The transcription factor MITF is a critical regulator of GPNMB expression in dendritic cells

BACKGROUND: Dendritic cells (DC) are the most potent antigen-presenting cells (APC) with the unique ability to activate naïve T cells and to initiate and maintain primary immune responses. Immunosuppressive and anti-inflammatory stimuli on DC such as the cytokine IL-10 suppress the activity of the transcription factor NF-κB what results in downregulation of costimulatory molecules, MHC and cytokine production. Glycoprotein NMB (GPNMB) is a transmembrane protein, which acts as a coinhibitory molecule strongly inhibiting T cell responses if present on APC. Interestingly, its expression on human monocyte-derived dendritic cells (moDC) is dramatically upregulated upon treatment with IL-10 but also by the BCR-ABL tyrosine kinase inhibitors (TKI) imatinib, nilotinib or dasatinib used for the treatment of chronic myeloid leukemia (CML). However, the molecular mechanisms responsible for GPNMB overexpression are yet unknown. RESULTS: The immunosuppressive cytokine IL-10 and the BCR-ABL TKI imatinib or nilotinib, that were examined here, concordantly inhibit the PI3K/Akt signaling pathway, thereby activating the downstream serine/threonine protein kinase GSK3ß, and subsequently the microphthalmia-associated transcription factor (MITF) that is phosphorylated and translocated into the nucleus. Treatment of moDC with a small molecule inhibitor of MITF activity reduced the expression of GPNMB at the level of mRNA and protein, indicating that GPNMB expression is in fact facilitated by MITF activation. In line with these findings, PI3K/Akt inhibition was found to result in GPNMB overexpression accompanied by reduced stimulatory capacity of moDC in mixed lymphocyte reactions (MLR) with allogeneic T cells that could be restored by addition of the GPNMB T cell ligand syndecan-4 (SD-4). CONCLUSIONS: In summary, imatinib, nilotinib or IL-10 congruently inhibit the PI3K/Akt signaling pathway thereby activating MITF in moDC, resulting in a tolerogenic phenotype. These findings extend current knowledge on the molecular mechanisms balancing activating and inhibitory signals in human DC and may facilitate the targeted manipulation of T cell responses in the context of DC-based immunotherapeutic interventions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12964-015-0099-5) contains supplementary material, which is available to authorized users

Semen inhibits Zika virus infection of cells and tissues from the anogenital region

Zika virus (ZIKV) causes severe birth defects and can be transmitted via sexual intercourse. Semen from ZIKV-infected individuals contains high viral loads and may therefore serve as an important vector for virus transmission. Here we analyze the effect of semen on ZIKV infection of cells and tissues derived from the anogenital region. ZIKV replicates in all analyzed cell lines, primary cells, and endometrial or vaginal tissues. However, in the presence of semen, infection by ZIKV and other flaviviruses is potently inhibited. We show that semen prevents ZIKV attachment to target cells, and that an extracellular vesicle preparation from semen is responsible for this anti-ZIKV activity. Our findings suggest that ZIKV transmission is limited by semen. As such, semen appears to serve as a protector against sexual ZIKV transmission, despite the availability of highly susceptible cells in the anogenital tract and high viral loads in this bodily fluid.Peer reviewe

Clinical and morphological aspects in children affected with hydranencephaly: an overview / Aspectos clínicos e morfológicos em crianças afetadas com hidranencefalia: uma visão geral

Objective: To demonstrate a general view on the clinical and morphological aspects in children with Hydranencephaly. Methodology: This is a study that uses the systematic review as a method. Data collection took place in September 2019 through the SciELO and EBESCO databases with the following descriptors:”hemihydranencephaly”, '' Rare diseases '', 'malformation'. For the selection of articles, the following were used: inclusion criteria: articles in Portuguese, English, full articles that portray the theme related to the literature review and articles published and indexed in the referred databases in the period from 2007 to 2019. Results and Discussion: Hydranencephaly is a condition that in Most are lethal with exceptions, this malformation of the central nervous system occurs after the closure of the neural tube, defined as total or partial absence of cerebral hemispheres, the entire cortex that would be irrigated by the carotids is nonexistent. however, the brainstem, diencephalon and part of the occipital cortex, irrigated by the posterior cerebral arteries, are formed and may exhibit electrical activity. In some cases they have severe neurological sequelae, psychomotor disability, visual impairment, deafness and progressive macroencephaly. Conclusion: Patients with this rare condition are subjected to several surgeries and antibiotic therapies for prolonged periods in an attempt to provide the best survival for the patient. irrigated by the posterior cerebral arteries, are formed and may exhibit electrical activity. In some cases they have severe neurological sequelae, psychomotor disability, visual impairment, deafness and progressive macroencephaly. Conclusion: Patients with this rare condition are subjected to several surgeries and antibiotic therapies for prolonged periods in an attempt to provide the best survival for the patient. irrigated by the posterior cerebral arteries, are formed and may exhibit electrical activity. In some cases they have severe neurological sequelae, psychomotor disability, visual impairment, deafness and progressive macroencephaly. Conclusion: Patients with this rare condition are subjected to several surgeries and antibiotic therapies for prolonged periods in an attempt to provide the best survival for the patient.  

MOESM1 of Increased susceptibility of CD4+ T cells from elderly individuals to HIV-1 infection and apoptosis is associated with reduced CD4 and enhanced CXCR4 and FAS surface expression levels

Additional file 1: Figure S1. Increased levels of apoptosis in lymphocytes from elderly donors. Gating strategy of flow cytometry analysis of death and apoptosis rates from mock or HIV-1 NL4-3 reporter virus infected GFP+ or GFP− cells. Figure S2. Expression of activation markers and viral LTR activity in HIV-1 infected PBMC cultures from young and elderly individuals. (A, B) Representative primary data and statistical evaluations of the expression levels of (A) CD69 and (B) CD25 on X4 or R5 HIV-1 NL4-3 reporter virus infected GFP+ or GFP− cells from young (Y) and elderly (O) blood donors. (C) GFP expression levels in PBMC cultures from young and elderly donors infected with X4 or R5 HIV-1 NL4-3 reporter constructs. Each symbol represents the result obtained for one individual PBMC donor from the young (blue) or elderly (red) groups

N4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation

宿主がHIV-1感染を抑制する新たなメカニズムの解明 --N4BP1によるRNA分解とその調節がウイルス再活性化を調節する--. 京都大学プレスリリース. 2019-05-29.RNA-modulating factors not only regulate multiple steps of cellular RNA metabolism, but also emerge as key effectors of the immune response against invading viral pathogens including human immunodeficiency virus type-1 (HIV-1). However, the cellular RNA-binding proteins involved in the establishment and maintenance of latent HIV-1 reservoirs have not been extensively studied. Here, we screened a panel of 62 cellular RNA-binding proteins and identified NEDD4-binding protein 1 (N4BP1) as a potent interferon-inducible inhibitor of HIV-1 in primary T cells and macrophages. N4BP1 harbours a prototypical PilT N terminus-like RNase domain and inhibits HIV-1 replication by interacting with and degrading viral mRNA species. Following activation of CD4+ T cells, however, N4BP1 undergoes rapid cleavage at Arg 509 by the paracaspase named mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1). Mutational analyses and knockout studies revealed that MALT1-mediated inactivation of N4BP1 facilitates the reactivation of latent HIV-1 proviruses. Taken together, our findings demonstrate that the RNase N4BP1 is an efficient restriction factor of HIV-1 and suggest that inactivation of N4BP1 by induction of MALT1 activation might facilitate elimination of latent HIV-1 reservoirs

Species-specific host factors rather than virus-intrinsic virulence determine primate lentiviral pathogenicity

International audienceHIV-1 causes chronic inflammation and AIDS in humans, whereas related simian immunodeficiency viruses (SIVs) replicate efficiently in their natural hosts without causing disease. It is currently unknown to what extent virus-specific properties are responsible for these different clinical outcomes. Here, we incorporate two putative HIV-1 virulence determinants, i.e., a Vpu protein that antagonizes tetherin and blocks NF-κB activation and a Nef protein that fails to suppress T cell activation via downmodulation of CD3, into a non-pathogenic SIVagm strain and test their impact on viral replication and pathogenicity in African green monkeys. Despite sustained high-level viremia over more than 4 years, moderately increased immune activation and transcriptional signatures of inflammation, the HIV-1-like SIVagm does not cause immunodeficiency or any other disease. These data indicate that species-specific host factors rather than intrinsic viral virulence factors determine the pathogenicity of primate lentiviruses