Project description:Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes an acute respiratory distress syndrome (ARDS) that resembles neonatal RDS – a condition attributable to the deficiency of the surface tension reducing factor surfactant. Using a novel multi-cell type, human-induced pluripotent stem cell (hiPSC)-derived lung organoid (LO) system, validated against primary lung cells, we found that surfactant proteins (SP) A, B, C and D are dynamically regulated by SARS-CoV-2 infection. In the absence of SP-B (including through the study of LOs from SP-B deficient patients), resistance to infection was impaired and inflammatory cytokine/chemokine production and interferon (IFN) responses were modulated in lung cells of non-hematopoietic origin and without a circulatory system, suggesting specialization of viral inflammatory responses by human lung cells. Such cells can be infected independent of ACE2 and TMPRSS2 expression via what we propose is a non-canonical endocytotic route. Single cell RNA sequencing revealed broad susceptibility of many lung cell types with differential expression of BSG, cathepsins, and ACE2 that all facilitate viral entry. SARS-CoV-2 triggers a rapid loss of lung cell viability via apoptosis that impairs viral dissemination evident in the presence of Bcl-xL antagonism. Treatment with exogenous surfactant, recombinant SP-B, or genomic correction of the SP-B deletion mutation restored resistance to SARS-CoV-2 infection and improved cell viability. These findings suggest an unrecognized specialized intrinsic intra-pulmonary inflammation-based feedback loop of developmental origin that autonomously, without the intercession of hematopoietic derivatives, attempts to restore lung homeostasis after infection by inhibiting viral dissemination, averting lung epithelial demise, and dampening inflammatory cascades -- an additional inherent host-pathogen defense system. Given that SP-B is central to this response, an antiviral role may now be ascribed to this structural component that heretofore had been regarded as necessary only for surface tension reduction.

			Action	DRS
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	SRR21800981_1.fastq.gz	Fastqsanger.gz
	SRR21800981_2.fastq.gz	Fastqsanger.gz
	SRR21800983_1.fastq.gz	Fastqsanger.gz
	SRR21800983_2.fastq.gz	Fastqsanger.gz

Dataset Information

GEO accession GSE214752 is currently private and is scheduled to be released on Dec 31, 2025.

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