ACE-engineered human iPSC-derived neutrophils enhance host defense against multidrug-resistant bacterial infections

Shibata, T.; Bhat, S. A.; Saito, S.; Dar, T. B.; GC, B.; Bernstein, E. A.; Khan, N.; Sareen, D.; Goodridge, H. S.; Tourtellotte, W. G.; Bernstein, K. E.; Khan, Z.

doi:10.64898/2026.11.09.765250

bioRxiv · 10.64898/2026.11.09.765250

ACE-engineered human iPSC-derived neutrophils enhance host defense against multidrug-resistant bacterial infections

Shibata, T.·Bhat, S. A.·Saito, S.·Dar, T. B.·GC, B.·Bernstein, E. A.·Khan, N.·Sareen, D.·Goodridge, H. S.·Tourtellotte, W. G.·Bernstein, K. E.·Khan, Z.

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Abstract

Severe neutropenia predisposes patients to life-threatening infections, while donor-dependent granulocyte transfusions are limited by availability and variable cell quality. Here, we engineered human induced pluripotent stem cells (iPSCs) to constitutively or inducibly express angiotensin-converting enzyme (ACE) and differentiated them into functional ACE-engineered neutrophils (ACE-iNeu). ACE expression enhanced granulocytic maturation, reactive oxygen species generation, inflammatory cytokine production, and antimicrobial signaling. ACE-iNeu exhibited enhanced bactericidal activity against methicillin-resistant Staphylococcus aureus and multidrug-resistant Pseudomonas aeruginosa. Following adoptive transfer into neutropenic mice, ACE-iNeu significantly reduced circulating and tissue bacterial burdens. Integrated metabolomic and transcriptomic analyses revealed ACE-associated alterations in adenine nucleotide abundance and developmental and inflammatory pathways. Together, these findings establish ACE engineering as a strategy to enhance the production and antimicrobial function of human iPSC-derived neutrophils and support further preclinical development of engineered granulocyte therapies for severe drug-resistant infections.

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Shibata, T., Bhat, S. A., Saito, S., Dar, T. B., GC, B., Bernstein, E. A., Khan, N., Sareen, D., Goodridge, H. S., Tourtellotte, W. G., Bernstein, K. E., Khan, Z.. 2026-11-11. ACE-engineered human iPSC-derived neutrophils enhance host defense against multidrug-resistant bacterial infections. https://doi.org/10.64898/2026.11.09.765250

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