Mast cell activation and KSHV infection in Kaposi sarcoma

Leona W. Ayers, Arturo Barbachano-Guerrero, Shane C McAllister, Julie A. Ritchie, Elizabeth Asiago-Reddy, Linda C. Bartlett, Ethel Cesarman, Dongliang Wang, Rosemary Rochford, Jeffrey N. Martin, Christine A. King

Research output: Contribution to journalArticle

Abstract

Purpose: Kaposi sarcoma (KS) is a vascular tumor initiated by infection of endothelial cells (ECs) with KS-associated herpesvirus (KSHV). KS is dependent on sustained proinflammatory signals provided by intralesional leukocytes and continued infection of new ECs. However, the sources of these cytokines and infectious virus within lesions are not fully understood. Here, mast cells (MCs) are identified as proinflammatory cells within KS lesions that are permissive for, and activated by, infection with KSHV. Experimental Design: Three validated MC lines were used to assess permissivity of MCs to infection with KSHV and to evaluate MCs activation following infection. Biopsies from 31 AIDS-KS cases and 11 AIDS controls were evaluated by IHC for the presence of MCs in KS lesions and assessment of MC activation state and infection with KSHV. Plasma samples from 26 AIDS-KS, 13 classic KS, and 13 healthy adults were evaluated for levels of MC granule contents tryptase and histamine. Results: In culture, MCs supported latent and lytic KSHV infection, and infection-induced MC degranulation. Within KS lesions, MCs were closely associated with spindle cells. Furthermore,MCactivation was extensive within patients with KS, reflected by elevated circulating levels of tryptase and a histamine metabolite. One patient with clinical signs of extensive MC activation was treated with antagonists of MC proinflammatory mediators, which resulted in a rapid and durable regression of AIDS-KS lesions. Conclusions: Using complimentary in vitro and in vivo studies we identify MCs as a potential long-lived reservoir for KSHV and a source of proinflammatory mediators within the KS lesional microenvironment. In addition, we identify MC antagonists as a promising novel therapeutic approach for KS.

Original languageEnglish (US)
Pages (from-to)5085-5097
Number of pages13
JournalClinical Cancer Research
Volume24
Issue number20
DOIs
StatePublished - Oct 15 2018

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Herpesviridae Infections
Kaposi's Sarcoma
Mast Cells
Herpesviridae
Infection
Acquired Immunodeficiency Syndrome
Tryptases
Histamine
Endothelial Cells
Cell Degranulation
Human Herpesvirus 8

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

Cite this

Ayers, L. W., Barbachano-Guerrero, A., McAllister, S. C., Ritchie, J. A., Asiago-Reddy, E., Bartlett, L. C., ... King, C. A. (2018). Mast cell activation and KSHV infection in Kaposi sarcoma. Clinical Cancer Research, 24(20), 5085-5097. https://doi.org/10.1158/1078-0432.CCR-18-0873

Mast cell activation and KSHV infection in Kaposi sarcoma. / Ayers, Leona W.; Barbachano-Guerrero, Arturo; McAllister, Shane C; Ritchie, Julie A.; Asiago-Reddy, Elizabeth; Bartlett, Linda C.; Cesarman, Ethel; Wang, Dongliang; Rochford, Rosemary; Martin, Jeffrey N.; King, Christine A.

In: Clinical Cancer Research, Vol. 24, No. 20, 15.10.2018, p. 5085-5097.

Research output: Contribution to journalArticle

Ayers, LW, Barbachano-Guerrero, A, McAllister, SC, Ritchie, JA, Asiago-Reddy, E, Bartlett, LC, Cesarman, E, Wang, D, Rochford, R, Martin, JN & King, CA 2018, 'Mast cell activation and KSHV infection in Kaposi sarcoma', Clinical Cancer Research, vol. 24, no. 20, pp. 5085-5097. https://doi.org/10.1158/1078-0432.CCR-18-0873
Ayers LW, Barbachano-Guerrero A, McAllister SC, Ritchie JA, Asiago-Reddy E, Bartlett LC et al. Mast cell activation and KSHV infection in Kaposi sarcoma. Clinical Cancer Research. 2018 Oct 15;24(20):5085-5097. https://doi.org/10.1158/1078-0432.CCR-18-0873
Ayers, Leona W. ; Barbachano-Guerrero, Arturo ; McAllister, Shane C ; Ritchie, Julie A. ; Asiago-Reddy, Elizabeth ; Bartlett, Linda C. ; Cesarman, Ethel ; Wang, Dongliang ; Rochford, Rosemary ; Martin, Jeffrey N. ; King, Christine A. / Mast cell activation and KSHV infection in Kaposi sarcoma. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 20. pp. 5085-5097.
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abstract = "Purpose: Kaposi sarcoma (KS) is a vascular tumor initiated by infection of endothelial cells (ECs) with KS-associated herpesvirus (KSHV). KS is dependent on sustained proinflammatory signals provided by intralesional leukocytes and continued infection of new ECs. However, the sources of these cytokines and infectious virus within lesions are not fully understood. Here, mast cells (MCs) are identified as proinflammatory cells within KS lesions that are permissive for, and activated by, infection with KSHV. Experimental Design: Three validated MC lines were used to assess permissivity of MCs to infection with KSHV and to evaluate MCs activation following infection. Biopsies from 31 AIDS-KS cases and 11 AIDS controls were evaluated by IHC for the presence of MCs in KS lesions and assessment of MC activation state and infection with KSHV. Plasma samples from 26 AIDS-KS, 13 classic KS, and 13 healthy adults were evaluated for levels of MC granule contents tryptase and histamine. Results: In culture, MCs supported latent and lytic KSHV infection, and infection-induced MC degranulation. Within KS lesions, MCs were closely associated with spindle cells. Furthermore,MCactivation was extensive within patients with KS, reflected by elevated circulating levels of tryptase and a histamine metabolite. One patient with clinical signs of extensive MC activation was treated with antagonists of MC proinflammatory mediators, which resulted in a rapid and durable regression of AIDS-KS lesions. Conclusions: Using complimentary in vitro and in vivo studies we identify MCs as a potential long-lived reservoir for KSHV and a source of proinflammatory mediators within the KS lesional microenvironment. In addition, we identify MC antagonists as a promising novel therapeutic approach for KS.",
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T1 - Mast cell activation and KSHV infection in Kaposi sarcoma

AU - Ayers, Leona W.

AU - Barbachano-Guerrero, Arturo

AU - McAllister, Shane C

AU - Ritchie, Julie A.

AU - Asiago-Reddy, Elizabeth

AU - Bartlett, Linda C.

AU - Cesarman, Ethel

AU - Wang, Dongliang

AU - Rochford, Rosemary

AU - Martin, Jeffrey N.

AU - King, Christine A.

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Y1 - 2018/10/15

N2 - Purpose: Kaposi sarcoma (KS) is a vascular tumor initiated by infection of endothelial cells (ECs) with KS-associated herpesvirus (KSHV). KS is dependent on sustained proinflammatory signals provided by intralesional leukocytes and continued infection of new ECs. However, the sources of these cytokines and infectious virus within lesions are not fully understood. Here, mast cells (MCs) are identified as proinflammatory cells within KS lesions that are permissive for, and activated by, infection with KSHV. Experimental Design: Three validated MC lines were used to assess permissivity of MCs to infection with KSHV and to evaluate MCs activation following infection. Biopsies from 31 AIDS-KS cases and 11 AIDS controls were evaluated by IHC for the presence of MCs in KS lesions and assessment of MC activation state and infection with KSHV. Plasma samples from 26 AIDS-KS, 13 classic KS, and 13 healthy adults were evaluated for levels of MC granule contents tryptase and histamine. Results: In culture, MCs supported latent and lytic KSHV infection, and infection-induced MC degranulation. Within KS lesions, MCs were closely associated with spindle cells. Furthermore,MCactivation was extensive within patients with KS, reflected by elevated circulating levels of tryptase and a histamine metabolite. One patient with clinical signs of extensive MC activation was treated with antagonists of MC proinflammatory mediators, which resulted in a rapid and durable regression of AIDS-KS lesions. Conclusions: Using complimentary in vitro and in vivo studies we identify MCs as a potential long-lived reservoir for KSHV and a source of proinflammatory mediators within the KS lesional microenvironment. In addition, we identify MC antagonists as a promising novel therapeutic approach for KS.

AB - Purpose: Kaposi sarcoma (KS) is a vascular tumor initiated by infection of endothelial cells (ECs) with KS-associated herpesvirus (KSHV). KS is dependent on sustained proinflammatory signals provided by intralesional leukocytes and continued infection of new ECs. However, the sources of these cytokines and infectious virus within lesions are not fully understood. Here, mast cells (MCs) are identified as proinflammatory cells within KS lesions that are permissive for, and activated by, infection with KSHV. Experimental Design: Three validated MC lines were used to assess permissivity of MCs to infection with KSHV and to evaluate MCs activation following infection. Biopsies from 31 AIDS-KS cases and 11 AIDS controls were evaluated by IHC for the presence of MCs in KS lesions and assessment of MC activation state and infection with KSHV. Plasma samples from 26 AIDS-KS, 13 classic KS, and 13 healthy adults were evaluated for levels of MC granule contents tryptase and histamine. Results: In culture, MCs supported latent and lytic KSHV infection, and infection-induced MC degranulation. Within KS lesions, MCs were closely associated with spindle cells. Furthermore,MCactivation was extensive within patients with KS, reflected by elevated circulating levels of tryptase and a histamine metabolite. One patient with clinical signs of extensive MC activation was treated with antagonists of MC proinflammatory mediators, which resulted in a rapid and durable regression of AIDS-KS lesions. Conclusions: Using complimentary in vitro and in vivo studies we identify MCs as a potential long-lived reservoir for KSHV and a source of proinflammatory mediators within the KS lesional microenvironment. In addition, we identify MC antagonists as a promising novel therapeutic approach for KS.

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