RT Journal Article
SR Electronic
T1 Bat pluripotent stem cells reveal unique entanglement between host and viruses
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.09.23.509261
DO 10.1101/2022.09.23.509261
A1 Marion Déjosez
A1 Arturo Marin
A1 Graham M. Hughes
A1 Ariadna E. Morales
A1 Carlos Godoy-Parejo
A1 Jonathan Gray
A1 Yiren Qin
A1 Arun A. Singh
A1 Hui Xu
A1 Javier Juste
A1 Carlos Ibáñez
A1 Kris M. White
A1 Romel Rosales
A1 Nancy J. Francoeur
A1 Robert P. Sebra
A1 Dominic Alcock
A1 Sébastien J. Puechmaille
A1 Andrzej Pastusiak
A1 Simon D.W. Frost
A1 Michael Hiller
A1 Richard A. Young
A1 Emma C. Teeling
A1 Adolfo García-Sastre
A1 Thomas P. Zwaka
YR 2022
UL http://biorxiv.org/content/early/2022/09/26/2022.09.23.509261.abstract
AB Bats have evolved features unique amongst mammals, including flight, laryngeal echolocation, and certain species have been shown to have a unique immune response that may enable them to tolerate viruses such as SARS-CoVs, MERS-CoVs, Nipah, and Marburg viruses. Robust cellular models have yet to be developed for bats, hindering our ability to further understand their special biology and handling of viral pathogens. To establish bats as new model study species, we generated induced pluripotent stem cells (iPSCs) from a wild greater horseshoe bat (Rhinolophus ferrumequinum) using a modified Yamanaka protocol. Rhinolophids are amongst the longest living bat species and are asymptomatic carriers of coronaviruses, including one of the viruses most closely related to SARS-CoV-2. Bat induced pluripotent stem (BiPS) cells were stable in culture, readily differentiated into all three germ layers, and formed complex embryoid bodies, including organoids. The BiPS cells were found to have a core pluripotency gene expression program similar to that of other species, but it also resembled that of cells attacked by viruses. The BiPS cells produced a rich set of diverse endogenized viral sequences and in particular retroviruses. We further validated our protocol by developing iPS cells from an evolutionary distant bat species Myotis myotis (greater mouse-eared bat) non-lethally sampled in the wild, which exhibited similar attributes to the greater horseshoe bat iPS cells, suggesting that this unique pluripotent state evolved in the ancestral bat lineage. Although previous studies have suggested that bats have developed powerful strategies to tame their inflammatory response, our results argue that they have also evolved mechanisms to accommodate a substantial load of endogenous viral sequences and suggest that the natural history of bats and viruses is more profoundly intertwined than previously thought. Further study of bat iPS cells and their differentiated progeny should advance our understanding of the role bats play as virus hosts, provide a novel method of disease surveillance, and enable the functional studies required to ascertain the molecular basis of bats’ unique traits.Competing Interest StatementTPZ, MD and AGS are inventors on patents and patent applications on the use of bat iPSCs, owned by the Icahn School of Medicine at Mount Sinai, New York. TPZ and RAY are the founders of Paratus Sciences and owns stock in the company. The AGS laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, and Merck, outside of the reported work. AGS has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories and Pfizer, outside of the reported work. AGS is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work. AM is the creator of Omics Bioinformatics and owns all the stocks of this company.