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Recombinant Chinese Hu191 measles virus exhibits a significant antitumor activity against nephroblastoma mediated by immunogenic form of apoptosis.

ABSTRACT: In previous studies oncolytic measles viruses (MVs) have shown significant antitumor activity against various tumors. In our research recombinant MV-Hu191 (rMV-Hu191), established via reverse genetics technology and expressing enhanced green fluorescent protein (EGFP), was evaluated for its therapeutic effects and related mechanisms against nephroblastoma cell lines. We built three different constructs based on rMV-Hu191 to express EGFP effectively. Our experiments showed that rMV-Hu191 expressing EGFP could efficiently infect and replicate in nephroblastoma cell lines. Caspase-induced apoptosis exerted a significant impact on MV-induced cell death, which was accompanied by emission of cellular ATP and high-mobility group protein 1 (HMGB1) and by translocation of calreticulin (CRT). Intratumoral injection of rMV-Hu191-EGFP resulted in significant regression of tumors in a G401 xenograft model. Our results indicate that the MV-Hu191 strain, which is widely used in China, is an appropriate vector for expression of foreign genes and could serve as a potentially good candidate for nephroblastoma therapy mediated by induction of apoptosis-associated immunogenic cell death (ICD).

SUBMITTER: Zhu M

PROVIDER: S-EPMC8129391 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In 2012, the first cases of infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) were identified. Since then, more than 1,000 cases of MERS-CoV infection have been confirmed; infection is typically associated with considerable morbidity and, in approximately 30% of cases, mortality. Currently, there is no protective vaccine available. Replication-competent recombinant measles virus (MV) expressing foreign antigens constitutes a promising tool to induce protective immunity against corresponding pathogens. Therefore, we generated MVs expressing the spike glycoprotein of MERS-CoV in its full-length (MERS-S) or a truncated, soluble variant of MERS-S (MERS-solS). The genes encoding MERS-S and MERS-solS were cloned into the vaccine strain MVvac2 genome, and the respective viruses were rescued (MVvac2-CoV-S and MVvac2-CoV-solS). These recombinant MVs were amplified and characterized at passages 3 and 10. The replication of MVvac2-CoV-S in Vero cells turned out to be comparable to that of the control virus MVvac2-GFP (encoding green fluorescent protein), while titers of MVvac2-CoV-solS were impaired approximately 3-fold. The genomic stability and expression of the inserted antigens were confirmed via sequencing of viral cDNA and immunoblot analysis. In vivo, immunization of type I interferon receptor-deficient (IFNAR(-/-))-CD46Ge mice with 2 × 10(5) 50% tissue culture infective doses of MVvac2-CoV-S(H) or MVvac2-CoV-solS(H) in a prime-boost regimen induced robust levels of both MV- and MERS-CoV-neutralizing antibodies. Additionally, induction of specific T cells was demonstrated by T cell proliferation, antigen-specific T cell cytotoxicity, and gamma interferon secretion after stimulation of splenocytes with MERS-CoV-S presented by murine dendritic cells. MERS-CoV challenge experiments indicated the protective capacity of these immune responses in vaccinated mice.Although MERS-CoV has not yet acquired extensive distribution, being mainly confined to the Arabic and Korean peninsulas, it could adapt to spread more readily among humans and thereby become pandemic. Therefore, the development of a vaccine is mandatory. The integration of antigen-coding genes into recombinant MV resulting in coexpression of MV and foreign antigens can efficiently be achieved. Thus, in combination with the excellent safety profile of the MV vaccine, recombinant MV seems to constitute an ideal vaccine platform. The present study shows that a recombinant MV expressing MERS-S is genetically stable and induces strong humoral and cellular immunity against MERS-CoV in vaccinated mice. Subsequent challenge experiments indicated protection of vaccinated animals, illustrating the potential of MV as a vaccine platform with the potential to target emerging infections, such as MERS-CoV.

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Recombinant Chinese Hu191 measles virus exhibits a significant antitumor activity against nephroblastoma mediated by immunogenic form of apoptosis.

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