Porcine Interferon Complex and Co-Evolution with Increasing Viral Pressure after Domestication

Consisting of nearly 60 functional genes, porcine interferon (IFN)-complex represents an evolutionary surge of IFN evolution in domestic ungulate species. To compare with humans and mice, each of these species contains about 20 IFN functional genes, which are better characterized using the conventional IFN-α/β subtypes as examples. Porcine IFN-complex thus represents an optimal model for studying IFN evolution that resulted from increasing viral pressure during domestication and industrialization. We hypothesize and justify that porcine IFN-complex may extend its functionality in antiviral and immunomodulatory activity due to its superior molecular diversity. Furthermore, these unconventional IFNs could even confer some functional and signaling novelty beyond that of the well-studied IFN-α/β subtypes. Investigations into porcine IFN-complex will further our understanding of IFN biology and promote IFN-based therapeutic designs to confront swine viral diseases

Discrimination, Coping, and Depression among Black Men Who Have Sex with Men

Black men who have sex with men (BMSM) have elevated risk for depression compared to the general population. BMSM’s capacity to cope with these experiences is not well understood. Increased understanding of how multiple forms of discrimination contribute to depression and how BMSM cope with discrimination can better inform interventions. Data come from 3,510 BMSM who attended Black Pride events in six U.S. cities from 2015-2017. Participants completed a health survey that ascertained their psychosocial health and resiliency profiles. Using multivariable logistic regression models, we tested the associations between type-specific discrimination (race, sexuality, HIV status) and depression. We then conducted sub-analyses to determine if coping attenuated the association between type-specific discrimination and depression. Our findings indicated that increased odds of depression among BMSM were associated with discrimination based on race (aOR=1.38, 95% CI = 1.08-1.76), sexual orientation (aOR=1.32, 95% CI = 1.01-1.72), and HIV status (aOR=1.53, 95% CI = 1.08-2.17). Sub-analyses indicated coping had inconsistent moderation effects between type-specific discrimination and depression. Our findings demonstrate that impact of various forms of discrimination on BMSM’s mental health and the mitigating role of coping. Interventions should seek to address depression by reducing experiences of discrimination and building coping resiliency

Viral Infections and Interferons in the Development of Obesity

Obesity is now a prevalent disease worldwide and has a multi-factorial etiology. Several viruses or virus-like agents including members of adenoviridae, herpesviridae, slow virus (prion), and hepatitides, have been associated with obesity; meanwhile obese patients are shown to be more susceptible to viral infections such as during influenza and dengue epidemics. We examined the co-factorial role of viral infections, particularly of the persistent cases, in synergy with high-fat diet in induction of obesity. Antiviral interferons (IFNs), as key immune regulators against viral infections and in autoimmunity, emerge to be a pivotal player in the regulation of adipogenesis. In this review, we examine the recent evidence indicating that gut microbiota uphold intrinsic IFN signaling, which is extensively involved in the regulation of lipid metabolism. However, the prolonged IFN responses during persistent viral infections and obesogenesis comprise reciprocal causality between virus susceptibility and obesity. Furthermore, some IFN subtypes have shown therapeutic potency in their anti-inflammation and anti-obesity activity

Xenopus Interferon Complex: Inscribing the Amphibiotic Adaption and Species-Specific Pathogenic Pressure in Vertebrate Evolution?

Several recent studies have revealed previously unknown complexity of the amphibian interferon (IFN) system. Being unique in vertebrate animals, amphibians not only conserve and multiply the fish-like intron-containing IFN genes, but also rapidly evolve amniote-like intronless IFN genes in each tested species. We postulate that the amphibian IFN system confers an essential model to study vertebrate immune evolution in molecular and functional diversity to cope with unprecedented pathophysiological requirement during terrestrial adaption. Studies so far have ascribed a potential role of these IFNs in immune regulation against intracellular pathogens, particularly viruses; however, many knowledge gaps remain elusive. Based on recent reports about IFN’s multifunctional properties in regulation of animal physiological and defense responses, we interpret that amphibian IFNs may evolve novel function pertinent to their superior molecular diversity. Such new function revealed by the emerging studies about antifungal and developmental regulation of amphibian IFNs will certainly promote our understanding of immune evolution in vertebrates to address current pathogenic threats causing amphibian decline

Reconstituting ring-rafts in bud-mimicking topography of model membranes.

During vesicular trafficking and release of enveloped viruses, the budding and fission processes dynamically remodel the donor cell membrane in a protein- or a lipid-mediated manner. In all cases, in addition to the generation or relief of the curvature stress, the buds recruit specific lipids and proteins from the donor membrane through restricted diffusion for the development of a ring-type raft domain of closed topology. Here, by reconstituting the bud topography in a model membrane, we demonstrate the preferential localization of cholesterol- and sphingomyelin-enriched microdomains in the collar band of the bud-neck interfaced with the donor membrane. The geometrical approach to the recapitulation of the dynamic membrane reorganization, resulting from the local radii of curvatures from nanometre-to-micrometre scales, offers important clues for understanding the active roles of the bud topography in the sorting and migration machinery of key signalling proteins involved in membrane budding

The design and in vivo evaluation of engineered I-OnuI-based enzymes for HEG gene drive.

The homing endonuclease gene (HEG) drive system, a promising genetic approach for controlling arthropod populations, utilises engineered nucleases to spread deleterious mutations that inactivate individual genes throughout a target population. Previous work with a naturally occurring LAGLIDADG homing endonuclease (I-SceI) demonstrated its feasibility in both Drosophila and Anopheles. Here we report on the next stage of this strategy: the redesign of HEGs with customized specificity in order to drive HEG-induced 'homing' in vivo via break-induced homologous recombination. Variants targeting a sequence within the Anopheles AGAP004734 gene were created from the recently characterized I-OnuI endonuclease, and tested for cleavage activity and frequency of homing using a model Drosophila HEG drive system. We observed cleavage and homing at an integrated reporter for all endonuclease variants tested, demonstrating for the first time that engineered HEGs can cleave their target site in insect germline cells, promoting targeted mutagenesis and homing. However, in comparison to our previously reported work with I-SceI, the engineered I-OnuI variants mediated homing with a reduced frequency, suggesting that site-specific cleavage activity is insufficient by itself to ensure efficient homing. Taken together, our experiments take a further step towards the development of a viable HEG-based population control strategy for insects

Generation of Polyclonal Rabbit Antisera Specific to the Zika Virus Capsid Protein

Zika virus (ZIKV), a mosquito-borne flavivirus, is an emerging zoonotic pathogen closely related to Japanese encephalitis virus, West Nile virus, dengue virus, and yellow fever virus. Although ZIKV infection generally produces only mild symptoms in some infected individuals, it has recently been associated with a growing number of neurological diseases, including Guillain-Barré syndrome in ZIKV-infected adults and microcephaly in infants born to ZIKV-infected women. Like all flaviviruses, ZIKV has a plus-strand RNA genome encoding ten functional proteins (designated C, prM, E, NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Of these ten, the C (capsid) protein is an essential structural protein required for the formation of infectious viral particles. In order to produce the antiserum specifically recognizing the ZIKV C protein in this study, we expressed and purified the ZIKV C protein as a glutathione-S-transferase (GST) fusion protein in E. coli. The ZIKV C protein-coding region was PCR-amplified using the genomic RNA of ZIKV PRVABC-59, and the amplicons were cloned into the pGEX-4T-1 E. coli expression vector. GST-C fusion proteins were purified using a glutathione sepharose column. Subsequently, the GST-C fusion proteins were used for immunization with rabbits. Western blot analysis using the ZIKV-infected Vero cell lysates were performed to examine the reactivity of the antisera to the ZIKV C protein. Thus, this study provides a useful reagent for the diagnosis and understanding of the viral morphogenesis in the ZIKV-infected cells

Genetic Elements Involved in Zika Virus Neuropathogenesis

Zikavirus (ZIKV) is a mosquito-borne flavivirus(Fig. 1) that is closely related to Japanese encephalitis, West Nile, yellow fever, and dengue viruses. ZIKV was first discovered in Uganda in 1947, but it was not until recent outbreaks, such as through Micronesia in 2007 and through Brazil in 2015 (Fig. 2), that it has been found to be associated with neurological diseases such as Guillain-Barrésyndrome and microcephaly

Cross-Species Genome-Wide Analysis Reveals Molecular and Functional Diversity of the Unconventional Interferon-ω Subtype

Innate immune interferons (IFNs), particularly type I IFNs, are primary mediators regulating animal antiviral, antitumor, and cell-proliferative activity. These antiviral cytokines have evolved remarkable molecular and functional diversity to confront ever-evolving viral threats and physiological regulation. We have annotated IFN gene families across 110 animal genomes, and showed that IFN genes, after originating in jawed fishes, had several significant evolutionary surges in vertebrate species of amphibians, bats and ungulates, particularly pigs and cattle. For example, pigs have the largest but still expanding type I IFN family consisting of nearly 60 IFN-coding genes that encode seven IFN subtypes including multigene subtypes of IFN-α, -δ, and -ω. Whereas, subtypes such as IFN-α and -β have been widely studied in many species, the unconventional subtypes such as IFN-ω have barely been investigated. We have cross-species defined the IFN evolution, and shown that unconventional IFN subtypes particularly the IFN-ω subtype have evolved several novel features including: (1) being a signature multi-gene subtype expanding primarily in mammals such as bats and ungulates, (2) emerging isoforms that have superior antiviral potency than typical IFN-α, (3) highly cross-species antiviral (but little anti-proliferative) activity exerted in cells of humans and other mammalian species, and (4) demonstrating potential novel molecular and functional properties. This study focused on IFN-ω to investigate the immunogenetic evolution and functional diversity of unconventional IFN subtypes, which may further IFN-based novel antiviral design pertinent to their cross-species high antiviral and novel activities