Protection against Lethal Encephalomyocarditis Virus Infection in the Absence of Serum-Neutralizing Antibodies

Neal, Zane C.; Splitter, Gary A.

doi:10.1128/jvi.72.10.8052-8060.1998

Cited by 13 publications

(7 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Levels of lymphocyte activation, notably of both CD4 ϩ and CD8 ϩ T cells, were also impaired in CD1d-KO EMCV-infected mice compared to those in wild-type animals. Consistent with the observations made in the present study, it was reported previously that in vivo resistance to EMCV infection is dependent on both CD4 ϩ and CD8 ϩ T cells (43,44).…”

Section: Discussionsupporting

confidence: 94%

“…Thus, it is plausible that CD1d-restricted T cells and/or CD1d-expressing APC serve as important mediators of antiviral T-cell responses, especially after the rapid initial productive viral infection round. Furthermore, their role may be essential for the eventual suppression of viral replication, since T-cellmediated responses were previously shown to confer protection against EMCV infection in vivo (43,44). The differences between wild-type and CD1d-KO mouse resistance are greatest at early-to-intermediate stages of the infectious cycle, consistent with rapid innate immune-like effects attributed to the CD1d system.…”

Section: Discussionmentioning

confidence: 77%

See 1 more Smart Citation

CD1d Mediates T-Cell-Dependent Resistance to Secondary Infection with Encephalomyocarditis Virus (EMCV) In Vitro and Immune Response to EMCV Infection In Vivo

Ilyinskii

Wang

Balk

et al. 2006

J Virol

View full text Add to dashboard Cite

The innate and adaptive immune responses have evolved distinct strategies for controlling different viral pathogens. Encephalomyocarditis virus (EMCV) is a picornavirus that can cause paralysis, diabetes, and myocarditis within days of infection. The optimal innate immune response against EMCV in vivo requires CD1d. Interaction of antigen-presenting cell CD1d with distinct natural killer T-cell ("NKT") populations can induce rapid gamma interferon (IFN-␥) production and NK-cell activation. The T-cell response of CD1d-deficient mice (lacking all NKT cells) against acute EMCV infection was further studied in vitro and in vivo. EMCV persisted at higher levels in CD1d-knockout (KO) splenocyte cultures infected in vitro. Furthermore, optimal resistance to repeat cycles of EMCV infection in vitro was also shown to depend on CD1d. However, this was not reflected in the relative levels of NK-cell activation but rather by the responses of both CD4؉ and CD8 ؉ T-cell populations. Repeated EMCV infection in vitro induced less IFN-␥ and alpha interferon (IFN-␣) from CD1d-deficient splenocytes than with the wild type. Furthermore, the level of EMCV replication in wild-type splenocytes was markedly and specifically increased by addition of blocking anti-CD1d antibody. Depletion experiments demonstrated that dendritic cells contributed less than the combination of NK and NKT cells to anti-EMCV responses and that none of these cell types was the main source of IFN-␣. Finally, EMCV infection in vivo produced higher levels of viremia in CD1d-KO mice than in wild-type animals, coupled with significantly less lymphocyte activation and IFN-␣ production. These results point to the existence of a previously unrecognized mechanism of rapid CD1d-dependent stimulation of the antiviral adaptive cellular immune response.

show abstract

Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 77%

CD1d Mediates T-Cell-Dependent Resistance to Secondary Infection with Encephalomyocarditis Virus (EMCV) In Vitro and Immune Response to EMCV Infection In Vivo

Ilyinskii

Wang

Balk

et al. 2006

J Virol

View full text Add to dashboard Cite

show abstract

“…Splenocytes (1 × 10 6 per well in 24‐well plates) were infected with EMCV‐D (multiplicity of Infection 0·1/cell to ensure viable cells for cytokine production) as previously described 50–54 or treated with 1 μg/ml anti‐CD3 monoclonal antibody (145‐2C11) bound to 24‐well plates. Murine IL‐12 was added where indicated at 1 ng/ml.…”

Section: Methodsmentioning

confidence: 99%

“…The virus infects pancreatic islet cells, the nervous system, and heart muscle in vivo but clearance of the virus results in the resolution of acute disease 44–49 . T lymphocytes, macrophages, NK cells, and NK‐like spleen cells have been reported to contribute to EMCV‐D resistance, and wild‐type (WT) mice can be protected by IL‐12 treatment and consequent IFN‐γ production 47–51 . Resistance to EMCV‐D correlates with early IFN‐γ production and IFN‐γ‐receptor‐deficient mice are highly susceptible, even when treated with IL‐12 51–54 .…”

Section: Introductionmentioning

confidence: 99%

Innate immune response to encephalomyocarditis virus infection mediated by CD1d

et al. 2003

View full text Add to dashboard Cite

SUMMARYCD1d-reactive natural killer T (NKT) cells can rapidly produce T helper type 1 (Th1) and/or Th2 cytokines, can activate antigen-presenting cell (APC) interleukin-12 (IL-12) production, and are implicated in the regulation of adaptive immune responses. The role of the CD1d system was assessed during infection with encephalomyocarditis virus (EMCV-D), a picornavirus that causes acute diabetes, paralysis and myocarditis. EMCV-D resistance depends on IL-12-mediated interferon-g (IFN-g) production. CD1d-de®cient mice, which also lack CD1d-reactive NKT cells, were substantially more sensitive to infection with EMCV-D. Infected CD1d knockout mice had decreased IL-12 levels in vitro and in vivo, and indeed were protected by treatment with exogenous IL-12. IFN-g production in CD1d knockout mice was decreased compared with that in wild-type (WT) mice in response to EMCV-D in vitro, although differences were not detected in vivo. Treatment with anti-asialo-GM1 antibody, to deplete NK cells, caused a marked increase in susceptibility of WT mice to EMCV-D infection, whereas CD1d knockout mice were little affected, suggesting that NK-cell-mediated protection is CD1d-dependent. Therefore, these data indicate that CD1d is essential for optimal responses to acute picornaviral infection. We propose that CD1d-reactive T cells respond to early immune signals and function in the innate immune response to a physiological viral infection by rapidly augmenting APC IL-12 production and activating NK cells.

show abstract

“…Moreover, there are several picornaviruses for which human seropositivity is low and infection typically is asymptomatic. Some of these viruses also can be highly antigenic and induce potent humoral and cellular immune responses to mediate indirect killing of tumor cells ( 8 – 12 ).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-Detargeted Mengovirus for Oncolytic Virotherapy

Ruiz

Hadac

Nace

et al. 2016

J Virol

View full text Add to dashboard Cite

Mengovirus, a member of the Picornaviridae family, has a broad cell tropism and can cause encephalitis and myocarditis in multiple mammalian species. Attenuation has been achieved by shortening the polycytidine tract in the 5′ noncoding region (NCR). A poly(C)-truncated strain of mengovirus, vMC24, resulted in significant tumor regression in immunocompetent BALB/c mice bearing syngeneic MPC-11 plasmacytomas, but the associated toxicities were unacceptable. To enhance its safety profile, microRNA target sequences complementary to miR-124 or miR-125 (enriched in nervous tissue), miR-133 and miR-208 (enriched in cardiac tissue), or miR-142 (control; enriched in hematopoietic tissues) were inserted into the vMC24 NCRs. The microRNA-detargeted viruses showed reduced replication and cell killing specifically in cells expressing the cognate microRNAs, but certain insertions additionally were associated with nonspecific suppression of viral fitness in vivo. In vivo toxicity testing confirmed that miR-124 targets within the 5′ NCR suppressed virus replication in the central nervous system while miR-133 and miR-208 targets in the 3′ NCR suppressed viral replication in cardiac tissue. A dual-detargeted virus named vMC24-NC, with miR-124 targets in the 5′ NCR and miR-133 plus miR-208 targets in the 3′ NCR, showed the suppression of replication in both nervous and cardiac tissues but retained full oncolytic potency when administered by intratumoral (106 50% tissue culture infectious doses [TCID50]) or intravenous (107 to 108 TCID50) injection into BALB/c mice bearing MPC-11 plasmacytomas. Overall survival of vMC24-NC-treated tumor-bearing mice was significantly improved compared to that of nontreated mice. MicroRNA-detargeted mengoviruses offer a promising oncolytic virotherapy platform that merits further development for clinical translation.IMPORTANCE The clinical potential of oncolytic virotherapy for cancer treatment has been well demonstrated, justifying the continued development of novel oncolytic viruses with enhanced potency. Here, we introduce mengovirus as a novel oncolytic agent. Mengovirus is appealing as an oncolytic virotherapy platform because of its small size, simple genome structure, rapid replication cycle, and broad cell/species tropism. However, mengovirus can cause encephalomyelitis and myocarditis. It can be partially attenuated by shortening the poly(C) tract in the 5′ NCR but remains capable of damaging cardiac and nervous tissue. Here, we further enhanced the safety profile of a poly(C)-truncated mengovirus by incorporating muscle- and neuron-specific microRNA target sequences into the viral genome. This dual-detargeted virus has reduced pathogenesis but retained potent oncolytic activity. Our data show that microRNA targeting can be used to further increase the safety of an attenuated mengovirus, providing a basis for its development as an oncolytic platform.

show abstract

Protection against Lethal Encephalomyocarditis Virus Infection in the Absence of Serum-Neutralizing Antibodies

Cited by 13 publications

References 41 publications

CD1d Mediates T-Cell-Dependent Resistance to Secondary Infection with Encephalomyocarditis Virus (EMCV) In Vitro and Immune Response to EMCV Infection In Vivo

CD1d Mediates T-Cell-Dependent Resistance to Secondary Infection with Encephalomyocarditis Virus (EMCV) In Vitro and Immune Response to EMCV Infection In Vivo

Innate immune response to encephalomyocarditis virus infection mediated by CD1d

MicroRNA-Detargeted Mengovirus for Oncolytic Virotherapy

Contact Info

Product

Resources

About