Immune checkpoint dysregulation in COVID-19 pathogenesis and disease severity.
Authors: Villalba Julian , Villalba Julian , Li Yijia , Shih Angela , Poli Sergio , Kunitoki Keiko , Alba George , Mehta Arnav , Loyola-Rodríguez Georgina , Alcántara Ismael Ramírez , Santana Monique , Lacerda Marcus , Ferreira Luiz , Dell'Aquila Marco , Arena Vincenzo , Stigliano Egidio , Calabrese Fiorella , Pezzuto Federica , Märkl Bruno , Hirschbühl Klaus , Lozano Maria , Argueta Alan , Ackermann Maximillian , Jonigk Danny , Werlein Christopher , Pomara Cristoforo , Salerno Monica , Uribe-Uribe Norma , Vázquez-Benítez Greissy , Anton Clara Salas , Tzankov Alexandar , Stalder Anna , Martínez Daniel , Francesqui Joel , Osborn Michael , Hanley Brian , Johnston Robert , Lacy J Matthew , Parra-Medina Rafael , Bradley Benjamin , Marshall Desiree , Schwensen Hanna Ferløv , Okudela Koji , Chen Sonja , Varga Zsuzsanna , Steinestel Konrad , Flikweert Antine , Harper Holly , Iles Linda , Aiolfi Alberto , Scendoni Roberto , d'Amati Giulia , Träger Lene Hoffmann , Çınar Hüseyin , Aguiar Diego , Fabro Alexandre , Dolhnokoff Marisa , Doglioni Claudio , Rossi Giulio , Poletti Venerino , Chilosi Marco , Herrmann Martin , Salmon Isabelle , Colville-Ebeling Bonnie , Poissy Julien , Pugh Matthew , Yan Lei , Haahr Martha , Reyes Fabiola , Gentili Matteo , Parry Blair , Garlin Michelle , Lo Ying-Chun , Hilburn Caroline , Elliott Grant , Martinez Leonardo , Rosas Ivan , Sade-Feldman Moshe , Hacohen Nir , Baden Lindsey , Stone James , Colvin Robert B. , Goldberg Marcia , Li Jonathan , Filbin Michael , Mino-Kenudson Mari , Schaller Tina , Kröncke Thomas , Gigli Laura Álvarez , Sessa Francesco , Caltabiano Rosario , Menter Thomas , Sellarés Jacobo , Storgaard Merete , Hamilton-Dutoit Stephen , Dannheim Katelyn , Macciò Umberto , Witte Hanno , Yick David , Bruni Barbara , Bona Davide , Pernazza Angelina , Leth Peter , Banner Jytte , Batah Sabrina , Silva Luiz Ferraz da , Duarte-Neto Amaro , Mauad Thais , Saldiva Paulo , Dubini Alessandra , Muñoz Luis , Hartmann Arndt , Remmelink Myriam , Jensen Thomas Hartvig Lindkær , Brøchner Christian , Gibier Jean-Baptiste , Gilbert Andrea , Aviles Alexis , Barth Jamie , Boyraz Baris , Madrigal Emilio , Araujo-Medina Milagros , Mendez-Pena Javier , Chebib Ivan , Hung Yin , Ly Amy , Hariri Lida , Rosales Ivy , Smith Rex-Neal , Caldwell Nicholas 
Published: October 2024

Accumulating evidence suggests dysregulated immune checkpoint (IC) signaling can exacerbate COVID-19 severity, but the role of these molecules in the pathogenesis of fatal COVID-19-related diffuse alveolar damage (DAD) remains elusive. Understanding how IC proteins influence acute lung injury due to COVID-19 can provide insights into potential therapeutic strategies to modulate immune responses and improve patient outcomes. Here, in a single-center autopsy cohort, we determined the cellular localization of ICs in lung tissue from cases of fatal COVID-19, DAD-comparators, and non-fibrotic controls by using immunohistochemistry, and investigated their association with clinical outcomes. We expanded our findings by performing analyses of publicly available single-cell RNA sequencing datasets from patients with fatal COVID-19 and non-fibrotic controls. We demonstrated the presence of protein-protein interaction networks of ICs in the lung cellular niche by performing transcriptomic profiling of lung tissue-derived RNA counts from patients with fatal COVID-19. Further, we leveraged data from the largest international, multi-center COVID-19 autopsy cohort and validated that, among patients with fatal COVID-19, those with higher PD-L1/CD274 expression in lung endothelial cells had more rapid clinical deterioration. Lastly, in a cohort of individuals with early COVID-19, IC plasma protein levels were elevated in those with persistent SARS-CoV-2 RNAemia and adverse clinical outcomes. Collectively, our data provide unique pathological insights into the role of IC dysregulation and differential disease severity in COVID-19.