Biology subjects

Andino, R.

Publications and source records attributed to Andino, R..

5 recordsLinked to original sources

bioRxiv2018

Antiviral adaptive immunity and tolerance in the mosquito Aedes aegyti

Mosquitoes spread pathogenic arboviruses while themselves tolerate infection. We here characterize an immunity pathway providing long-term antiviral protection and define how this pathway discriminates between self and non-self. Mosquitoes use viral RNAs to create viral derived cDNAs (vDNAs) central to the antiviral response. vDNA molecules are acquired through a process of reverse-transcription and recombination directed by endogenous retrotransposons. These vDNAs are thought to integrate in the host genome as endogenous viral elements (EVEs). Sequencing of pre-integrated vDNA revealed that the acquisition process exquisitely distinguishes viral from host RNA, providing one layer of self-nonself discrimination. Importantly, we show EVE-derived piRNAs have antiviral activity and are loaded onto Piwi4 to inhibit virus replication. In a second layer of self-non-self discrimination, Piwi4 preferentially loads EVE-derived piRNAs, discriminating against transposon-targeting piRNAs. Our findings define a fundamental virus-specific immunity pathway in mosquitoes that uses EVEs as a potent and specific antiviral transgenerational mechanism.

immunology↗

bioRxiv2018

Genetic recombination of poliovirus facilitates subversion of host barriers to infection

The contribution of RNA recombination to viral fitness and pathogenesis is poorly defined. Here, we isolate a recombination-deficient, poliovirus variant and find that, while recombination is detrimental to virus replication in tissue culture, recombination is important for pathogenesis in infected animals. Notably, recombination-defective virus exhibits severe attenuation following intravenous inoculation that is associated with a significant reduction in population size during intra-host spread. Because the impact of high mutational loads manifests most strongly at small population sizes, our data suggest that the repair of mutagenized genomes is an essential function of recombination and that this function may drive the long-term maintenance of recombination in viral species despite its associated fitness costs.\n\nSignificance StatementRNA recombination is a widespread but poorly understood feature of RNA virus replication. For poliovirus, recombination is involved in the emergence of neurovirulent circulating vaccine-derived poliovirus, which has hampered global poliovirus eradication efforts. This emergence illustrates the power of recombination to drive major adaptive change; however, it remains unclear if these adaptive events represent the primary role of recombination in virus survival. Here, we identify a viral mutant with a reduced rate of recombination and find that recombination also plays a central role in the spread of virus within animal hosts. These results highlight a novel approach for improving the safety of live attenuated vaccines and further our understanding of the role of recombination in virus pathogenesis and evolution.

microbiology↗

bioRxiv2017

Protection from epidemics is a driving force for evolution of lifespan setpoints

Most living organisms age, as determined by species-specific limits to lifespan1-6. The biological driving force for a genetically-defined limit on the lifespan of a given species (herein called \"lifespan setpoint\") remains poorly understood. Here we present mathematical models suggesting that an upper limit of individual lifespans protects their cohort population from infection-associated penalties. A shorter lifespan setpoint helps control pathogen spread within a population, prevents the establishment and progression of infections, and accelerates pathogen clearance from the population when compared to populations with long-lived individuals. Strikingly, shorter-living variants efficiently displace longer-living individuals in populations that are exposed to pathogens and exist in spatially structured niches. The beneficial effects of shorter lifespan setpoints are even more evident in the context of zoonotic transmissions, where pathogens undergo adaptation to a new host. We submit that the selective pressure of infectious disease provides an evolutionary driving force to limit individual lifespan setpoints after reproductive maturity to secure its kins fitness. Our findings have important public health implications for efforts to extend humans lifespan.

evolutionary biology↗

bioRxiv2017

Hsp90 dictates viral sequence space by balancing the evolutionary tradeoffs between protein stability, aggregation and translation rate

Acquisition of mutations is central to evolution but the detrimental effects of most mutations on protein folding and stability limit protein evolvability. Molecular chaperones, which suppress aggregation and facilitate polypeptide folding, are proposed to promote sequence diversification by buffering destabilizing mutations. However, whether and how chaperones directly control protein evolution remains poorly understood. Here, we examine the effect of reducing the activity of the key eukaryotic chaperone Hsp90 on poliovirus evolution. Contrary to predictions of a buffering model, inhibiting Hsp90 increases population sequence diversity and promotes accumulation of mutations reducing protein stability. Explaining this counterintuitive observation, we find that Hsp90 offsets the evolutionary tradeoff between protein stability and aggregation. Lower chaperone levels favor sequence variants of reduced hydrophobicity, thus decreasing protein aggregation propensity but at a cost to protein stability. Notably, reducing Hsp90 activity also promotes clusters of codon-deoptimized synonymous mutations at inter-domain boundaries, likely to promote local ribosomal slowdown to facilitate cotranslational domain folding. Our results reveal how a chaperone can shape the sequence landscape at both the protein and RNA levels to harmonize the competing constraints posed by protein stability, aggregation propensity and translation rate on successful protein biogenesis.

evolutionary biology↗

bioRxiv2017

Long-read assembly of the Aedes aegypti genome reveals the nature of heritable adaptive immunity sequences

The Aedes aegypti mosquito is a major vector for arboviruses including dengue, chikungunya and Zika virus. Combating the spread of these viruses requires a more complete understanding of the mosquito immune system. Recent studies have implicated genomic endogenous viral elements (EVEs) derived from non-retroviral RNA viruses in insect immunity. Because these elements are inserted into repetitive regions of the mosquito genome, their large-scale structure and organization with respect to other genomic elements has been difficult to resolve with short-read sequencing. To better define the origin, diversity and biological role of EVEs, we employed single-molecule, real-time sequencing technology to generate a high quality, long-read assembly of the Ae. aegypti-derived Aag2 cell line genome. We leverage the quality and contiguity of this assembly to characterize the diversity and genomic context of EVEs in the genome of this important model system. We find that EVEs in the Aag2 genome are acquired through recombination by LTR retrotransposons, and organize into larger loci (>50kbp) characterized by high LTR density. These EVE containing loci are associated with increased transcription factor binding sight density and increased production of anti-genomic piRNAs. We also detected piRNA processing corresponding to on-going viral infection. This global view of EVEs and piRNA responses demonstrates the ubiquity and diversity of these heritable elements that define small-RNA mediated antiviral immunity in mosquitoes.

genomics↗