Analysis of KSHV B lymphocyte lineage tropism in human tonsil reveals efficient infection of CD138+ plasma cells

Aalam, Farizeh; Nabiee, Romina; Castano, Jesus Ramirez; Totonchy, Jennifer

doi:10.1101/2020.01.17.910612

Cited by 4 publications

(18 citation statements)

References 31 publications

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“…GAPDH was used as a housekeeping gene and normalizing factor for the viral gene expression data. This data is consistent with our previous data showing a mix of lytic and latent transcripts in infected lymphocytes [10]. These data reveal no significant influence of either supplementation or neutralization on lytic gene expression (Fig 3F).…”

Section: Resultssupporting

confidence: 93%

“…Our results presented in this study indicate that KSHV can influence cytokine production in tonsilderived lymphocytes and that the host inflammatory state contributes to the dramatic variation in susceptibility we observe among our tonsil lymphocyte specimens [12]. This result is not surprising considering dysregulation of the inflammatory environment is a hallmark of all KSHVassociated malignancies [24,26,27].…”

Section: Discussionsupporting

confidence: 61%

“…In this study, we use our well-established tonsil lymphocyte infection model to explore whether KSHV alters cytokine secretion early in infection and whether cytokine levels have an effect on the establishment of KSHV infection. We identify IL-21 as a factor that specifically influences KSHV infection in plasma cells, which we previously characterized as a highly targeted cell type in early infection [12]. We demonstrate that IL-21 signaling increases plasma cell levels in our ex vivo model system and that this effect promotes overall KSHV infection.…”

Section: Introductionmentioning

confidence: 59%

“…However, their contribution to the early stages of KSHV infection and whether the cytokine milieu in the oral cavity contributes to hostlevel susceptibility to KSHV infection is unclear. KSHV-infected cells in KSHV-associated lymphoproliferative diseases generally display plasma cell or plasmablast features [11], and our recent work showed that KSHV targets plasma cells in early infection in tonsil B lymphocytes [12]. Whether the KSHV-infected plasma cells we observe arise from direct infection or differentiation from a precursor B cell subset remains to be established.…”

Section: Introductionmentioning

confidence: 72%

“…As with our previous studies exploring factors influencing susceptibility of tonsil samples to KSHV infection, we concentrated data collection on 3 dpi, as the earliest timepoint in which infection can be reliably detected, in order to maximize our ability to identify intrinsic susceptibility factors and minimize the contribution of cell culture artifacts that accumulate over time in the cultures. We identify IL-21 as a factor that specifically influences KSHV infection in plasma cells, which we previously characterized as a highly targeted cell type in early infection [10]. We show that supplementation of tonsil lymphocyte cultures with IL-21 enhances total infection while IL-21 neutralization decreases total KSHV infection at early times post-infection.…”

Section: Introductionmentioning

confidence: 81%

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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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Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 81%

See 3 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

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

Alomari

Totonchy

2022

Front. Immunol.

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IntroductionFactors influencing Kaposi’s sarcoma-associated herpesvirus (KSHV) transmission and the early stages of KSHV infection in the human immune system remain poorly characterized. KSHV is known to extensively manipulate the host immune system and the cytokine milieu, and cytokines are known to influence the progression of KSHV-associated diseases. Our previous work identified the early targeting of plasma cells for KSHV infection. In this study, we examine whether IL-21, a cytokine known to profoundly influence plasma cell fate, influences the early stages of KSHV infection in B lymphocytes.MethodsUsing our unique model of ex vivo KSHV infection in tonsil lymphocytes, we investigate the influence of IL-21 supplementation, IL-21 neutralization, the distribution of IL-21 receptor on B cell subsets and IL-21 secreting T cell subsets on the establishment of KSHV infection in human B cells.ResultsWe show that IL-21 signaling promotes KSHV infection by promoting both total plasma cell numbers and increasing KSHV infection in plasma cells as early as 3 days post-infection. We further demonstrate that the synergistic effect of KSHV infection and IL-21 treatment on plasma cell frequencies is due to differentiation of new plasma cells from naïve B cell precursors. We examine T cells secreting IL-21 in our tonsil specimens and determine that IL-21 producing CD8+ central memory T cells are correlated with plasma cell frequencies and KSHV targeting of plasma cells.DiscussionThese results demonstrate the novel finding that differentiation of new plasma cells is involved in the early stages of KSHV infection in B cells, and that IL-21 signaling can potentiate this effect thereby increasing the overall magnitude of KSHV infection at early timepoints. These results suggest that IL-21 signaling represents a host-level susceptibility factor for the establishment of KSHV infection.

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

Palmerin

Aalam

Nabiee

et al. 2021

Viruses

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Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of multiple cancers in immunocompromised patients including two lymphoproliferative disorders associated with KSHV infection of B lymphocytes. Despite many years of research into the pathogenesis of KSHV associated diseases, basic questions related to KSHV molecular virology remain unresolved. One such unresolved question is the cellular receptors and viral glycoproteins needed for KSHV entry into primary B lymphocytes. In this study, we assess the contributions of KSHV glycoprotein H (gH) and the cellular receptor DC-SIGN to KSHV infection in tonsil-derived B lymphocytes. Our results show that (1) neither KSHV-gH nor DC-SIGN are essential for entry into any B cell subset, (2) DC-SIGN does play a role in KSHV entry into tonsil-derived B cells, but in all B cell subtypes alternative entry mechanisms exist, (3) KSHV-gH can participate in KSHV entry into centrocytes via a DC-SIGN independent entry mechanism, and (4) in the absence of KSHV-gH, DC-SIGN is required for KSHV entry into centrocytes. Our results provide a first glimpse into the complexity of KSHV entry in the lymphocyte compartment and highlight that multiple subset-dependent entry mechanisms are employed by KSHV which depend upon multiple cellular receptors and multiple KSHV glycoproteins.

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Analysis of KSHV B lymphocyte lineage tropism in human tonsil reveals efficient infection of CD138+ plasma cells

Cited by 4 publications

References 31 publications

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

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

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

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

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