TY - JOUR T1 - MALT1 controls attenuated rabies virus by inducing early inflammation and T cell activation in the brain. JF - J Virol Y1 - 2018 A1 - E Kip A1 - J Staal A1 - L Verstrepen A1 - H Tima Giresse A1 - Sanne Terryn A1 - Marta Romano A1 - K Lemeire A1 - Vanessa Suin A1 - Assia Hamouda A1 - Kalai, M A1 - Beyaert, R A1 - Steven Van Gucht KW - MALT1 KW - Rabies AB -

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-κB signalling 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. While 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 (ERA) and observed increased susceptibility with ERA in MALT1-/- mice. Indeed, following intranasal infection with ERA, wild-type mice developed mild transient clinical signs with recovery at 35 DPI. Interestingly, MALT1-/- mice developed severe disease requiring euthanasia around 17 DPI. A decreased induction of inflammatory gene expression and cell infiltration and activation was observed in MALT1-/- mice at 10DPI as compared to MALT1+/+ infected mice. At 17 DPI, however, inflammatory cell activation was comparable to the one 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, 59000 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 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.

M3 - 10.1128/JVI.02029-17 ER -