The lung employs an intrinsic surfactant-mediated inflammatory response for viral defense.
Sandra L LeibelRachael N McVicarRabi MuradElizabeth M KwongAlex E ClarkAsuka AlvaradoBethany A GrimmigRuslan NuryyevRandee E YoungJamie Casey LeeWeiqi PengYanfang Peipei ZhuEric GriffisCameron J NowellKang LiuBrian JamesSuzie AlarconAtul MalhotraLinden J GearingPaul J HertzogCheska Marie GalapateKoen M O GalenkampCosimo CommissoDavey M SmithXin SunAaron F CarlinBen A CrokerEvan Y SnyderPublished in: bioRxiv : the preprint server for biology (2023)
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes an acute respiratory distress syndrome (ARDS) that resembles surfactant deficient RDS. 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 inflammatory cytokine/chemokine production and interferon (IFN) responses are dynamically regulated autonomously within the lung following SARS-CoV-2 infection, an intrinsic defense mechanism mediated by surfactant proteins (SP). Single cell RNA sequencing revealed broad infectability of most lung cell types through canonical (ACE2) and non-canonical (endocytotic) viral entry routes. SARS-CoV-2 triggers rapid apoptosis, impairing viral dissemination. In the absence of surfactant protein B (SP-B), resistance to infection was impaired and cytokine/chemokine production and IFN responses were modulated. Exogenous surfactant, recombinant SP-B, or genomic correction of the SP-B deletion restored resistance to SARS-CoV-2 and improved viability.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- single cell
- acute respiratory distress syndrome
- stem cells
- inflammatory response
- extracorporeal membrane oxygenation
- rna seq
- cell cycle arrest
- dendritic cells
- oxidative stress
- endothelial cells
- mechanical ventilation
- cell death
- immune response
- induced apoptosis
- high glucose
- intensive care unit
- toll like receptor
- small molecule
- high throughput
- lipopolysaccharide induced
- lps induced
- copy number
- drug induced
- mesenchymal stem cells
- cell therapy
- innate immune
- angiotensin ii
- signaling pathway
- induced pluripotent stem cells
- sensitive detection