Sphingosine kinase 2 restricts T cell immunopathology but permits viral persistence

Studstill, Caleb J.; Pritzl, Curtis J.; Seo, Young-­Jin; Kim, Dae Y.; Xia, Chuan; Wolf, Jennifer J.; Nistala, Ravi; Vijayan, Madhuvanthi; Cho, Yong-Bin; Kang, Kyung‐Won; Lee, Sang-Myeong; Hahm, Bumsuk

doi:10.1172/jci125297

Cited by 19 publications

(18 citation statements)

References 98 publications

(125 reference statements)

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“…We have recently identified a cellular protein, sphingosine kinase 2 (SphK2), which is important for regulating T cell exhaustion, specifically through an intrinsic mechanism in CD4 + T cells [ 123 ]. SphK2 is an enzyme responsible for the generation of sphingosine 1-phosphate (S1P), a bioactive lipid metabolite, which regulates diverse cellular and disease conditions.…”

Section: Regulation Of T Cell Exhaustionmentioning

confidence: 99%

Chronic LCMV Infection Is Fortified with Versatile Tactics to Suppress Host T Cell Immunity and Establish Viral Persistence

Studstill

Hahm

2021

Viruses

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Ever since the immune regulatory strains of lymphocytic choriomeningitis virus (LCMV), such as Clone 13, were isolated, LCMV infection of mice has served as a valuable model for the mechanistic study of viral immune suppression and virus persistence. The exhaustion of virus-specific T cells was demonstrated during LCMV infection, and the underlying mechanisms have been extensively investigated using LCMV infection in mouse models. In particular, the mechanism for gradual CD8+ T cell exhaustion at molecular and transcriptional levels has been investigated. These studies revealed crucial roles for inhibitory receptors, surface markers, regulatory cytokines, and transcription factors, including PD-1, PSGL-1, CXCR5, and TOX in the regulation of T cells. However, the action mode for CD4+ T cell suppression is largely unknown. Recently, sphingosine kinase 2 was proven to specifically repress CD4+ T cell proliferation and lead to LCMV persistence. As CD4+ T cell regulation was also known to be important for viral persistence, research to uncover the mechanism for CD4+ T cell repression could help us better understand how viruses launch and prolong their persistence. This review summarizes discoveries derived from the study of LCMV in regard to the mechanisms for T cell suppression and approaches for the termination of viral persistence with special emphasis on CD8+ T cells.

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Section: Regulation Of T Cell Exhaustionmentioning

confidence: 99%

Chronic LCMV Infection Is Fortified with Versatile Tactics to Suppress Host T Cell Immunity and Establish Viral Persistence

Studstill

Hahm

2021

Viruses

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“…Side effects can only be studied in a whole organism in the presence of a functional immune system. Often, effects on the immune system dominate the overall antiviral response, as for example, in the case of persistent lymphocytic choriomeningitis virus (LCMV) infection of mice, where inhibition of the SphK2 stimulates the T cell response and elimination of the infection ( Studstill et al, 2020 ). Especially with respect to SARS-CoV-2 infection, it will be interesting to see if repurposed drugs affecting sphingolipid metabolism will be of use to reduce viral replication in vivo and accelerate viral clearance.…”

Section: Discussionmentioning

confidence: 99%

The Manifold Roles of Sphingolipids in Viral Infections

et al. 2021

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Sphingolipids are essential components of eukaryotic cells. In this review, we want to exemplarily illustrate what is known about the interactions of sphingolipids with various viruses at different steps of their replication cycles. This includes structural interactions during entry at the plasma membrane or endosomal membranes, early interactions leading to sphingolipid-mediated signal transduction, interactions with internal membranes and lipids during replication, and interactions during virus assembly and budding. Targeted interventions in sphingolipid metabolism – as far as they can be tolerated by cells and organisms – may open novel possibilities to support antiviral therapies. Human immunodeficiency virus type 1 (HIV-1) infections have intensively been studied, but for other viral infections, such as influenza A virus (IAV), measles virus (MV), hepatitis C virus (HCV), dengue virus, Ebola virus, and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), investigations are still in their beginnings. As many inhibitors of sphingolipid metabolism are already in clinical use against other diseases, repurposing studies for applications in some viral infections appear to be a promising approach.

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“…Thus, in addition to preventing S1P-mediated cellular activation which overall is mainly beneficial for viral replication, fingolimod has apparently virus-specific targets as well. Although it did not mechanistically address the role of S1P or S1PR signaling, a recent study provided compelling evidence that SphK2, the enzyme required to activate fingolimod, efficiently prevented clearance of LCMV in experimentally infected mice by restricting T cell immunopathology and promoting viral persistence [ 151 ]. Based on its anti-inflammatory activity, fingolimod (or, in general terms, inhibitors of S1P receptor signaling) has also been evaluated for its beneficial effect in virally-induced immunopathology when brought about by hyperinflammation through the activity of immune effector cells or cytokine storm.…”

Section: Outlook and Perspectivesmentioning

confidence: 99%

Sphingolipids: Effectors and Achilles Heals in Viral Infections?

Schneider‐Schaulies

Schumacher

Wigger

et al. 2021

Cells

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As viruses are obligatory intracellular parasites, any step during their life cycle strictly depends on successful interaction with their particular host cells. In particular, their interaction with cellular membranes is of crucial importance for most steps in the viral replication cycle. Such interactions are initiated by uptake of viral particles and subsequent trafficking to intracellular compartments to access their replication compartments which provide a spatially confined environment concentrating viral and cellular components, and subsequently, employ cellular membranes for assembly and exit of viral progeny. The ability of viruses to actively modulate lipid composition such as sphingolipids (SLs) is essential for successful completion of the viral life cycle. In addition to their structural and biophysical properties of cellular membranes, some sphingolipid (SL) species are bioactive and as such, take part in cellular signaling processes involved in regulating viral replication. It is especially due to the progress made in tools to study accumulation and dynamics of SLs, which visualize their compartmentalization and identify interaction partners at a cellular level, as well as the availability of genetic knockout systems, that the role of particular SL species in the viral replication process can be analyzed and, most importantly, be explored as targets for therapeutic intervention.

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Sphingosine kinase 2 restricts T cell immunopathology but permits viral persistence

Cited by 19 publications

References 98 publications

Chronic LCMV Infection Is Fortified with Versatile Tactics to Suppress Host T Cell Immunity and Establish Viral Persistence

Chronic LCMV Infection Is Fortified with Versatile Tactics to Suppress Host T Cell Immunity and Establish Viral Persistence

The Manifold Roles of Sphingolipids in Viral Infections

Sphingolipids: Effectors and Achilles Heals in Viral Infections?

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