A therapy for suppressing canonical and noncanonical SARS-CoV-2 viral entry and an intrinsic intrapulmonary inflammatory response

• 成果类型: Article
• 署名作者: Leibel, Sandra L.; Mcvicar, Rachael N.; Murad, Rabi; Kwong, Elizabeth M.; Clark, Alex E.; Alvarado, Asuka; Grimmig, Bethany A.; Nuryyev, Ruslan; Young, Randee E.; Lee, Jamie C.; Peng, Weiqi; Zhu, Yanfang P.; Griffis, Eric; Nowell, Cameron J.; James, Brian; Alarcon, Suzie; Malhotra, Atul; Gearing, Linden J.; Hertzog, Paul J.; Galapate, Cheska M.; Galenkamp, Koen M. O.; Commisso, Cosimo; Smith, Davey M.; Sun, Xin; Carlin, Aaron F.; Sidman, Richard L.; Croker, Ben A.; Snyder, Evan Y.
• 署名单位: University of California System; University of California San Diego; Sanford Burnham Prebys Medical Discovery Institute; University of California System; University of California San Diego; University of California System; University of California San Diego; La Jolla Institute for Immunology; University of California System; University of California San Diego; Hudson Institute of Medical Research; Monash University; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9304
• DOI: 10.1073/pnas.2408109121
• 发表日期: 2024-07-23
• 关键词: pulmonary surfactant; respiratory-distress; preterm infants; stem-cells; protein; pathophysiology; differentiation; domain

摘要

The 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.