A Unique Case of Hemophagocytic Lymphohistiocytosis Secondary to Varicella Zoster Virus

Reddy, Rekha M.; Brown, Christopher R.; Khurana, Tanvi; Hale, William B.

doi:10.14309/00000434-201610001-01826

Cited by 2 publications

(1 citation statement)

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“…Interestingly, both familial and sporadic HLH might present with an infectious trigger, and herpesviruses are the most common causes of virus-induced HLH, with Epstein-Barr-virus (EBV) and cytomegalovirus (CMV) accounting for more than 50% of virus-associated HLH [27]. Similarly, VZV can trigger HLH upon primary infection or reactivation, although this is mostly reported in patients with underlying immunosuppression or fHLH [23,[29][30][31].…”

Section: Recent Reports Have Described the Occurrence Of Haemophagocy...mentioning

confidence: 99%

Impaired STING activation due to a variant in the E3 ubiqitin ligase AMFR in a patient with severe VZV infection and hemophagocytic lymphohistiocytosis

Thomsen¹,

Heinz²,

Hollensen³

et al. 2022

Preprint

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Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus exclusively infecting humans, where it causes two distinct pathologies: varicella (chickenpox) upon primary infection and herpes zoster (shingles) following reactivation. In susceptible individuals, VZV can give rise to more severe clinical manifestations, including disseminated infection, pneumonitis, encephalitis, and vasculopathy. Here we describe a 3-year-old boy with severe VZV infection involving the central nervous system, subsequently triggering longstanding hemophagocytic lymphohistiocytosis (HLH). We found that the patient carries a rare monoallelic variant in autocrine motility factor receptor AMFR encoding an ubiquitin ligase involved in innate cytosolic DNA sensing and interferon (IFN) production through the cyclic GMP-AMP synthase – stimulator of IFN genes (cGAS-STING) pathway. Peripheral blood mononuclear cells (PBMCs) from the patient exhibited impaired signaling downstream of STING in response to the cGAS agonists 2’3’-cGAMP and dsDNA, as well as decreased IFN induction in response to herpes virus. VZV replication in patient PBMCs was found to be slightly increased compared to healthy controls. Overexpression of the variant AMFR p.R594C resulted in decreased K27-linked STING ubiquitination compared to expression of WT AMFR. This work links defective AMFR-STING signaling to severe VZV disease and hyperinflammation and suggests a direct role for cGAS-STING in control of viral infections in humans.

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Section: Recent Reports Have Described the Occurrence Of Haemophagocy...mentioning

confidence: 99%

Impaired STING activation due to a variant in the E3 ubiqitin ligase AMFR in a patient with severe VZV infection and hemophagocytic lymphohistiocytosis

Thomsen¹,

Heinz²,

Hollensen³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

Impaired STING Activation Due to a Variant in the E3 Ubiquitin Ligase AMFR in a Patient with Severe VZV Infection and Hemophagocytic Lymphohistiocytosis

Thomsen,

Skouboe,

Møhlenberg

et al. 2024

J Clin Immunol

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Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus exclusively infecting humans, causing two distinct pathologies: varicella (chickenpox) upon primary infection and herpes zoster (shingles) following reactivation. In susceptible individuals, VZV can give rise to more severe clinical manifestations, including disseminated infection, pneumonitis, encephalitis, and vasculopathy with stroke. Here, we describe a 3-year-old boy in whom varicella followed a complicated course with thrombocytopenia, hemorrhagic and necrotic lesions, pneumonitis, and intermittent encephalopathy. Hemophagocytic lymphohistiocytosis (HLH) was strongly suspected and as the condition deteriorated, HLH therapy was initiated. Although the clinical condition improved, longstanding hemophagocytosis followed despite therapy. We found that the patient carries a rare monoallelic variant in autocrine motility factor receptor (AMFR), encoding a ubiquitin ligase involved in innate cytosolic DNA sensing and interferon (IFN) production through the cyclic GMP-AMP synthase–stimulator of IFN genes (cGAS-STING) pathway. Peripheral blood mononuclear cells (PBMCs) from the patient exhibited impaired signaling downstream of STING in response dsDNA and 2'3'-cGAMP, agonists of cGAS and STING, respectively, and fibroblasts from the patient showed impaired type I IFN responses and significantly increased VZV replication. Overexpression of the variant AMFR R594C resulted in decreased K27-linked STING ubiquitination compared to WT AMFR. Moreover, ImageStream technology revealed reduced STING trafficking from ER to Golgi in cells expressing the patient AMFR R594C variant. This was supported by a dose-dependent dominant negative effect of expression of the patient AMFR variant as measured by IFN-β reporter gene assay. Finally, lentiviral transduction with WT AMFR partially reconstituted 2'3'-cGAMP-induced STING-mediated signaling and ISG expression in patient PBMCs. This work links defective AMFR-STING signaling to severe VZV disease and hyperinflammation and suggests a direct role for cGAS-STING in the control of viral infections in humans. In conclusion, we describe a novel genetic etiology of severe VZV disease in childhood, also representing the first inborn error of immunity related to a defect in the cGAS-STING pathway.

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A Unique Case of Hemophagocytic Lymphohistiocytosis Secondary to Varicella Zoster Virus

Cited by 2 publications

References 0 publications

Impaired STING activation due to a variant in the E3 ubiqitin ligase AMFR in a patient with severe VZV infection and hemophagocytic lymphohistiocytosis

Impaired STING activation due to a variant in the E3 ubiqitin ligase AMFR in a patient with severe VZV infection and hemophagocytic lymphohistiocytosis

Impaired STING Activation Due to a Variant in the E3 Ubiquitin Ligase AMFR in a Patient with Severe VZV Infection and Hemophagocytic Lymphohistiocytosis

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