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

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.

Automated summary

The immune response to chronic viral infection is finely balanced between viral control and immunopathology, with suppressive neutrophils playing a key role in chronic infection. Inhibiting PIM1 kinase can selectively reduce immunosuppression mediated by suppressive neutrophils, leading to enhanced CD8 T cell function and improved viral control. This highlights the importance of targeting specific myeloid cell populations to modulate immune responses in chronic viral infections.