The Interferon-stimulated gene Ifi27l2a restricts West Nile virus infection and pathogenesis in a cell-type and region-specific manner

The mammalian host responds to viral infections by inducing expression of hundreds of interferon-stimulated genes (ISGs). While the functional significance of many ISGs has yet to be determined, their cell type and temporal nature of expression suggest unique activities against specific pathogens. Using a combination of ectopic expression and gene silencing approaches in cell culture, we previously identified Ifi27l2a as a candidate antiviral ISG within neuronal subsets of the central nervous system (CNS) that restricts infection by West Nile virus (WNV), an encephalitic flavivirus of global concern. To investigate the physiological relevance of Ifi27l2a in the context of viral infection, we generated Ifi27l2a(−/−) mice. Although adult mice lacking Ifi27l2a were more vulnerable to lethal WNV infection, the viral burden was greater only within the CNS, particularly in the brain stem, cerebellum, and spinal cord. Within neurons of the cerebellum and brain stem, in the context of WNV infection, a deficiency of Ifi27l2a was associated with less cell death, which likely contributed to sustained viral replication and higher titers in these regions. Infection studies in a primary cell culture revealed that Ifi27l2a(−/−) cerebellar granule cell neurons and macrophages but not cerebral cortical neurons, embryonic fibroblasts, or dendritic cells sustained higher levels of WNV infection than wild-type cells and that this difference was greater under conditions of beta interferon (IFN-β) pretreatment. Collectively, these findings suggest that Ifi27l2a has an antiviral phenotype in subsets of cells and that at least some ISGs have specific inhibitory functions in restricted tissues. IMPORTANCE The interferon-stimulated Ifi27l2a gene is expressed differentially within the central nervous system upon interferon stimulation or viral infection. Prior studies in cell culture suggested an antiviral role for Ifi27l2a during infection by West Nile virus (WNV). To characterize its antiviral activity in vivo, we generated mice with a targeted gene deletion of Ifi27l2a. Based on extensive virological analyses, we determined that Ifi27l2a protects mice from WNV-induced mortality by contributing to the control of infection of the hindbrain and spinal cord, possibly by regulating cell death of neurons. This antiviral activity was validated in granule cell neurons derived from the cerebellum and in macrophages but was not observed in other cell types. Collectively, these data suggest that Ifi27l2a contributes to innate immune restriction of WNV in a cell-type- and tissue-specific manner

Cellular and humoral immunity protect against vaginal Zika virus infection in mice

ABSTRACT Zika virus (ZIKV), which can cause devastating disease in fetuses of infected pregnant women, can be transmitted by mosquito inoculation and sexual routes. Little is known about immune protection against sexually transmitted ZIKV. In this study, we show that previous infection through intravaginal or subcutaneous routes with a contemporary Brazilian strain of ZIKV can protect against subsequent intravaginal challenge with a homologous strain. Both routes of inoculation induced high titers of ZIKV-specific and neutralizing antibody in serum and the vaginal lumen. Virus-specific T cells were recruited to and retained in the female reproductive tract after intravaginal and subcutaneous ZIKV infection. Studies in mice with genetic or acquired deficiencies in B and/or T cells demonstrated that both lymphocyte populations redundantly protect against intravaginal challenge in ZIKV-immune animals. Passive transfer of ZIKV-immune IgG or T cells significantly limited intravaginal infection of naive mice, although antibody more effectively prevented dissemination throughout the reproductive tract. Collectively, our experiments begin to establish the immune correlates of protection against intravaginal ZIKV infection, which should inform vaccination strategies in nonpregnant and pregnant women. IMPORTANCE The recent ZIKV epidemic resulted in devastating outcomes in fetuses and may affect reproductive health. Unlike other flaviviruses, ZIKV can be spread by sexual contact as well as a mosquito vector. While previous studies have identified correlates of protection for mosquito-mediated infection, few have focused on immunity against sexual transmission. As exposure to ZIKV via mosquito bite has likely occurred to many living in areas where ZIKV is endemic, our study addresses whether this route of infection can protect against subsequent sexual exposure. We demonstrate that subcutaneous ZIKV infection can protect against subsequent vaginal infection by generating both local antiviral T cell and antibody responses. Our research begins to define the immune correlates of protection for ZIKV infection in the vagina and provides a foundation for testing ZIKV vaccines against sexual transmission. </jats:p

The measurement of genetic diversity in mycobacterium tuberculosis using random amplified polymorphic DNA profiling

Mycobacterium tuberculosis has caused a resurgence in pulmonary disease in both developed and developing countries in recent times, particularly amongst people infected with the human immunodeficiency virus. The disease has assumed epidemic proportions in South Africa and in the Eastern Cape Province in particular. Of further concern is the isolation of increasing numbers of multiply drug resistant strains. Knowledge of the genetic capability of this organism is essential for the successful development of novel antibiotics and vaccines in an attempt to bring the global pandemic under control. Measurement of the genetic diversity of the organism may significantly contribute to such knowledge, and is of vital importance in monitoring epidemics and in improving treatment and control of the disease. This will entail answering a number of questions related to the degree of genetic diversity amongst strains, to the difference between urban and rural strains, and between drug resistant and drug sensitive strains, and to the geographical distribution of strains. In order to establish such baseline information, RAPD profiling of a large population of isolates from the western and central regions of the Eastern Cape Province was undertaken. A smaller number of drug resistant strains from a small area of KwaZulu-Natal were also analysed, with a view to establishing the genetic difference between strains from the two provinces. Cluster analysis, analysis of molecular variance and Geographical Information Systems technology were used to analyse the RAPD profiles generated. An unexpectedly high degree of genetic diversity was detected in strains from both provinces. While no correlation was seen between genetic diversity and either urban-rural situation or geographical location, a small degree of population structure could be correlated with drug resistance in the Eastern Cape. Furthermore, a significant degree of population structure was detected between strains from the two provinces, although this was still within the parameters for conspecific populations. Future work is necessary to further characterise strains from rural areas of both provinces, as well as from the eastern region of the Eastern Cape in an attempt to pinpoint the cause of the separation of the provincial populations

Melanin-based colorations signal strategies to cope with poor and rich environments

One hypothesis for the maintenance of genetic variation states that alternative genotypes are adapted to different environmental conditions (i.e., genotype-by-environment interaction G×E) that vary in space and time. Although G×E has been demonstrated for morphological traits, little evidence has been given whether these G×E are associated with traits used as signal in mate choice. In three wild bird species, we investigated whether the degree of melanin-based coloration, a heritable trait, covaries with nestling growth rate in rich and poor environments. Variation in the degree of reddish-brown phaeomelanism is pronounced in the barn owl (Tyto alba) and tawny owl (Strix aluco), and variation in black eumelanism in the barn owl and Alpine swift (Apus melba). Melanin-based coloration has been shown to be a criterion in mate choice in the barn owl. We cross-fostered hatchlings to test whether nestlings sired by parents displaying melanin-based colorations to different extent exhibit alternative growth trajectories when raised by foster parents in poor (experimentally enlarged broods) and rich (experimentally reduced broods) environments. With respect to phaeomelanism, barn owl and tawny owl offspring sired by redder parents grew more rapidly in body mass only in experimentally reduced broods. With respect to eumelanism, Alpine swift offspring of darker fathers grew their wings more rapidly only in experimentally enlarged broods, a difference that was not detected in reduced broods. These interactions between parental melanism and offspring growth rate indicate that individuals display substantial plasticity in response to the rearing environment which is associated with the degree of melanism: at least with respect to nestling growth, phaeomelanic and eumelanic individuals are best adapted to rich and poor environments, respectively. It now remains to be investigated why eumelanism and phaeomelanism have a different signaling function and what the lifelong consequences of these melanism-dependent allocation strategies are. This is important to fully appraise the role played by environmental heterogeneity in maintaining variation in the degree of melanin-based coloratio

Psychiatric, neuropediatric, and neuropsychological symptoms in a case of hypomelanosis of Ito

This case report presents a thirteen year-old boy who was diagnosed as having Hypomelanosis of Ito. The developmental history includes severe failure to thrive, and moderate atypical autism as well as diverse clinical and neuropsychological symptoms are present. The pattern of neuropsychological functioning, which can be partially related to the neurophysiological findings, is discussed within the context of existing neuropsychological theories about autistic disorder

Offspring social network structure predicts fitness in families.

addresses: Centre for Ecology and Conservation, Biosciences, College of Life and Environmental Sciences, University of Exeter, Cornwall Campus, Penryn, Cornwall TR10 9EZ, UK. [email protected]: PMCID: PMC3497231types: Journal Article; Research Support, Non-U.S. Gov'tSocial structures such as families emerge as outcomes of behavioural interactions among individuals, and can evolve over time if families with particular types of social structures tend to leave more individuals in subsequent generations. The social behaviour of interacting individuals is typically analysed as a series of multiple dyadic (pair-wise) interactions, rather than a network of interactions among multiple individuals. However, in species where parents feed dependant young, interactions within families nearly always involve more than two individuals simultaneously. Such social networks of interactions at least partly reflect conflicts of interest over the provision of costly parental investment. Consequently, variation in family network structure reflects variation in how conflicts of interest are resolved among family members. Despite its importance in understanding the evolution of emergent properties of social organization such as family life and cooperation, nothing is currently known about how selection acts on the structure of social networks. Here, we show that the social network structure of broods of begging nestling great tits Parus major predicts fitness in families. Although selection at the level of the individual favours large nestlings, selection at the level of the kin-group primarily favours families that resolve conflicts most effectively

Interferon regulatory factor 5-dependent immune responses in the draining lymph node protect against West Nile Virus infection

Upon activation of Toll-like and RIG-I-like receptor signaling pathways, the transcription factor IRF5 translocates to the nucleus and induces antiviral immune programs. The recent discovery of a homozygous mutation in the immunoregulatory gene guanine exchange factor dedicator of cytokinesis 2 (Dock2(mu/mu)) in several Irf5(−/−) mouse colonies has complicated interpretation of immune functions previously ascribed to IRF5. To define the antiviral functions of IRF5 in vivo, we infected backcrossed Irf5(−/−) × Dock2(wt/wt) mice (here called Irf5(−/−) mice) and independently generated CMV-Cre Irf5(fl/fl) mice with West Nile virus (WNV), a pathogenic neurotropic flavivirus. Compared to congenic wild-type animals, Irf5(−/−) and CMV-Cre Irf5(fl/fl) mice were more vulnerable to WNV infection, and this phenotype was associated with increased infection in peripheral organs, which resulted in higher virus titers in the central nervous system. The loss of IRF5, however, was associated with only small differences in the type I interferon response systemically and in the draining lymph node during WNV infection. Instead, lower levels of several other proinflammatory cytokines and chemokines, as well as fewer and less activated immune cells, were detected in the draining lymph node 2 days after WNV infection. WNV-specific antibody responses in Irf5(−/−) mice also were blunted in the context of live or inactivated virus infection and this was associated with fewer antigen-specific memory B cells and long-lived plasma cells. Our results with Irf5(−/−) mice establish a key role for IRF5 in shaping the early innate immune response in the draining lymph node, which impacts the spread of virus infection, optimal B cell immunity, and disease pathogenesis. IMPORTANCE Although the roles of IRF3 and IRF7 in orchestrating innate and adaptive immunity after viral infection are established, the function of the related transcription factor IRF5 remains less certain. Prior studies in Irf5(−/−) mice reported conflicting results as to the contribution of IRF5 in regulating type I interferon and adaptive immune responses. The lack of clarity may stem from a recently discovered homozygous loss-of-function mutation of the immunoregulatory gene Dock2 in several colonies of Irf5(−/−) mice. Here, using a mouse model with a deficiency in IRF5 and wild-type Dock2 alleles, we investigated how IRF5 modulates West Nile virus (WNV) pathogenesis and host immune responses. Our in vivo studies indicate that IRF5 has a key role in shaping the early proinflammatory cytokine response in the draining lymph node, which impacts immunity and control of WNV infection

NEST – una plataforma para acelerar la innovación en edificios

The speed and quality of innovation in the construction sector has to be substantially increased in order to meet the pressing challenges associated with the building stock. For this purpose, the NEST project was started in Switzerland. NEST is a flexible and open research and technology transfer platform for partners from academia and industry where new solutions can be implemented and validated in a real life environment. NEST consists of a backbone, the static part, and research units which serve as office or living space where people live and work. Each unit is addressing specific research topics such as timber construction or digital fabrication and bears numerous innovation objects which are subject to continuous development and evaluation. NEST is a vertical neighbourhood of units, which are connected to a water hub and an energy hub. Once the research questions in a unit are answered and new products have been developed, the unit is deconstructed and replaced by a new unit addressing new topics.La calidad en la innovación dentro del sector de la construcción debe ser rápidamente adaptada para cumplir con los inmediatos desafíos relacionados con la mejora de las edificaciones actuales. NEST es una plataforma de investigación y transferencia tecnológica flexible y abierta a universidades e industrias donde nuevas soluciones pueden ser implementadas y validadas en un entorno real. NEST consiste en una estructura fija con una serie módulos individuales que son utilizados como oficinas o apartamentos donde poder vivir y trabajar. Además, cada uno de estos módulos actúa a modo de laboratorio donde se investigan diferentes aspectos como el uso de madera como material de construcción o la fabricación digital y donde, continuamente, se lleva a cabo el desarrollo de materiales innovadores, así como su evaluación. NEST es un edificio modular cuyas unidades están individualmente conectadas por medio de redes comunes de suministro de energía y gestión y tratamiento de aguas. Cuando finalizan los estudios asociados a un módulo y los nuevos productos han sido optimizados, éste es desinstalado y remplazado por una nueva unidad de cara a abordar nuevos retos e investigaciones