BAI1 orchestrates macrophage inflammatory response to HSV infection-implications for oncolytic viral therapy

Chelsea Bolyard, W. Hans Meisen, Yeshavanth Banasavadi-Siddegowda, Jayson Hardcastle, Ji Young Yoo, Eric S. Wohleb, Jeffrey Wojton, Jun Ge Yu, Samuel Dubin, Maninder Khosla, Bo Xu, Jonathan Smith, Christopher Alvarez-Breckenridge, Pete Pow-Anpongkul, Flavia Pichiorri, Jianying Zhang, Matthew Old, Dan Zhu, Erwin G. Van Meir, Jonathan P. GodboutMichael A. Caligiuri, Jianhua Yu, Balveen Kaur

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Purpose: Brain angiogenesis inhibitor (BAI1) facilitates phagocytosis and bacterial pathogen clearance by macrophages; however, its role in viral infections is unknown. Here, we examined the role of BAI1, and its N-terminal cleavage fragment (Vstat120) in antiviral macrophage responses to oncolytic herpes simplex virus (oHSV). Experimental Design: Changes in infiltration and activation of monocytic and microglial cells after treatment of glioma-bearing mice brains with a control (rHSVQ1) or Vstat120-expressing (RAMBO) oHSV was analyzed using flow cytometry. Co-culture of infected glioma cells with macrophages or microgliawas used to examine antiviral signaling. Cytokine array gene expression and Ingenuity Pathway Analysis (IPA) helped evaluate changes in macrophage signaling in response to viral infection. TNFα-blocking antibodies andmacrophages derived from Bai1-/- mice were used. Results: RAMBO treatment of mice reduced recruitment and activation of macrophages/microglia in mice with brain tumors, and showed increased virus replication compared with rHSVQ1. Cytokine gene expression array revealed that RAMBO significantly altered the macrophage inflammatory response to infected glioma cells via altered secretion of TNFα. Furthermore, we showed that BAI1 mediated macrophage TNFα induction in response to oHSV therapy. Intracranial inoculation of wild-type/RAMBO virus in Bai1-/- or wild-type non-tumor-bearing mice revealed the safety of this approach. Conclusions: We have uncovered a new role for BAI1 in facilitating macrophage anti-viral responses. We show that arming oHSV with antiangiogenic Vstat120 also shields them from inflammatory macrophage antiviral response, without reducing safety.

Original languageEnglish (US)
Pages (from-to)1809-1819
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number7
DOIs
StatePublished - Apr 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine

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