Single-cell analysis identifies conserved features of immune dysfunction in simulated microgravity and spaceflight

Fei Wu, Huixun Du, Eliah Overbey, JangKeun Kim, Priya Makhijani, Nicolas Martin, Chad A. Lerner, Khiem Nguyen, Jordan Baechle, Taylor R. Valentino, Matias Fuentealba, Juliet M. Bartleson, Heather Halaweh, Shawn Winer, Cem Meydan, Francine Garrett-Bakelman, Nazish Sayed, Simon Melov, Masafumi Muratani, Akos A. Gerencser, Herbert G. Kasler, Afshin Beheshti, Christopher E. Mason (), David Furman () and Daniel A. Winer ()
Additional contact information
Fei Wu: Buck Institute for Research on Aging
Huixun Du: Buck Institute for Research on Aging
Eliah Overbey: Weill Cornell Medicine
JangKeun Kim: Weill Cornell Medicine
Priya Makhijani: Buck Institute for Research on Aging
Nicolas Martin: Buck Institute for Research on Aging
Chad A. Lerner: Buck Institute for Research on Aging
Khiem Nguyen: Buck Institute for Research on Aging
Jordan Baechle: Buck Institute for Research on Aging
Taylor R. Valentino: Buck Institute for Research on Aging
Matias Fuentealba: Buck Institute for Research on Aging
Juliet M. Bartleson: Buck Institute for Research on Aging
Heather Halaweh: Buck Institute for Research on Aging
Shawn Winer: University of Toronto
Cem Meydan: Weill Cornell Medicine
Francine Garrett-Bakelman: University of Virginia
Nazish Sayed: Stanford University School of Medicine
Simon Melov: Buck Institute for Research on Aging
Masafumi Muratani: University of Tsukuba
Akos A. Gerencser: Buck Institute for Research on Aging
Herbert G. Kasler: Buck Institute for Research on Aging
Afshin Beheshti: NASA Ames Research Center
Christopher E. Mason: Weill Cornell Medicine
David Furman: Buck Institute for Research on Aging
Daniel A. Winer: Buck Institute for Research on Aging

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract Microgravity is associated with immunological dysfunction, though the mechanisms are poorly understood. Here, using single-cell analysis of human peripheral blood mononuclear cells (PBMCs) exposed to short term (25 hours) simulated microgravity, we characterize altered genes and pathways at basal and stimulated states with a Toll-like Receptor-7/8 agonist. We validate single-cell analysis by RNA sequencing and super-resolution microscopy, and against data from the Inspiration-4 (I4) mission, JAXA (Cell-Free Epigenome) mission, Twins study, and spleens from mice on the International Space Station. Overall, microgravity alters specific pathways for optimal immunity, including the cytoskeleton, interferon signaling, pyroptosis, temperature-shock, innate inflammation (e.g., Coronavirus pathogenesis pathway and IL-6 signaling), nuclear receptors, and sirtuin signaling. Microgravity directs monocyte inflammatory parameters, and impairs T cell and NK cell functionality. Using machine learning, we identify numerous compounds linking microgravity to immune cell transcription, and demonstrate that the flavonol, quercetin, can reverse most abnormal pathways. These results define immune cell alterations in microgravity, and provide opportunities for countermeasures to maintain normal immunity in space.

Date: 2024
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DOI: 10.1038/s41467-023-42013-y

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