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mSphere ; 1(2)2016 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27303731


Filoviruses are the causative agents of an increasing number of disease outbreaks in human populations, including the current unprecedented Ebola virus disease (EVD) outbreak in western Africa. One obstacle to controlling these epidemics is our poor understanding of the host range of filoviruses and their natural reservoirs. Here, we investigated the role of the intracellular filovirus receptor, Niemann-Pick C1 (NPC1) as a molecular determinant of Ebola virus (EBOV) host range at the cellular level. Whereas human cells can be infected by EBOV, a cell line derived from a Russell's viper (Daboia russellii) (VH-2) is resistant to infection in an NPC1-dependent manner. We found that VH-2 cells are resistant to EBOV infection because the Russell's viper NPC1 ortholog bound poorly to the EBOV spike glycoprotein (GP). Analysis of panels of viper-human NPC1 chimeras and point mutants allowed us to identify a single amino acid residue in NPC1, at position 503, that bidirectionally influenced both its binding to EBOV GP and its viral receptor activity in cells. Significantly, this single residue change perturbed neither NPC1's endosomal localization nor its housekeeping role in cellular cholesterol trafficking. Together with other recent work, these findings identify sequences in NPC1 that are important for viral receptor activity by virtue of their direct interaction with EBOV GP and suggest that they may influence filovirus host range in nature. Broader surveys of NPC1 orthologs from vertebrates may delineate additional sequence polymorphisms in this gene that control susceptibility to filovirus infection. IMPORTANCE Identifying cellular factors that determine susceptibility to infection can help us understand how Ebola virus is transmitted. We asked if the EBOV receptor Niemann-Pick C1 (NPC1) could explain why reptiles are resistant to EBOV infection. We demonstrate that cells derived from the Russell's viper are not susceptible to infection because EBOV cannot bind to viper NPC1. This resistance to infection can be mapped to a single amino acid residue in viper NPC1 that renders it unable to bind to EBOV GP. The newly solved structure of EBOV GP bound to NPC1 confirms our findings, revealing that this residue dips into the GP receptor-binding pocket and is therefore critical to the binding interface. Consequently, this otherwise well-conserved residue in vertebrate species influences the ability of reptilian NPC1 proteins to bind to EBOV GP, thereby affecting viral host range in reptilian cells.

Elife ; 42015 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-26698106


Biological factors that influence the host range and spillover of Ebola virus (EBOV) and other filoviruses remain enigmatic. While filoviruses infect diverse mammalian cell lines, we report that cells from African straw-colored fruit bats (Eidolon helvum) are refractory to EBOV infection. This could be explained by a single amino acid change in the filovirus receptor, NPC1, which greatly reduces the affinity of EBOV-NPC1 interaction. We found signatures of positive selection in bat NPC1 concentrated at the virus-receptor interface, with the strongest signal at the same residue that controls EBOV infection in Eidolon helvum cells. Our work identifies NPC1 as a genetic determinant of filovirus susceptibility in bats, and suggests that some NPC1 variations reflect host adaptations to reduce filovirus replication and virulence. A single viral mutation afforded escape from receptor control, revealing a pathway for compensatory viral evolution and a potential avenue for expansion of filovirus host range in nature.

Filoviridae/fisiologia , Especificidade de Hospedeiro , Glicoproteínas de Membrana/metabolismo , Receptores Virais/metabolismo , Ligação Viral , Animais , Linhagem Celular , Quirópteros
Theor Biol Med Model ; 7: 36, 2010 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-20727172


BACKGROUND: Ultrasound elasticity imaging provides biomechanical and elastic properties of vascular tissue, with the potential to distinguish between tissue motion and tissue strain. To validate the ability of ultrasound elasticity imaging to predict structurally defined physical changes in tissue, strain measurement patterns during angioplasty in four bovine carotid artery pathology samples were compared to the measured physical characteristics of the tissue specimens. METHODS: Using computational image-processing techniques, the circumferences of each bovine artery specimen were obtained from ultrasound and pathologic data. RESULTS: Ultrasound-strain-based and pathology-based arterial circumference measurements were correlated with an R2 value of 0.94 (p = 0.03). The experimental elasticity imaging results confirmed the onset of deformation of an angioplasty procedure by indicating a consistent inflection point where vessel fibers were fully unfolded and vessel wall strain initiated. CONCLUSION: These results validate the ability of ultrasound elasticity imaging to measure localized mechanical changes in vascular tissue.

Angioplastia/métodos , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Estresse Mecânico , Animais , Bovinos , Módulo de Elasticidade , Ultrassonografia
Semin Dial ; 23(1): 105-9, 2010 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20331827


Ultrasonography for the noninvasive assessment of tissue properties has enjoyed widespread success. With the growing emphasis in recent years on arteriovenous fistulae (AVFs) for dialysis vascular access in patients with end-stage renal disease, and on reducing AVF failures, there is increasing interest in ultrasound for the preoperative evaluation of the mechanical and elastic properties of arteries and veins. This study used high-resolution ultrasound with phase-sensitive speckle tracking to obtain in vivo vein elasticity measurements during dilation. The results of this novel ultrasound technique were then compared to a computer model of venous strain. The computer model and ultrasound analysis of the vessel wall demonstrated internally consistent positive and negative longitudinal strain values as the vein wall underwent dilation. These results support further investigation of the use of phase-sensitive speckle tracking for ultrasound venous mapping for preoperative vascular access evaluation.

Técnicas de Imagem por Elasticidade/métodos , Veias/diagnóstico por imagem , Veias/fisiologia , Complacência (Medida de Distensibilidade) , Análise de Elementos Finitos , Humanos , Masculino , Pessoa de Meia-Idade
Theor Biol Med Model ; 5: 22, 2008 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-18986548


BACKGROUND: End-stage renal disease (ESRD) confers a large health-care burden for the United States, and the morbidity associated with vascular access failure has stimulated research into detection of vascular access stenosis and low flow prior to thrombosis. We present data investigating the possibility of using differential pressure (DeltaP) monitoring to estimate access flow (Q) for dialysis access monitoring, with the goal of utilizing micro-electro-mechanical systems (MEMS) pressure sensors integrated within the shaft of dialysis needles. METHODS: A model of the arteriovenous graft fluid circuit was used to study the relationship between Q and the DeltaP between two dialysis needles placed 2.5-20.0 cm apart. Tubing was varied to simulate grafts with inner diameters of 4.76-7.95 mm. Data were compared with values from two steady-flow models. These results, and those from computational fluid dynamics (CFD) modeling of DeltaP as a function of needle position, were used to devise and test a method of estimating Q using DeltaP and variable dialysis pump speeds (variable flow) that diminishes dependence on geometric factors and fluid characteristics. RESULTS: In the fluid circuit model, DeltaP increased with increasing volume flow rate and with increasing needle-separation distance. A nonlinear model closely predicts this DeltaP-Q relationship (R2 > 0.98) for all graft diameters and needle-separation distances tested. CFD modeling suggested turbulent needle effects are greatest within 1 cm of the needle tip. Utilizing linear, quadratic and combined variable flow algorithms, dialysis access flow was estimated using geometry-independent models and an experimental dialysis system with the pressure sensors separated from the dialysis needle tip by distances ranging from 1 to 5 cm. Real-time DeltaP waveform data were also observed during the mock dialysis treatment, which may be useful in detecting low or reversed flow within the access. CONCLUSION: With further experimentation and needle design, this geometry-independent approach may prove to be a useful access flow monitoring method.

Derivação Arteriovenosa Cirúrgica/instrumentação , Derivação Arteriovenosa Cirúrgica/métodos , Modelos Biológicos , Algoritmos , Velocidade do Fluxo Sanguíneo/fisiologia , Biologia Computacional/instrumentação , Biologia Computacional/métodos , Diálise/instrumentação , Diálise/métodos , Humanos , Pressão