Suppression of DC-SIGN and gH Reveals Complex, Subset-Specific Mechanisms for KSHV Entry in Primary B Lymphocytes

Palmerin, Nancy; Aalam, Farizeh; Nabiee, Romina; Muniraju, Murali; Ogembo, Javier Gordon; Totonchy, Jennifer

doi:10.3390/v13081512

Cited by 4 publications

(1 citation statement)

References 21 publications

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“…In the current study, we evaluate how IFN-γ affects KSHV infection of primary B lymphocytes using our well-established model of ex vivo infection in human tonsil lymphocytes [ 14 , 15 , 16 ]. We demonstrate that IFN-γ can inhibit KSHV infection in B cells at an early stage.…”

Section: Introductionmentioning

confidence: 99%

Host-Level Susceptibility and IRF1 Expression Influence the Ability of IFN-γ to Inhibit KSHV Infection in B Lymphocytes

Alomari

Totonchy

2022

Viruses

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Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with vascular endothelial cell tumor, Kaposi’s sarcoma (KS) and lymphoproliferative disorder, multicentric Castleman’s disease (MCD), primary effusion lymphoma (PEL) and KSHV inflammatory cytokine syndrome (KICS). Dysregulation of proinflammatory cytokines is found in most KSHV associated diseases. However, little is known about the role of host microenvironment in the regulation of KSHV establishment in B cells. In the present study, we demonstrated that IFN-γ has a strong inhibitory effect on KSHV infection but only in a subset of tonsil-derived lymphocyte samples that are intrinsically more susceptible to infection, contain higher proportions of naïve B cells, and display increased levels of IRF1 and STAT1-pY701. The effect of IFN-γ in responsive samples was associated with increased frequencies of germinal center B cells (GCB) and decreased infection of plasma cells, suggesting that IFN-γ-mediated modulation of viral dynamics in GC can inhibit the establishment of KSHV infection.

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Section: Introductionmentioning

confidence: 99%

Host-Level Susceptibility and IRF1 Expression Influence the Ability of IFN-γ to Inhibit KSHV Infection in B Lymphocytes

Alomari

Totonchy

2022

Viruses

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IL-21 signaling promotes the establishment of KSHV infection in human tonsil lymphocytes by increasing early targeting of plasma cells

Totonchy

Alomari

Aalam

et al. 2021

Preprint

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Kaposi’s sarcoma-associated herpesvirus (KSHV) extensively manipulates the host immune system and the cytokine milieu, and cytokines are known to influence the progression of KSHVassociated diseases. However, the precise role of cytokines in the early stages of KSHV infection remains undefined. Here, using our unique model of KSHV infection in tonsil lymphocytes, we investigate the influence of host cytokines on the establishment of KSHV infection in B cells. Our data demonstrate that KSHV manipulates the host cytokine microenvironment during early infection and susceptibility generally associated with downregulation of multiple cytokines. However, we show that IL-21 signaling promotes KSHV infection by promoting both plasma cell numbers and increasing KSHV infection in plasma cells. Our data reveal that IL-21 producing T cells, particularly Th17/Tc17 and central memory CD8+ T cells may represent immunological factors that modulate host-level susceptibility to KSHV infection. These results suggest that IL-21 plays a significant role in the early stages of KSHV infection in the human immune system and may represent a novel mechanism to be further explored in the context of preventing KSHV transmission.

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Kaposi sarcoma-associated herpesvirus complement control protein (KCP) and glycoprotein K8.1 are not required for viral infection in vitro or in vivo

Muniraju,

Mutsvunguma,

Reidel

et al. 2024

J Virol

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Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, is the causal agent of Kaposi sarcoma, a cancer that appears as tumors on the skin or mucosal surfaces, as well as primary effusion lymphoma and KSHV-associated multicentric Castleman disease, which are B-cell lymphoproliferative disorders. Effective prophylactic and therapeutic strategies against KSHV infection and its associated diseases are needed. To develop these strategies, it is crucial to identify and target viral glycoproteins involved in KSHV infection of host cells. Multiple KSHV glycoproteins expressed on the viral envelope are thought to play a pivotal role in viral infection, but the infection mechanisms involving these glycoproteins remain largely unknown. We investigated the role of two KSHV envelope glycoproteins, KSHV complement control protein (KCP) and K8.1, in viral infection in various cell types in vitro and in vivo . Using our newly generated anti-KCP antibodies, previously characterized anti-K8.1 antibodies, and recombinant mutant KSHV viruses lacking KCP, K8.1, or both, we demonstrated the presence of KCP and K8.1 on the surface of both virions and KSHV-infected cells. We showed that KSHV lacking KCP and/or K8.1 remained infectious in KSHV-susceptible cell lines, including epithelial, endothelial, and fibroblast, when compared to wild-type recombinant KSHV. We also provide the first evidence that KSHV lacking K8.1 or both KCP and K8.1 can infect human B cells in vivo in a humanized mouse model. Thus, these results suggest that neither KCP nor K8.1 is required for KSHV infection of various host cell types and that these glycoproteins do not determine KSHV cell tropism. IMPORTANCE Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic human gamma-herpesvirus associated with the endothelial malignancy Kaposi sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman disease. Determining how KSHV glycoproteins such as complement control protein (KCP) and K8.1 contribute to the establishment, persistence, and transmission of viral infection will be key for developing effective anti-viral vaccines and therapies to prevent and treat KSHV infection and KSHV-associated diseases. Using newly generated anti-KCP antibodies, previously characterized anti-K8.1 antibodies, and recombinant mutant KSHV viruses lacking KCP and/or K8.1, we show that KCP and K8.1 can be found on the surface of both virions and KSHV-infected cells. Furthermore, we show that KSHV lacking KCP and/or K8.1 remains infectious to diverse cell types susceptible to KSHV in vitro and to human B cells in vivo in a humanized mouse model, thus providing evidence that these viral glycoproteins are not required for KSHV infection.

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Suppression of DC-SIGN and gH Reveals Complex, Subset-Specific Mechanisms for KSHV Entry in Primary B Lymphocytes

Cited by 4 publications

References 21 publications

Host-Level Susceptibility and IRF1 Expression Influence the Ability of IFN-γ to Inhibit KSHV Infection in B Lymphocytes

Host-Level Susceptibility and IRF1 Expression Influence the Ability of IFN-γ to Inhibit KSHV Infection in B Lymphocytes

IL-21 signaling promotes the establishment of KSHV infection in human tonsil lymphocytes by increasing early targeting of plasma cells

Kaposi sarcoma-associated herpesvirus complement control protein (KCP) and glycoprotein K8.1 are not required for viral infection in vitro or in vivo

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