective therapeutics. Drug combination strategies offer several advantages over monotherapies. They have the potential to achieve greater efficacy, to increase the therapeutic index of drugs and to reduce the emergence of drug resistance. We assessed the in vitro synergistic interaction between remdesivir and ivermectin, both approved by the US Food and Drug Administration, and demonstrated enhanced antiviral activity against severe acute respiratory syndrome coronavirus-2. Whilst the in vitro synergistic activity reported here does not support the clinical application of this combination treatment strategy due to insufficient exposure of ivermectin in vivo, the data do warrant further investigation. Efforts to define the mechanisms underpinning the observed synergistic action could lead to the development of novel treatment strategies.