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 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.

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.

Objectives: Mumps used to affect children between 2 and 15 years old. The mumpsemeasleserubella (MMR) vaccine is available, with vaccine coverage rate of about 85% after two vaccine doses. Recently new mumps outbreaks have emerged in highly vaccinated populations; the causes for these new outbreaks are yet unknown. We tested if a difference in seroneutralizing capacity against the vaccine and wild-type viruses existed and if waning immunity could be detected. Methods: In this study, 570 serum samples (age group 2e3 years (n ¼ 96), 8e9 years (n ¼ 95), 13 e14 years (n ¼ 94), 18e20 years (n ¼ 96), 24e26 years (n ¼ 92) and 50 þ years (n ¼ 97)) in Belgium were tested in the rapid fluorescent foci inhibition test for their neutralizing capacity against the vaccine and wild-type viruses. Results: Neutralizing antibodies against the vaccine strain were present in 84% (81/97) of the 2e3-year, 74% (70/95) of the 8e9-year, 81% (76/94) of the 13e14-year, 76% (73/96) of the 18e20-year, 67% (62/92) of the 24e26-year and 77% (75/97) of the 50þ-year age group serum samples. For all age groups, only about half of these serum samples were also positive for the wild-type virus. The geometric mean titres for the vaccine and wild-type virus for all younger age groups, except for 24e26 years, were significantly different, demonstrating poor in vitro cross-neutralization. Conclusions: A possible contribution of antigenic differences between the genotype A and G mumps virus as well as other immune factors, in addition to lower-than-optimal vaccination coverage and waning immunity, could explain the poor in vitro cross-neutralization and should be further studied.

High-risk multisystem organ (RO+) Langerhans cell histiocytosis (LCH) has the least survival. We present the outcome of RO+ LCH in a pediatric single center. Fifty RO+ LCH patients, treated between 07/2007 and 07/2015, were retrospectively analyzed. Induction vinblastine (VBL) and prednisone (PRED) with intermediate-dose methotrexate (idMTX) was adopted until 2012 (n=20) wherein idMTX was omitted (n=30). The 3-year overall survival (OS) of MTX and non-MTX groups was 75% and 63%, respectively, P=0.537, while the event-free survival (EFS) was 36.9% and 13.2%, respectively, P=0.005. At week 12 of induction, “better status” was obtained in 80% of those receiving MTX, and 55% of those who were not. The statistically significant factors associated with both poor OS and EFS were trihemopoietic cytopenias, hepatic dysfunction, tri RO+ combination, and single induction. The factors associated with disease progression (DP) on induction were trihemopoietic cytopenias, hepatic dysfunction, and lack of idMTX, while those for disease reactivations (REA), the season of autumn/winter, lung disease, male sex, and idMTX were the associated factors. The 1-year OS was remarkably affected with the occurrence of DP versus REA versus none, wherein it was 47%, 93%, and 95%, respectively, P=0.001. In conclusion, idMTX is associated with better EFS. DP on induction remains of dismal prognosis in relation to disease REA afterwards. Risk stratification should highlight the role of trihemopoietic cytopenias, hepatic dysfunction, tri RO+, central nervous system risk site, and lung association.

Introduction and aim: Several studies report conflicting results about 18 F-FDG/PET and MIBG scans and their diagnostic as well as prognostic significance in children with neuroblastoma. The current study was meant to evaluate both modalities and to compare them in relation to standardized modes of evaluation. Results: FDG/PET showed good results in detecting NB at all sites. FDG/PET also showed a higher sensitivity and specificity, and a better PPV/NPV than MIBG which was not statistically significant. Concordance between paired scans (MIBG, and PET) was found in 55.7% of cases (Kappa=0.001) for primary tumor site, and in 7% for bone and 19.4% for bone marrow. The significance of concordance between both modalities was only demonstrated for metastatic boney lesions. There were 13 patients having stage III neuroblastoma (43.3%) while 17 patients (56.7%) were having stage IV disease. 23 Patients were categorized as high risk (76.7%) while 7 patients (23.3%) were intermediate risk. Both, PET/CT scan and MIBG were more sensitive in detecting disease at stage IV than stage III. Patients and Conclusion:18 F-FDG/PET scan can be used effectively in both diagnosis and management decisions for children with neuroblastoma, it is a good complementary tool especially in detecting bone metastasis, although further clinical trials must agree on definite analytical aspects between both modalities.