Impact of a Demyelination-Inducing Central Nervous System Virus on Expression of Demyelination Genes in Type 2 Lymphoid Cells

Abstract

We recently reported the role of innate lymphoid cells type 2 (ILC2s) in CNS demyelination using an HSV-IL-2 model of CNS demyelination. Here we studied how ILC2s respond to HSV-IL-2 at the cellular level using cytokine and gene expression profiling. ILC2s infected with HSV-IL-2 expressed higher levels of GM-CSF, IL-5, IL-6, IL-13, IP-10, MIP-2, and RANTES, which include proinflammatory cytokines, than did those infected with parental control virus. In contrast, TH2 cytokines IL-4 and IL-9, which are typically expressed by ILC2s, were not induced upon HSV-IL-2 infection. RNA-Seq analysis of HSV-IL-2 infected ILC2s showed significant upregulation of over 350 genes and downregulation of 157 genes compared with parental virus-infected ILC2s. GO term analysis indicated that genes related to “mitosis” and “inflammatory response” were among the upregulated genes, suggesting that HSV-IL-2 infection drives the excessive proliferation and atypical inflammatory response of ILC2s. This change in ILC2 activation state could underlie the pathology of demyelinating diseases. IMPORTANCE Innate lymphocytes have plasticity and can change functionality; innate lymphoid cells type 2 (ILC2s) can convert to ILC1 or ILC3 cells, or change their activation state to produce IL-17 or IL-10 depending on environmental cues. In this study, we investigated the gene and cytokine profile of ILC2s, which play a major role in HSV-IL-2-induced CNS demyelination. ILC2s infected with HSV-IL-2 displayed a massive remodeling of cellular state. Additionally, ILC2s infected with HSV-IL-2 differed from those infected with parental HSV in cellular and viral gene expression profiles and in cytokine/chemokine induction, and displayed enhanced activation and proinflammatory responses. These changes in ILC2 activation state could underlie the pathology of demyelinating diseases. These results also highlight the possible importance of pathogens as environmental cues to modify innate lymphocyte functionalities.

Immunopathology of herpes simplex virus‐associated neuroinflammation: Unveiling the mysteries

“…Their crucial role lies in activating and amplifying virus‐specific CD8+ T cells, thereby influencing the immune response dynamics 285 . The initiation of an effective immune response during HE hinges on the participation of CCR2 and CX3CR1 receptors, which facilitate the intricate interplay of resistant components 286,287 . MMP‐9 assumes significance in the context of HE due to its substantial involvement in promoting cerebrovascular complications.…”

“…285 The initiation of an effective immune response during HE hinges on the participation of CCR2 and CX3CR1 receptors, which facilitate the intricate interplay of resistant components. 286,287 MMP-9 assumes significance in the context of HE due to its substantial involvement in promoting cerebrovascular complications. These complications significantly contribute to this condition's elevated mortality and morbidity rates.…”