03170nas a2200457   4500000000100000008004100001260001500042100002100057700002300078700001500101700002300116700001800139700001900157700002300176700001900199700002000218700001700238700001500255700001900270700001700289700002200306700001600328700001800344700001800362700002200380700002000402700002300422700002500445700002000470700001900490700001200509700002000521700002200541700001800563700001900581245013400600856005300734300001600787490000800803520190100811       2024                            d  c2024-07-231 aSandra L. Leibel1 aRachael N. McVicar1 aRabi Murad1 aElizabeth M. Kwong1 aAlex E. Clark1 aAsuka Alvarado1 aBethany A. Grimmig1 aRuslan Nuryyev1 aRandee E. Young1 aJamie C. Lee1 aWeiqi Peng1 aYanfang P. Zhu1 aEric Griffis1 aCameron J. Nowell1 aBrian James1 aSuzie Alarcon1 aAtul Malhotra1 aLinden J. Gearing1 aPaul J. Hertzog1 aCheska M. Galapate1 aKoen M. O. Galenkamp1 aCosimo Commisso1 aDavey M. Smith1 aXin Sun1 aAaron F. Carlin1 aRichard L. Sidman1 aBen A. Croker1 aEvan Y. Snyder00aA therapy for suppressing canonical and noncanonical SARS-CoV-2 viral entry and an intrinsic intrapulmonary inflammatory response  uhttps://www.pnas.org/doi/10.1073/pnas.2408109121  ae24081091210 v1213 aThe prevalence of “long COVID” is just one of the conundrums highlighting how little we know about the lung’s response to viral infection, particularly to syndromecoronavirus-2 (SARS-CoV-2), for which the lung is the point of entry. We used an in vitro human lung system to enable a prospective, unbiased, sequential single-cell level analysis of pulmonary cell responses to infection by multiple SARS-CoV-2 strains. Starting with human induced pluripotent stem cells and emulating lung organogenesis, we generated and infected three-dimensional, multi-cell-type-containing lung organoids (LOs) and gained several unexpected insights. First, SARS-CoV-2 tropism is much broader than previously believed: Many lung cell types are infectable, if not through a canonical receptor-mediated route (e.g., via Angiotensin-converting encyme 2(ACE2)) then via a noncanonical “backdoor” route (via macropinocytosis, a form of endocytosis). Food and Drug Administration (FDA)-approved endocytosis blockers can abrogate such entry, suggesting adjunctive therapies. Regardless of the route of entry, the virus triggers a lung-autonomous, pulmonary epithelial cell–intrinsic, innate immune response involving interferons and cytokine/chemokine production in the absence of hematopoietic derivatives. The virus can spread rapidly throughout human LOs resulting in mitochondrial apoptosis mediated by the prosurvival protein Bcl-xL. This host cytopathic response to the virus may help explain persistent inflammatory signatures in a dysfunctional pulmonary environment of long COVID. The host response to the virus is, in significant part, dependent on pulmonary Surfactant Protein-B, which plays an unanticipated role in signal transduction, viral resistance, dampening of systemic inflammatory cytokine production, and minimizing apoptosis. Exogenous surfactant, in fact, can be broadly therapeutic.