Explaining Pathogenicity of Congenital Zika and Guillain-Barré Syndromes: Does Dysregulation of RNA Editing Play a Role?

Previous studies of Zika virus (ZIKV) pathogenesis have focused primarily on virus-driven pathology and neurotoxicity, as well as host-related changes in cell proliferation, autophagy, immunity, and uterine function. It is now hypothesized that ZIKV pathogenesis arises instead as an (unintended) consequence of host innate immunity, specifically, as the side effect of an otherwise well-functioning machine. The hypothesis presented here suggests a new way of thinking about the role of host immune mechanisms in disease pathogenesis, focusing on dysregulation of post-transcriptional RNA editing as a candidate driver of a broad range of observed neurodevelopmental defects and neurodegenerative clinical symptoms in both infants and adults linked with ZIKV infections. The authors collect and synthesize existing evidence of ZIKV-mediated changes in the expression of adenosine deaminases acting on RNA (ADARs), known links between abnormal RNA editing and pathogenesis, as well as ideas for future research directions, including potential treatment strategies.

Diversity and Dynamics of "Candidatus Endobugula" and Other Symbiotic Bacteria in Chinese Populations of the Bryozoan, Bugula neritina.

Bugula neritina is a common invasive cosmopolitan bryozoan that harbors (like many sessile marine invertebrates) a symbiotic bacterial (SB) community. Among the SB of B. neritina, "Candidatus Endobugula sertula" continues to receive the greatest attention, because it is the source of bryostatins. The bryostatins are potent bioactive polyketides, which have been investigated for their therapeutic potential to treat various cancers, Alzheimer's disease, and AIDS. In this study, we compare the metagenomics sequences for the 16S ribosomal RNA gene of the SB communities from different geographic and life cycle samples of Chinese B. neritina. Using a variety of approaches for estimating alpha/beta diversity and taxonomic abundance, we find that the SB communities vary geographically with invertebrate and fish mariculture and with latitude and environmental temperature. During the B. neritina life cycle, we find that the diversity and taxonomic abundances of the SB communities change with the onset of host metamorphosis, filter feeding, colony formation, reproduction, and increased bryostatin production. "Ca. Endobugula sertula" is confirmed as the symbiont of the Chinese "Ca. Endobugula"/B. neritina symbiosis. Our study extends our knowledge about B. neritina symbiosis from the New to the Old World and offers new insights into the environmental and life cycle factors that can influence its SB communities, "Ca. Endobugula," and bryostatins more globally.

RNA editing by the host ADAR system affects the molecular evolution of the Zika virus.

Zika virus (ZIKV) is a mosquito-transmitted flavivirus, linked to microcephaly and fetal death in humans. Here, we investigate whether host-mediated RNA editing of adenosines (ADAR) plays a role in the molecular evolution of ZIKV. Using complete coding sequences for the ZIKV polyprotein, we show that potential ADAR substitutions are underrepresented at the ADAR-resistant GA dinucleotides of both the positive and negative strands, that these changes are spatially and temporally clustered (as expected of ADAR editing) for three branches of the viral phylogeny, and that ADAR mutagenesis can be linked to its codon usage. Furthermore, resistant GA dinucleotides are enriched on the positive (but not negative) strand, indicating that the former is under stronger purifying selection than the latter. ADAR editing also affects the evolution of the rhabdovirus sigma. Our study now documents that host ADAR editing is a mutation and evolutionary force of positive- as well as negative-strand RNA viruses.

Role of Host-Driven Mutagenesis in Determining Genome Evolution of Sigma Virus (DMelSV; Rhabdoviridae) in Drosophila melanogaster.

Sigma virus (DMelSV) is ubiquitous in natural populations of Drosophila melanogaster. Host-mediated, selective RNA editing of adenosines to inosines (ADAR) may contribute to control of viral infection by preventing transcripts from being transported into the cytoplasm or being translated accurately; or by increasing the viral genomic mutation rate. Previous PCR-based studies showed that ADAR mutations occur in DMelSV at low frequency. Here we use SOLiDTM deep sequencing of flies from a single host population from Athens, GA, USA to comprehensively evaluate patterns of sequence variation in DMelSV with respect to ADAR. GA dinucleotides, which are weak targets of ADAR, are strongly overrepresented in the positive strand of the virus, consistent with selection to generate ADAR resistance on this complement of the transient, double-stranded RNA intermediate in replication and transcription. Potential ADAR sites in a worldwide sample of viruses are more likely to be "resistant" if the sites do not vary among samples. Either variable sites are less constrained and hence are subject to weaker selection than conserved sites, or the variation is driven by ADAR. We also find evidence of mutations segregating within hosts, hereafter referred to as hypervariable sites. Some of these sites were variable only in one or two flies (i.e., rare); others were shared by four or even all five of the flies (i.e., common). Rare and common hypervariable sites were indistinguishable with respect to susceptibility to ADAR; however, polymorphism in rare sites were more likely to be consistent with the action of ADAR than in common ones, again suggesting that ADAR is deleterious to the virus. Thus, in DMelSV, host mutagenesis is constraining viral evolution both within and between hosts.

Unique structure and regulation of the nematode detoxification gene regulator, SKN-1: implications to understanding and controlling drug resistance.

Nematodes parasitize an alarming number of people and agricultural animals globally and cause debilitating morbidity and mortality. Anthelmintics have been the primary tools used to control parasitic nematodes for the past several decades, but drug resistance is becoming a major obstacle. Xenobiotic detoxification pathways defend against drugs and other foreign chemicals in diverse organisms, and evidence is accumulating that they play a role in mediating resistance to anthelmintics in nematodes. Related antioxidation pathways may also provide filarial parasites with protection against host free-radical-mediated immune responses. Upstream regulatory pathways have received almost no attention in nematode parasites, despite their potential to coregulate multiple detoxification and antioxidation genes. The nuclear eurythroid 2-related factor 2 (NRF2) transcription factor mediates inducible detoxification and antioxidation defenses in mammals, and recent studies have demonstrated that it promotes multidrug resistance in some human tumors. Recent studies in the free-living model nematode, Caenorhabditis elegans, have defined the homologous transcription factor, SKN-1, as a master regulator of detoxification and antioxidation genes. Despite similar functions, SKN-1 and NRF2 have important differences in structure and regulatory pathways. Protein alignment and phylogenetic analyses indicate that these differences are shared among many nematodes, making SKN-1 a candidate for specifically targeting nematode detoxification and antioxidation.

Utility of DNA viruses for studying human host history: case study of JC virus.

Microbial pathogens, and viruses in particular, can serve as important complements to traditional genetic markers when investigating the population histories of their human host. The range of mutation rates for DNA viruses suggests that DNA viruses can be useful markers of both recent and ancient events in their host histories. Here, we assess the utility of a well known DNA virus, JC virus (JCV), for investigating human history and demography. Using complete coding viral genomes, we confirm the phylogeographic structure of JCV in populations worldwide and provide coalescent estimates of its evolutionary rate under two alternative models of its history. Using these rate estimates, we compare Bayesian skyline plots of population size changes for JCV to those of its human host as estimated with coding mitochondrial genomes of the latter. These comparisons, when combined with other evidence including a log Bayes Factor model test, show that JCV is evolving rapidly and is therefore tracking the recent history of its human host. These results support the hypothesis that post-World War II societal changes are most likely responsible for the recent demographic patterns observed among different regional JCV populations. In sum, fast evolving DNA viruses, such as JCV, can complement RNA viruses to provide novel insights about the recent history and demography of their human host.