KSHV infection drives poorly cytotoxic CD56-negative natural killer cell differentiation in vivo upon KSHV/EBV dual infection

Caduff, Nicole; McHugh, Donal; Rieble, Lisa; Forconi, Catherine S.; Ong’echa, John Michael; Oluoch, Peter O.; Raykova, Ana; Murer, Anita; Böni, Michelle; Zuppiger, Lara; Schulz, Thomas F.; Blackbourn, David J.; Chijioke, Obinna; Moormann, Ann M.; Münz, Christian

doi:10.1016/j.celrep.2021.109056

Cited by 19 publications

(33 citation statements)

References 87 publications

(129 reference statements)

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“…This co-infection can be frequently found in primary effusion lymphoma (PEL) that is 100% associated with KSHV and, in the majority of cases (90%), also harbors EBV [ 127 , 132 , 133 ]. More recently, it was also found that EBV infection supports persistent KSHV infection both in humanized mice [ 131 , 134 ] and in vitro [ 130 , 135 ]. Consistent with these findings are the observations that KSHV is usually not found without EBV co-infection in African children [ 136 , 137 ], and that the monkey orthologs of these viruses can be co-transmitted in macaques [ 138 ].…”

Section: Role Of Co-infections On Ebv Infection Immune Control and Oncogenesismentioning

confidence: 99%

“…Consistent with these findings are the observations that KSHV is usually not found without EBV co-infection in African children [ 136 , 137 ], and that the monkey orthologs of these viruses can be co-transmitted in macaques [ 138 ]. Moreover, co-infection of EBV with KSHV in humanized mice causes increased lymphoma formation, and the emerging lymphomas display some features of plasma cell differentiation [ 131 , 134 ] which is characteristic for PELs [ 133 ]. These PEL-like tumors have an elevated reactivation of EBV to its lytic replication ( Figure 2 C).…”

Section: Role Of Co-infections On Ebv Infection Immune Control and Oncogenesismentioning

confidence: 99%

“…These PEL-like tumors have an elevated reactivation of EBV to its lytic replication ( Figure 2 C). Co-infection with lytic replication-deficient BZLF1 knockout EBV and wild-type KSHV reduces lymphoma formation [ 131 , 134 ]. In addition, this co-infection drives NK cells into a dysfunctional CD56 − CD16 + CD38 + CXCR6 + differentiation stage [ 134 ].…”

Section: Role Of Co-infections On Ebv Infection Immune Control and Oncogenesismentioning

confidence: 99%

“…Co-infection with lytic replication-deficient BZLF1 knockout EBV and wild-type KSHV reduces lymphoma formation [ 131 , 134 ]. In addition, this co-infection drives NK cells into a dysfunctional CD56 − CD16 + CD38 + CXCR6 + differentiation stage [ 134 ]. Thus, KSHV seems to enhance EBV-associated lymphomagenesis both by transactivating EBV lytic replication and possibly by immune modulation.…”

Section: Role Of Co-infections On Ebv Infection Immune Control and Oncogenesismentioning

confidence: 99%

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Roles of Lytic Viral Replication and Co-Infections in the Oncogenesis and Immune Control of the Epstein–Barr Virus

Deng

Münz

2021

Cancers

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Epstein–Barr virus (EBV) is the prototypic human tumor virus whose continuous lifelong immune control is required to prevent lymphomagenesis in the more than 90% of the human adult population that are healthy carriers of the virus. Here, we review recent evidence that this immune control has not only to target latent oncogenes, but also lytic replication of EBV. Furthermore, genetic variations identify the molecular machinery of cytotoxic lymphocytes as essential for this immune control and recent studies in mice with reconstituted human immune system components (humanized mice) have begun to provide insights into the mechanistic role of these molecules during EBV infection. Finally, EBV often does not act in isolation to cause disease. Some of EBV infection-modulating co-infections, including human immunodeficiency virus (HIV) and Kaposi sarcoma-associated herpesvirus (KSHV), have been modeled in humanized mice. These preclinical in vivo models for EBV infection, lymphomagenesis, and cell-mediated immune control do not only promise a better understanding of the biology of this human tumor virus, but also the possibility to explore vaccine candidates against it.

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Section: Role Of Co-infections On Ebv Infection Immune Control and Oncogenesismentioning

confidence: 99%

Section: Role Of Co-infections On Ebv Infection Immune Control and Oncogenesismentioning

confidence: 99%

Section: Role Of Co-infections On Ebv Infection Immune Control and Oncogenesismentioning

confidence: 99%

Section: Role Of Co-infections On Ebv Infection Immune Control and Oncogenesismentioning

confidence: 99%

See 2 more Smart Citations

Roles of Lytic Viral Replication and Co-Infections in the Oncogenesis and Immune Control of the Epstein–Barr Virus

Deng

Münz

2021

Cancers

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“…Both EBV- and KSHV-encoded miRNAs compromise MICB expression [ 126 ], while K5 of KSHV ubiquitinates both MICA and MICB for internalization and degradation [ 127 ]. Thus, both viruses seem to compromise NK cell recognition, even so their co-infection leads to the differentiation of CD56-negative NK cells with poor function [ 128 ].…”

Section: Manipulation Of Antigen Presentation and Immune Recognition By Ebv And Kshvmentioning

confidence: 99%

Regulation of the Macroautophagic Machinery, Cellular Differentiation, and Immune Responses by Human Oncogenic γ-Herpesviruses

Münz

2021

Viruses

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The human γ-herpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) encode oncogenes for B cell transformation but are carried by most infected individuals without symptoms. For this purpose, they manipulate the anti-apoptotic pathway macroautophagy, cellular proliferation and apoptosis, as well as immune recognition. The mechanisms and functional relevance of these manipulations are discussed in this review. They allow both viruses to strike the balance between efficient persistence and dissemination in their human hosts without ever being cleared after infection and avoiding pathologies in most of their carriers.

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Omenn Syndrome in Two Infants with Different Hypomorphic Variants in Janus Kinase 3

Tsilifis,

Spegarova,

Good

et al. 2024

J Clin Immunol

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Biallelic null or hypomorphic variants in JAK3 cause SCID and less frequently Omenn syndrome. We investigated homozygous hypomorphic JAK3 mutations in two patients, and expression and function of a novel JAK3R431P variant in Omenn syndrome. Immunophenotyping of PBMC from the patient with the novel JAK3R431P variant was undertaken, by flow cytometry and Phosflow after stimulation with IL-2, IL-7, and IL-15. JAK3 expression was investigated by Western blotting. We report two patients with homozygous hypomorphic JAK3 variants and clinical features of Omenn syndrome. One patient had a previously described JAK3R775H variant, and the second had a novel JAK3R431P variant. One patient with a novel JAK3R431P variant had normal expression of JAK3 in immortalised EBV-LCL cells but reduced phosphorylation of STAT5 after stimulation with IL-2, IL-7, and IL-15 consistent with impaired kinase activity. These results suggest the JAK3R431P variant to be hypomorphic. Both patients are alive and well after allogeneic haematopoietic stem cell transplantation. They have full donor chimerism, restitution of thymopoiesis and development of appropriate antibody responses following vaccination. We expand the phenotype of hypomorphic JAK3 deficiency and demonstrate the importance of functional testing of novel variants in disease-causing genes.

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KSHV infection drives poorly cytotoxic CD56-negative natural killer cell differentiation in vivo upon KSHV/EBV dual infection

Cited by 19 publications

References 87 publications

Roles of Lytic Viral Replication and Co-Infections in the Oncogenesis and Immune Control of the Epstein–Barr Virus

Roles of Lytic Viral Replication and Co-Infections in the Oncogenesis and Immune Control of the Epstein–Barr Virus

Regulation of the Macroautophagic Machinery, Cellular Differentiation, and Immune Responses by Human Oncogenic γ-Herpesviruses

Omenn Syndrome in Two Infants with Different Hypomorphic Variants in Janus Kinase 3

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