Inhibition of MALT1 Decreases Neuroinflammation and Pathogenicity of Virulent Rabies Virus in Mice

Abstract

Rabies virus is a neurovirulent RNA virus, which causes about 59000 human deaths each year. Treatment for rabies does not exist due to incomplete understanding of the pathogenesis. MALT1 mediates activation of several immune cell types and is involved in the proliferation and survival of cancer cells. MALT1 acts as a scaffold protein for NF-κB signaling and a cysteine protease that cleaves substrates, leading to the expression of immunoregulatory genes. Here, we examined the impact of genetic or pharmacological MALT1 inhibition in mice on disease development after infection with the virulent rabies virus strain CVS-11. Morbidity and mortality were significantly delayed in compared to mice, which was associated with a lower viral load, proinflammatory gene expression and infiltration and activation of immune cells in brain. Specific deletion of in T cells also delayed disease development while deletion in myeloid cells, neuronal cells or NK cells had no effect. Disease development was also delayed in mice treated with the MALT1 protease inhibitor mepazine, and in knock-in mice expressing a catalytically inactive MALT1 mutant protein, showing an important role of MALT1 proteolytic activity. The described protective effect of MALT1 inhibition against infection with a virulent rabies virus is the precise opposite of the sensitizing effect of MALT1 inhibition that we previously observed in case of infection with an attenuated rabies virus strain. Together, these data demonstrate that the role of immunoregulatory responses in rabies pathogenicity is dependent on virus virulence, and reveal the potential of MALT1 inhibition for therapeutic intervention. Rabies virus is a neurotropic RNA virus that causes encephalitis and still poses an enormous challenge to animal and public health. Efforts to establish reliable therapeutic strategies have been unsuccessful and are hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular protease that mediates the activation of several innate and adaptive immune cells in response to multiple receptors, and therapeutic MALT1 targeting is believed to be a valid approach for autoimmunity and MALT1-addicted cancers. Here, we study the impact of MALT1 deficiency on brain inflammation and disease development in response to infection of mice with the highly virulent CVS-11 rabies virus. We demonstrate that pharmacological or genetic MALT1 inhibition decreases neuroinflammation and extends the survival of CVS-11 infected mice, providing new insights in the biology of MALT1 and rabies virus infection.

Mepazine Inhibits RANK-Induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function

“…In the present study, we show that the MALT1 inhibitor mepazine strongly inhibits RANK-induced osteoclastogenesis via a MALT1-independent mechanism. Mepazine has been frequently used in several in vitro and in vivo studies to demonstrate a role for MALT1 [3,4,5,6,7,8,39,40,41,42,43,44]. Most importantly, the therapeutic effect of mepazine in mouse models of autoimmune disease and ABC-type DLBCL has strengthened the belief in therapeutic targeting of MALT1.…”

“…Phenothiazines are best known from their long history as neuroleptic antipsychotic drugs due to their dopamine blocking properties [2]. Specific phenothiazines, including mepazine, were found to inhibit mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) [3,4] and to exert therapeutic activity in preclinical models of several diseases, including multiple sclerosis [5], activated B cell subtype of diffuse-large B cell lymphoma (ABC-DLBCL) [3], viral infection [6,7], and colitis [8]. MALT1 (PCASP1 [9]) is an intracellular signaling protein that plays a key role in innate and adaptive immunity [10,11].…”

Monophosphoryl-Lipid A (MPLA) is an Efficacious Adjuvant for Inactivated Rabies Vaccines

“…Rabies virus (RABV), a single negative-strand RNA virus, belonging to the Lyssavirus genus within the Rhabdoviridae family, is still responsible for 59,000-61,000 human deaths annually, mostly in developing countries [1][2][3]. The RABV genome encodes five structural proteins, including nucleocapsid protein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and large polymerase (L) [4].…”

Dual Role of Toll-Like Receptor 7 in the Pathogenesis of Rabies Virus in a Mouse Model

“…For example, mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1), a scaffold protein in NF-B, serves different roles in response to different RABV strains. After infection with the nonpathogenic RABV vaccine strain ERA, all MALT1 Ϫ/Ϫ mice succumb to rabies, suggesting that MALT1 was required for the effective clearance of ERA, whereas MALT1 Ϫ/Ϫ mice show decreased inflammation in the brains and extended survival postinfection with the virulent CVS-11 strain, demonstrating that MALT1 exacerbated the acute immunopathology caused by CVS-11 (36,37). One reason for the different responses to different strains may be that strains which spread rapidly and facilitate immune cell infiltration into the CNS are more likely to present a risk of immunopathology (30).…”