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MALT1 controls attenuated rabies virus by inducing early inflammation and T cell activation in the brain

Elodie Kip (UGent) , Jens Staal (UGent) , Lynn Verstrepen (UGent) , HG Tima, S Terryn, M Romano, Kelly Lemeire (UGent) , V Suin, A Hamouda, M Kalai, et al.
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Abstract
MALT1 is involved in the activation of immune responses, as well as in the proliferation and survival of certain cancer cells. MALT1 acts as a scaffold protein for NF-kappa B signaling and a cysteine protease that cleaves substrates, further promoting the expression of immunoregulatory genes. Deregulated MALT1 activity has been associated with autoimmunity and cancer, implicating MALT1 as a new therapeutic target. Although MALT1 deficiency has been shown to protect against experimental autoimmune encephalomyelitis, nothing is known about the impact of MALT1 on virus infection in the central nervous system. Here, we studied infection with an attenuated rabies virus, Evelyn-Rotnycki-Abelseth (ERA) virus, and observed increased susceptibility with ERA virus in MALT1(-/-) mice. Indeed, after intranasal infection with ERA virus, wild-type mice developed mild transient clinical signs with recovery at 35 days postinoculation (dpi). Interestingly, MALT1(-/-) mice developed severe disease requiring euthanasia at around 17 dpi. A decreased induction of inflammatory gene expression and cell infiltration and activation was observed in MALT1(-/-) mice at 10 dpi compared to MALT1(-/-) infected mice. At 17 dpi, however, the level of inflammatory cell activation was comparable to that observed in MALT1(-/-) mice. Moreover, MALT1(-/-) mice failed to produce virus-neutralizing antibodies. Similar results were obtained with specific inactivation of MALT1 in T cells. Finally, treatment of wild-type mice with mepazine, a MALT1 protease inhibitor, also led to mortality upon ERA virus infection. These data emphasize the importance of early inflammation and activation of T cells through MALT1 for controlling the virulence of an attenuated rabies virus in the brain. IMPORTANCE Rabies virus is a neurotropic virus which can infect any mammal. Annually, 59,000 people die from rabies. Effective therapy is lacking and hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular protein involved in innate and adaptive immunity and is an interesting therapeutic target because MALT1-deregulated activity has been associated with autoimmunity and cancers. The role of MALT1 in viral infection is, however, largely unknown. Here, we study the impact of MALT1 on virus infection in the brain, using the attenuated ERA rabies virus in different models of MALT1-deficient mice. We reveal the importance of MALT1-mediated inflammation and T cell activation to control ERA virus, providing new insights in the biology of MALT1 and rabies virus infection.
Keywords
CENTRAL-NERVOUS-SYSTEM, KAPPA-B ACTIVATION, COMBINED IMMUNODEFICIENCY, BARRIER PERMEABILITY, ABC-DLBCL, PARACASPASE, INFECTION, CLEAVAGE, ENHANCEMENT, EXPRESSION, ERA, MALT1, immunity, neuroinflammation, rabies virus

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Citation

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MLA
Kip, Elodie et al. “MALT1 Controls Attenuated Rabies Virus by Inducing Early Inflammation and T Cell Activation in the Brain.” JOURNAL OF VIROLOGY 92.8 (2018): n. pag. Print.
APA
Kip, E., Staal, J., Verstrepen, L., Tima, H., Terryn, S., Romano, M., Lemeire, K., et al. (2018). MALT1 controls attenuated rabies virus by inducing early inflammation and T cell activation in the brain. JOURNAL OF VIROLOGY, 92(8).
Chicago author-date
Kip, Elodie, Jens Staal, Lynn Verstrepen, HG Tima, S Terryn, M Romano, Kelly Lemeire, et al. 2018. “MALT1 Controls Attenuated Rabies Virus by Inducing Early Inflammation and T Cell Activation in the Brain.” Journal of Virology 92 (8).
Chicago author-date (all authors)
Kip, Elodie, Jens Staal, Lynn Verstrepen, HG Tima, S Terryn, M Romano, Kelly Lemeire, V Suin, A Hamouda, M Kalai, Rudi Beyaert, and Steven Van Gucht. 2018. “MALT1 Controls Attenuated Rabies Virus by Inducing Early Inflammation and T Cell Activation in the Brain.” Journal of Virology 92 (8).
Vancouver
1.
Kip E, Staal J, Verstrepen L, Tima H, Terryn S, Romano M, et al. MALT1 controls attenuated rabies virus by inducing early inflammation and T cell activation in the brain. JOURNAL OF VIROLOGY. 2018;92(8).
IEEE
[1]
E. Kip et al., “MALT1 controls attenuated rabies virus by inducing early inflammation and T cell activation in the brain,” JOURNAL OF VIROLOGY, vol. 92, no. 8, 2018.
@article{8558920,
  abstract     = {MALT1 is involved in the activation of immune responses, as well as in the proliferation and survival of certain cancer cells. MALT1 acts as a scaffold protein for NF-kappa B signaling and a cysteine protease that cleaves substrates, further promoting the expression of immunoregulatory genes. Deregulated MALT1 activity has been associated with autoimmunity and cancer, implicating MALT1 as a new therapeutic target. Although MALT1 deficiency has been shown to protect against experimental autoimmune encephalomyelitis, nothing is known about the impact of MALT1 on virus infection in the central nervous system. Here, we studied infection with an attenuated rabies virus, Evelyn-Rotnycki-Abelseth (ERA) virus, and observed increased susceptibility with ERA virus in MALT1(-/-) mice. Indeed, after intranasal infection with ERA virus, wild-type mice developed mild transient clinical signs with recovery at 35 days postinoculation (dpi). Interestingly, MALT1(-/-) mice developed severe disease requiring euthanasia at around 17 dpi. A decreased induction of inflammatory gene expression and cell infiltration and activation was observed in MALT1(-/-) mice at 10 dpi compared to MALT1(-/-) infected mice. At 17 dpi, however, the level of inflammatory cell activation was comparable to that observed in MALT1(-/-) mice. Moreover, MALT1(-/-) mice failed to produce virus-neutralizing antibodies. Similar results were obtained with specific inactivation of MALT1 in T cells. Finally, treatment of wild-type mice with mepazine, a MALT1 protease inhibitor, also led to mortality upon ERA virus infection. These data emphasize the importance of early inflammation and activation of T cells through MALT1 for controlling the virulence of an attenuated rabies virus in the brain. 
IMPORTANCE Rabies virus is a neurotropic virus which can infect any mammal. Annually, 59,000 people die from rabies. Effective therapy is lacking and hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular protein involved in innate and adaptive immunity and is an interesting therapeutic target because MALT1-deregulated activity has been associated with autoimmunity and cancers. The role of MALT1 in viral infection is, however, largely unknown. Here, we study the impact of MALT1 on virus infection in the brain, using the attenuated ERA rabies virus in different models of MALT1-deficient mice. We reveal the importance of MALT1-mediated inflammation and T cell activation to control ERA virus, providing new insights in the biology of MALT1 and rabies virus infection.},
  articleno    = {e02029-17},
  author       = {Kip, Elodie and Staal, Jens and Verstrepen, Lynn and Tima, HG and Terryn, S and Romano, M and Lemeire, Kelly and Suin, V and Hamouda, A and Kalai, M and Beyaert, Rudi and Van Gucht, Steven},
  issn         = {0022-538X},
  journal      = {JOURNAL OF VIROLOGY},
  keywords     = {CENTRAL-NERVOUS-SYSTEM,KAPPA-B ACTIVATION,COMBINED IMMUNODEFICIENCY,BARRIER PERMEABILITY,ABC-DLBCL,PARACASPASE,INFECTION,CLEAVAGE,ENHANCEMENT,EXPRESSION,ERA,MALT1,immunity,neuroinflammation,rabies virus},
  language     = {eng},
  number       = {8},
  pages        = {20},
  title        = {MALT1 controls attenuated rabies virus by inducing early inflammation and T cell activation in the brain},
  url          = {http://dx.doi.org/10.1128/JVI.02029-17},
  volume       = {92},
  year         = {2018},
}

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