Sphingosine kinase 2 suppresses neutrophil responses to promote viral persistence while attenuating immune pathology

Vijayamahantesh, V.; He, Y.; Jiang, L.; Huerter, H.; Jung, K. I.; McKenna, S.; Studstill, C. J.; Allen, L.-A. H.; Nistala, R.; Xu, D.; Hahm, B.

doi:10.1101/2025.09.08.674905

bioRxiv · 10.1101/2025.09.08.674905

Sphingosine kinase 2 suppresses neutrophil responses to promote viral persistence while attenuating immune pathology

Vijayamahantesh, V.·He, Y.·Jiang, L.·Huerter, H.·Jung, K. I.·McKenna, S.·Studstill, C. J.·Allen, L.-A. H.·Nistala, R.·Xu, D.·Hahm, B.

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Abstract

Chronic virus infections often suppress immune cell functions which helps in restricting immune pathology but leads to viral persistence. However, the underlying mechanisms are incompletely understood. We recently found that sphingosine kinase 2 (SphK2)-deficient (Sphk2-/-) mice succumbed to lymphocytic choriomeningitis virus (LCMV) infection due to immune pathology. In addition to heightened T cell immunity, a notable increase of neutrophils was observed in LCMV-infected Sphk2-/- mice. Depletion of neutrophils increased the viability of virus-infected Sphk2-/- mice, supporting a role of SphK2-deficient neutrophils in viral immune pathogenesis. Further, SphK2-deficient neutrophils expressed lower levels of the immune suppressive marker CD244 during infection. Importantly, adoptively transferred SphK2-deficient neutrophils demonstrated intrinsic regulation of CD244 and improved virus-specific T cell responses, resulting in diminished viral burden. Transcriptomic analysis revealed increased expression of pro-inflammatory and antiviral genes in SphK2-deficient neutrophils. These results indicate that SphK2 promotes suppressive neutrophil responses and regulates neutrophil-associated immune pathology during a persistent infection. Our findings may help design new immune therapeutics to control chronic viral diseases. SignificanceNeutrophils are the sentinels of the innate immune system; they can reshape innate and adaptive immune responses. During chronic illnesses, such as persistent viral infections, neutrophils can suppress the host immune response and help in disease progression. Here, we demonstrate regulation of neutrophil expansion and functions by sphingosine kinase 2 (SphK2) during LCMV infection. SphK2-deficient neutrophils express a reduced level of inhibitory receptor CD244, exert immune stimulatory effects on T cells, and promote virus clearance. Further, transcriptomic analysis reveals that SphK2 deficiency leads to the development of proinflammatory neutrophils. Our study identifies SphK2, a host factor, as being critical for neutrophil suppression that regulates dysfunctional T cell response and virus persistence.

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Vijayamahantesh, V., He, Y., Jiang, L., Huerter, H., Jung, K. I., McKenna, S., Studstill, C. J., Allen, L.-A. H., Nistala, R., Xu, D., Hahm, B.. 2025-09-14. Sphingosine kinase 2 suppresses neutrophil responses to promote viral persistence while attenuating immune pathology. https://doi.org/10.1101/2025.09.08.674905

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