Structural Basis of Chemokine Sequestration by CrmD, a Poxvirus-Encoded Tumor Necrosis Factor Receptor

Pathogens have evolved sophisticated mechanisms to evade detection and destruction by the host immune system. Large DNA viruses encode homologues of chemokines and their receptors, as well as chemokine-binding proteins (CKBPs) to modulate the chemokine network in host response. The SECRET domain (smallpox virus-encoded chemokine receptor) represents a new family of viral CKBPs that binds a subset of chemokines from different classes to inhibit their activities, either independently or fused with viral tumor necrosis factor receptors (vTNFRs). Here we present the crystal structures of the SECRET domain of vTNFR CrmD encoded by ectromelia virus and its complex with chemokine CX3CL1. The SECRET domain adopts a β-sandwich fold and utilizes its β-sheet I surface to interact with CX3CL1, representing a new chemokine-binding manner of viral CKBPs. Structure-based mutagenesis and biochemical analysis identified important basic residues in the 40s loop of CX3CL1 for the interaction. Mutation of corresponding acidic residues in the SECRET domain also affected the binding for other chemokines, indicating that the SECRET domain binds different chemokines in a similar manner. We further showed that heparin inhibited the binding of CX3CL1 by the SECRET domain and the SECRET domain inhibited RAW264.7 cell migration induced by CX3CL1. These results together shed light on the structural basis for the SECRET domain to inhibit chemokine activities by interfering with both chemokine-GAG and chemokine-receptor interactions

Scwannoma intramedular: relato de caso Intramedullary schwannoma: case report

A localização intramedular de schwannoma é rara, correspondendo a 0,3% dos tumores nesta topografia. Os autores relatam o caso de uma paciente leucoderma de 52 anos, que apresentou sintomas de compressão devido à presença de schwannoma intramedular localizado em nível de C4 a C6. Não foram encontrados sinais de neurofibromatose, enfermidade que tem sido associada ao desenvolvimento da lesão. Os exames de ressonância magnética nuclear e a biópsia transoperatórIa foram fatores decisivos no planejamento e na execução do tratamento, ao estabelecer as características, localização e diagnóstico da lesão. Sua boa delimitação e sua localização posterior facilitaram a exérese total. O exame histopatológico transoperatórIo permitiu a instituição de procedimento cirúrgico adequado. A célula de Schwann não é normalmente encontrada no sistema nervoso central e sua presença neste local tem sido objeto de várias teorias expostas no texto deste trabalho, que aborda também revisão de aspectos clínicos, diagnóstico por imagem, patologia, diagnóstico diferencial e tratamento dos schwannomas. E provável que, com os métodos propedêuticos atualmente disponíveis, venha a ser encontrado maior número destas lesões no futuro.<br>The intramedullary localization of schwannomas is rare, corresponding to 0.3% of all intraspinal tumors. The authors report the case of a 52 year-old white female patient that presented with symptoms of spinal compression by the presence of an intramedullary schwannoma at the level C4-C6. There were no symptoms of neurofibromatosis, entity frequently related to the lesion. The magnetic resonance imaging examination and the per-operatory biopsy were decisive factors in planning and executing the treatment , by establishing the characteristics, location and diagnosis of the lesion. Its delimitation and posterior location have facilitated total surgical exeresis. The transoperatively histopathologic examination allowed adequate surgical procedure. The Schwann cell is not found normally in the central nervous system and its presence in this site has been subject of many theories exposed in this paper, which proposes comprehensive review of the clinical aspects, imaging diagnosis, pathology, differential diagnosis and treatment of schwannomas. It is probable that, with the advances verified in the available diagnostic methods, a greater number of these lesions may be diagnosed in the future

Primary progressive aphasia: analisys of 16 cases Afasia progressiva primária: análise de 16 casos

Primary progressive aphasia (PPA) is an intriguing syndrome, showing some peculiar aspects that differentiate it from classical aphasic pictures caused by focal cerebral lesions or dementia. The slow and progressive deterioration of language occurring in these cases provides an interesting model to better understand the mechanisms involved in the linguistic process. We describe clinical and neuroimaging aspects found in 16 cases of PPA. Our patients underwent language and neuropsychological evaluation, magnetic resonance imaging (MRI) and single photon emission computerized tomography (SPECT). We observed a clear distinction in oral expression patterns; patients were classified as fluent and nonfluent. Anomia was the earliest and most evident symptom in both groups. Neuroimaging pointed to SPECT as a valuable instrument in guiding the differential diagnosis, as well as in making useful clinical and anatomical correlations. This report and a comparison to literature are an attempt to contribute to a better understanding of PPA.<br>A afasia progressiva primária (APP) é uma síndrome que tem despertado grande interesse devido a aspectos particulares que a diferenciam das afasias clássicas (secundárias a lesões cerebrais focais) e dos quadros demenciais. A deterioração lenta e progressiva da linguagem presente nesses casos fornece um interessante modelo de observação dos mecanismos subjacentes ao processamento linguístico. Descrevemos as características clínicas e de neuroimagem de 16 casos de APP. Os pacientes foram submetidos a exame de linguagem, neuropsicológico, ressonância magnética (RM) e tomografia computadorizada por emissão de fóton único (SPECT). Clinicamente pudemos observar uma nítida distinção nos padrões de produção oral, sendo os pacientes agrupados em fluentes e não-fluentes. Anomia foi o sintoma mais precoce e evidente nos dois subgrupos. Os achados de neuroimagem permitem destacar a sensibilidade do SPECT como instrumento diagnóstico. O registro e a comparação destes casos aos da literatura são uma tentativa de contribuir para a compreensão da APP

Targeting CCL5 in inflammation

&lt;br&gt;Introduction: Chemokines play important roles in inflammation and in immune responses. This article will discuss the current literature on the C–C chemokine ligand 5 (CCL5), and whether it is a therapeutic target in the context of various allergic, autoimmune or infectious diseases.&lt;/br&gt; &lt;br&gt;Areas covered: Small-molecule inhibitors, chemokine and chemokine receptor-deficient mice, antibodies and modified chemokines are the current tools available for CCL5 research, and there are several ongoing clinical trials targeting the CCL5 receptors, CCR1, CCR3 and CCR5. There are fewer studies specifically targeting the chemokine itself and clinical studies with anti-CCL5 antibodies are still to be carried out.&lt;/br&gt; &lt;br&gt;Expert opinion: Although clinical trials are strongly biased toward HIV treatment and prevention with blockers of CCR5, the therapeutic potential for CCL5 and its receptors in other diseases is relevant. Overall, it is not likely that specific targeting of CCL5 will result in new adjunct strategies for the treatment of infectious diseases with a major inflammatory component. However, targeting CCL5 could result in novel therapies for chronic inflammatory diseases, where it may decrease inflammatory responses and fibrosis, and certain solid tumors, where it may have a role in angiogenesis.&lt;/br&gt

Antibody-mediated prevention and treatment of HIV-1 infection

Novel broadly neutralizing antibodies targeting HIV-1 hold promise for their use in the prevention and treatment of HIV-1 infection. Pre-clinical results have encouraged the evaluation of these antibodies in healthy and HIV-1-infected humans. In first clinical trials, highly potent broadly neutralizing antibodies have demonstrated their safety and significant antiviral activity by reducing viremia and delaying the time to viral rebound in individuals interrupting antiretroviral therapy. While emerging antibody-resistant viral variants have indicated limitations of antibody monotherapy, strategies to enhance the efficacy of broadly neutralizing antibodies in humans are under investigation. These include the use of antibody combinations to prevent viral escape, antibody modifications to increase the half-life and the co-administration of latency-reversing agents to target the cellular reservoir of HIV-1. We provide an overview of the results of pre-clinical and clinical studies of broadly HIV-1 neutralizing antibodies, discuss their implications and highlight approaches for the ongoing advancement into humans