Suppressive neutrophils require PIM1 for metabolic fitness and survival during chronic viral infection

Peter J. Volberding; Gang Xin; Moujtaba Y. Kasmani; Achia Khatun; Ashley K. Brown; Christine Nguyen; Jennifer S. Stancill; Eli Martinez; John A. Corbett; Weiguo Cui

doi:10.1016/j.celrep.2021.109160

Suppressive neutrophils require PIM1 for metabolic fitness and survival during chronic viral infection

Peter J. Volberding, Gang Xin, Moujtaba Y. Kasmani, Achia Khatun, Ashley K. Brown, Christine Nguyen, Jennifer S. Stancill, Eli Martinez, John A. Corbett, Weiguo Cui^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

The immune response to a chronic viral infection is uniquely tailored to balance viral control and immunopathology. The role of myeloid cells in shaping the response to chronic viral infection, however, is poorly understood. We perform single-cell RNA sequencing of myeloid cells during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection to address this question. Our analysis identifies a cluster of suppressive neutrophils that is enriched in chronic infection. Furthermore, suppressive neutrophils highly express the gene encoding Proviral integration site for Moloney murine leukemia virus-1 (PIM1), a kinase known to promote mitochondrial fitness and cell survival. Pharmacological inhibition of PIM1 selectively diminishes suppressive neutrophil-mediated immunosuppression without affecting the function of monocytic myeloid-derived suppressor cells (M-MDSCs). Decreased accumulation of suppressive neutrophils leads to increased CD8 T cell function and viral control. Mechanistically, PIM kinase activity is required for maintaining fused mitochondrial networks in suppressive neutrophils, but not in M-MDSCs, and loss of PIM kinase function causes increased suppressive neutrophil apoptosis.

Original language	English (US)
Article number	109160
Journal	Cell reports
Volume	35
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2021.109160
State	Published - May 25 2021

Funding

This work is supported by NIH grants AI125741 and AI148403 (to W.C.) and DK127526 (to M.Y.K.); by an American Cancer Society research scholar grant (to W.C.); and by an Advancing a Healthier Wisconsin Endowment (AHW) grant (to W.C). G.X. is supported by The Elizabeth Elser Doolittle Postdoctoral Fellowship . M.Y.K. and A.K.B. are members of the Medical Scientist Training Program at the Medical College of Wisconsin (MCW), which is partially supported by a training grant from NIGMS ( T32-GM080202 ). This research was completed in part with computational resources and technical support provided by the Research Computing Center at MCW.

Keywords

LCMV
PIM1
PMN-MDSC
T cell function
chronic viral infection
metabolism
mitochondrial dynamics
single-cell RNA sequencing
suppressive neutrophil

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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title = "Suppressive neutrophils require PIM1 for metabolic fitness and survival during chronic viral infection",

abstract = "The immune response to a chronic viral infection is uniquely tailored to balance viral control and immunopathology. The role of myeloid cells in shaping the response to chronic viral infection, however, is poorly understood. We perform single-cell RNA sequencing of myeloid cells during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection to address this question. Our analysis identifies a cluster of suppressive neutrophils that is enriched in chronic infection. Furthermore, suppressive neutrophils highly express the gene encoding Proviral integration site for Moloney murine leukemia virus-1 (PIM1), a kinase known to promote mitochondrial fitness and cell survival. Pharmacological inhibition of PIM1 selectively diminishes suppressive neutrophil-mediated immunosuppression without affecting the function of monocytic myeloid-derived suppressor cells (M-MDSCs). Decreased accumulation of suppressive neutrophils leads to increased CD8 T cell function and viral control. Mechanistically, PIM kinase activity is required for maintaining fused mitochondrial networks in suppressive neutrophils, but not in M-MDSCs, and loss of PIM kinase function causes increased suppressive neutrophil apoptosis.",

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author = "Volberding, {Peter J.} and Gang Xin and Kasmani, {Moujtaba Y.} and Achia Khatun and Brown, {Ashley K.} and Christine Nguyen and Stancill, {Jennifer S.} and Eli Martinez and Corbett, {John A.} and Weiguo Cui",

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AU - Brown, Ashley K.

AU - Nguyen, Christine

AU - Stancill, Jennifer S.

AU - Martinez, Eli

AU - Corbett, John A.

AU - Cui, Weiguo

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N2 - The immune response to a chronic viral infection is uniquely tailored to balance viral control and immunopathology. The role of myeloid cells in shaping the response to chronic viral infection, however, is poorly understood. We perform single-cell RNA sequencing of myeloid cells during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection to address this question. Our analysis identifies a cluster of suppressive neutrophils that is enriched in chronic infection. Furthermore, suppressive neutrophils highly express the gene encoding Proviral integration site for Moloney murine leukemia virus-1 (PIM1), a kinase known to promote mitochondrial fitness and cell survival. Pharmacological inhibition of PIM1 selectively diminishes suppressive neutrophil-mediated immunosuppression without affecting the function of monocytic myeloid-derived suppressor cells (M-MDSCs). Decreased accumulation of suppressive neutrophils leads to increased CD8 T cell function and viral control. Mechanistically, PIM kinase activity is required for maintaining fused mitochondrial networks in suppressive neutrophils, but not in M-MDSCs, and loss of PIM kinase function causes increased suppressive neutrophil apoptosis.

AB - The immune response to a chronic viral infection is uniquely tailored to balance viral control and immunopathology. The role of myeloid cells in shaping the response to chronic viral infection, however, is poorly understood. We perform single-cell RNA sequencing of myeloid cells during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection to address this question. Our analysis identifies a cluster of suppressive neutrophils that is enriched in chronic infection. Furthermore, suppressive neutrophils highly express the gene encoding Proviral integration site for Moloney murine leukemia virus-1 (PIM1), a kinase known to promote mitochondrial fitness and cell survival. Pharmacological inhibition of PIM1 selectively diminishes suppressive neutrophil-mediated immunosuppression without affecting the function of monocytic myeloid-derived suppressor cells (M-MDSCs). Decreased accumulation of suppressive neutrophils leads to increased CD8 T cell function and viral control. Mechanistically, PIM kinase activity is required for maintaining fused mitochondrial networks in suppressive neutrophils, but not in M-MDSCs, and loss of PIM kinase function causes increased suppressive neutrophil apoptosis.

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Suppressive neutrophils require PIM1 for metabolic fitness and survival during chronic viral infection

Abstract

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