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bioRxiv2018

Identification of Klebsiella pneumoniae complex members using MALDI-TOF mass spectrometry

Klebsiella pneumoniae (phylogroup Kp1), one of the most problematic pathogens associated with antibiotic resistance worldwide, is phylogenetically closely related to K. quasipneumoniae [subsp. quasipneumoniae (Kp2) and subsp. similipneumoniae (Kp4)], K. variicola (Kp3) and two unnamed phylogroups (Kp5 and Kp6). Together, Kp1 to Kp6 make-up the K. pneumoniae complex. Currently, the phylogroups can be reliably identified only by gene sequencing. Misidentification using standard methods is common and the clinical significance of K. pneumoniae complex members is therefore imprecisely defined. Here, we evaluated the potential of MALDI-TOF mass spectrometry to discriminate K. pneumoniae complex members. We report for the first time the existence of mass spectrometry biomarkers associated with the phylogroups, with a sensitivity and specificity ranging between 80-100% and 97-100%, respectively. Strains within phylogroups Kp1, Kp2, Kp4 and Kp5 each shared two specific peaks not observed in other phylogroups. Kp3 strains shared a peak that was only observed otherwise in Kp5. Finally, Kp6 had a diagnostic peak shared only with Kp1. Kp3 and Kp6 could therefore be identified by exclusion criteria (lacking Kp5 and Kp1-specific peaks, respectively). Further, ranked Pearson correlation clustering of spectra grouped strains according to their phylogroup. These results call for incorporation of spectra of all K. pneumoniae complex members into reference MALDI-TOF spectra databases, in which they are currently lacking. This advance may allow for simple and precise identification of K. pneumoniae and closely related species, opening the way to a better understanding of their epidemiology, ecology and pathogenesis.

microbiology↗

bioRxiv2018

The pyriproxyfen metabolite 4’OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors

Epidemiological and experimental studies have raised questions as to whether the insecticide pyriproxyfen (PPF) could be implicated in the increased incidence of microcephaly associated with ZIKA infection during pregnancy. This pesticide is documented as a thyroid hormone (TH) disrupting chemical. We investigated whether environmentally relevant amounts of its main metabolite, 4-OH-pyriproxyfen (4-OH-PPF), modified TH signaling and early neuronal development. First, an in silico study revealed strong affinity of 4-OH-PPF to fit the ligand binding pocket of TH receptors (TRs). Further, in vitro assays on human cell lines showed 4OH-PPF (> 3 mg/L) to act as a TR antagonist. Next, using a transgenic Xenopus TH-sensitive reporter system, Tg(thibz:GFP) tadpoles showed that 4OH-PPF (> 10-7 mg/L) displayed TH-disruptive activity and reduced tadpole mobility (> 10-1 mg/L). Exposure to 4OH-PPF significantly reduced Xenopus head size at levels equivalent to the maximum recommended daily intake of PPF (3x 10-1 mg/L). Most strikingly, in both the Xenopus system in vivo and in mouse neurosphere cultures, environmentally relevant concentrations of 4OH-PPF increased expression of the gene encoding an RNA-binding protein that enables ZIKA replication: Musashi-1 (msi1) in neurogenic brain areas. We conclude that first, the PPF metabolite, 4OH-PPF, disrupts thyroid signaling, neuronal development and behavior in Xenopus embryos, and second, that it increases Musashi-1 levels in neurogenic zones of both mouse and Xenopus, creating the potential to enhance viral replication. As PPF is used in areas with high microcephaly incidence and is readily broken down to 4OH-PPF, these findings provide a plausible mechanism whereby PPF could, through modulating expression of Musashi-1, exacerbate the effects of ZIKA virus infection.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC=\"FIGDIR/small/352088_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (23K):\norg.highwire.dtl.DTLVardef@12f397borg.highwire.dtl.DTLVardef@166bbdforg.highwire.dtl.DTLVardef@1b83665org.highwire.dtl.DTLVardef@fb5a30_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2018

Validation and automation of a high-throughput multi-targeted method for semi-quantification of endogenous metabolites from different biological matrices using tandem mass spectrometry

The use of metabolomics profiling to understand metabolism under different physiological states has increased in recent years, which created the need for robust analytical platforms. Here, we present a validated method for targeted and semi-quantitative analysis of 102 polar metabolites that covers major metabolic pathways from 24 classes in a single 17.5-min assay. The method has been optimized for a wide range of biological matrices from various organisms, and involves automated sample preparation, and data processing using in-house developed R package. To ensure reliability, the method was validated for accuracy, precision, selectivity, specificity, linearity, recovery, and stability according to European Medicines Agency guidelines. We demonstrated excellent repeatability of the retention times (CV<4%), calibration curves (R2[≥]0.980) in their respective wide dynamic concentration ranges (CV<3%), and concentrations (CV<25%) of quality control samples interspersed within 25 batches analyzed over a period of one-year. The robustness was demonstrated through high correlation between metabolite concentrations measured using our method and NIST reference values (R2=0.967), including cross-platform comparability against the BIOCRATES AbsoluteIDQp180 kit (R2=0.975) and NMR analyses (R2=0.884). We have shown that our method can be successfully applied in many biomedical research fields and clinical trials, including epidemiological studies for biomarker discovery. In summary, a thorough validation demonstrated that our method is reproducible, robust, reliable, and suitable for metabolomics studies.

biochemistry↗

bioRxiv2018

Antibody responses to the Zika virus polyprotein in pregnant and non-pregnant macaques

The specificity of the antibody response against Zika virus (ZIKV) is not well-characterized. This is due, in part, to the antigenic similarity between ZIKV and closely related dengue virus (DENV) serotypes. Since these and other similar viruses co-circulate, are spread by the same mosquito species, and can cause similar acute clinical syndromes, it is difficult to disentangle ZIKV-specific antibody responses from responses to closely-related arboviruses in humans. Here we use high-density peptide microarrays to profile anti-ZIKV antibody reactivity in pregnant and non-pregnant macaque monkeys with known exposure histories and compare these results to reactivity following DENV infection. We also compare cross-reactive binding of ZIKV-immune sera to the full proteomes of 28 arboviruses. We independently confirm a purported ZIKV-specific IgG antibody response targeting ZIKV nonstructural protein 2B (NS2B) that was recently reported in ZIKV-infected people and we show that antibody reactivity in pregnant animals can be detected as late as 127 days post-infection (dpi). However, we also show that these responses wane over time, sometimes rapidly, and in one case the response was elicited following DENV infection in a previously ZIKV-exposed animal. These results suggest epidemiologic studies assessing seroprevalence of ZIKV immunity using linear epitope-based strategies will remain challenging to interpret due to susceptibility to false positive results. However, the method used here demonstrates the potential for rapid profiling of proteome-wide antibody responses to a myriad of neglected diseases simultaneously and may be especially useful for distinguishing antibody reactivity among closely related pathogens.\n\nAuthor summaryZIKV has emerged as a vector-borne pathogen capable of causing serious illness in infected adults and congenital birth defects. The vulnerability of communities to future ZIKV outbreaks will depend, in part, on the prevalence and longevity of protective immunity, thought to be mediated principally by antibodies. We currently lack diagnostic assays able to differentiate ZIKV-specific antibodies from antibodies produced following infection with closely related DENV, and we do not know how long anti-ZIKV responses are detectable. Here we profile antibodies recognizing linear epitopes throughout the entire ZIKV polyprotein, and we profile cross-reactivity with the proteomes of other co-endemic arboviruses. We show that while ZIKV-specific antibody binding can be detected, these responses are generally weak and ephemeral, and false positives may arise through DENV infection. This may complicate efforts to discern ZIKV infection and to determine ZIKV seroprevalence using linear epitope-based assays. The method used in this study, however, has promise as a tool for profiling antibody responses for a broad array of neglected tropical diseases and other pathogens and in distinguishing serology of closely-related viruses.

microbiology↗

bioRxiv2018

Disease transmission mode has little effect on simulated canine rabies elimination

Disease transmission in animal populations can be affected by density or by frequency of contacts between individuals, although many models assume linear density-dependent transmission. We used rabies and free-roaming dogs (Canis familiaris) in two Nepalese cities as a model system to explore the impact of linear and non-linear density-dependent disease transmission on disease elimination achieved through rabies vaccination or vaccination and sterilisation. Strongly non-linear transmission approximated realistic frequency dependent transmission. Free roaming dogs, abundant in many parts of the developing world, are responsible for most cases of rabies transmission to humans. Most models of rabies transmission assume that the disease transmission rate is linearly density-dependent, although a recent empirical study did not find evidence to support this assumption. Rabies vaccination, culling and dog sterilisation are employed to eliminate rabies or to reduce the numbers of human cases. We created a continuous-time deterministic compartmental model to describe rabies epidemiology within a dog population and to analyse the two modes of transmission. Under each transmission mode, we investigated the efficacy of dog vaccination and fertility control to eliminate rabies. To investigate the effect of dog density on disease control efforts, models were run for cities with high and low dog population densities using data from the Nepalese cities. The results showed that, at low population density, the amount of control effort required for disease elimination did not differ substantially between different transmission modes. At high population density, the effort required to achieve disease elimination was only higher for linear density-dependent than for non-linear transmission due to the exact value of the transmission rate, beta. The model suggests that although disease transmission mode may alter the impact of control on rabies elimination, this impact is relatively small and probably not relevant to disease management.

ecology↗

bioRxiv2018

The washing machine as a reservoir for transmission of ESBL-producing Klebsiella oxytoca in newborns

During the period from April 2012 to May 2013, 13 newborns and one child in a paediatric hospital ward in Germany were found to be colonised with a distinct clinical clone of an (extended spectrum {beta}-lactamase) (ESBL)-producing Klebsiella oxytoca. This clone was specific to this hospital and had not been previously isolated in Germany.\n\nA source-tracking analysis was carried out to identify the source and transmission pathways of the ESBL-producing K. oxytoca clone. A systematic environmental survey of the ward and an audit of the procedures for cleaning and disinfecting surfaces, instruments, incubators, and washing machines was performed. Microbiological samples were obtained from environmental surfaces. Risk factors were analysed for epidemiological linkage.\n\nIsolates of an ESBL-producing K. oxytoca were found in the detergent drawer and on the rubber door seal of a washing machine and in two sinks. These strains were typed by pulsed-field-gel-electrophoresis (PFGE) and compared with the isolates from the newborns and their clothing and found to be identical. The retrospective analysis demonstrated that only newborns who had worn clothes that had been washed in the washing machine were colonised with the identical clone. After the washing machine was taken out of use, no further cases were detected over the following 4-year period.\n\nWe conclude that washing machines are potential reservoirs and vectors for transmission of Enterobacteriaceae, and likely other bacteria.\n\nImportanceWashing machines should be further investigated as possible sites for horizontal gene transfer (ESBL-/carbapenemase-genes) and cross-contamination of clinically important Gram-negative strains. Particularly in the healthcare sector, the knowledge of possible (re-) contamination of laundry (patients clothes, staff uniforms) with multidrug-resistant Gram-negative bacteria could help to prevent and control nosocomial infections. To date, the potential of the washing machine as a source and vector of antibiotic-resistant gram-negative bacteria causing an outbreak in a clinical setting has not been investigated. This report shows that sampling of washing machines should be included in environmental audits associated with outbreak control management, and conditions for the laundering of baby 64 clothing should be reviewed.

microbiology↗

bioRxiv2018

The multifurcating skyline plot

A variety of methods based on coalescent theory have been developed to infer demographic history from gene sequences sampled from natural populations. The \"skyline plot\" and related approaches are commonly employed as exible prior distributions for phylogenetic trees in the Bayesian analysis of pathogen gene sequences. In this work we extend the classic and generalised skyline plot methods to phylogenies that contain one or more multifurcations (i.e. hard polytomies). We use the theory of {Lambda}-coalescents (specifically, Beta(2,)-coalescents) to develop the \"multifurcating skyline plot\", which estimates a piecewise constant function of effective population size through time, conditional on a time-scaled multifurcating phylogeny. We implement a smoothing procedure and extend the method to serially-sampled (heterochronous) data, but we do not address here the problem of estimating trees with multifurcations from gene sequence alignments. We validate our estimator on simulated data using maximum likelihood and find that parameters of the Beta(2,)-coalescent process can be estimated accurately. Lastly we apply the multifurcating skyline plot to a molecular clock phylogeny of 1,610 Ebola virus sequences from the 2014-2016 West African outbreak. We artificially collapse short branches in this empirical phylogeny in order to mimic different levels of multifurcation and show that variance in the reproductive success of the pathogen through time can be estimated by combining the skyline plot with epidemiological case count data.

bioinformatics↗

bioRxiv2018

MALARIA and BURKITT′S LYMPHOMA: An IN SILICO ANALYSIS of GENE EXPRESSION LINKS BETWEEN MALARIA and BURKITT’S LYMPHOMA and POTENTIAL ANTICANCER ACTIVITY of ARTEMISININ DERIVATIVES

BackgroundBurkitts lymphoma (BL) is an aggressive form of B-cell non-Hodgkin lymphoma. Endemic subtype of the disease showed a remarkable statistical and epidemiological association with malaria infection. Despite the numerous studies performed to explain this association; molecular mechanisms underlie such coincidence still remain unclear. Dissecting molecular mechanisms which link Malaria infection and Burkitts lymphoma can provide insights about reported anticancer action of certain antimalarial drugs, namely artemisinin derivatives.\n\nMethodsHere we applied an integrative approach to investigate for potential links between malaria infection and endemic Burkitts lymphoma regarding their gene expression, and further explore common molecular mechanisms through which artemisinin compounds might act in endemic Burkitts lymphoma. Using gene expression data of malaria (Plasmodium falciparum infected erythroblasts) and endemic Burkitts lymphoma from Gene Expression Omnibus database, expression patterns in the two conditions were examined through clustering analysis using Self Organizing Maps, and then by significance testing of differentially expressed genes in each condition followed by Functional annotation using Gene Ontology clustering and Pathways analysis.\n\nResultsClustering analysis identified a significant overlap between the expression patterns in endemic Burkitts lymphoma and Plasmodium falciparum infected cells. Four out of the 12 identified clusters contained genes with similar expression patterns in both conditions. Differential expression analysis identified 1689 genes as significantly differentially expressed in endemic Burkitts lymphoma and 405 in malaria. Those genes were found to be related to important Gene Ontology terms and pathways. Interestingly 65% of the identified pathways in Malaria were overlapped with those identified in endemic Burkitts lymphoma. Several of these pathways reported to be related to actions of artemisinin derivatives.\n\nConclusionOur In-silico analysis showed a significant molecular convergence between endemic Burkitts lymphoma and malaria. A number of 43pathways which demonstrated enrichment in tumour were shared with Plasmodium falciparum infected erythrocytes. Such pathways represent potential targets for antimalarial drugs to exert therapeutic effects in such malignancy.

bioinformatics↗

bioRxiv2018

Genomics of Cryptococcus neoformans

C. neoformans var. grubii (C. neoformans) is an environmentally acquired pathogen causing 181 000 HIV-associated deaths each year. We used whole genome sequencing (WGS) to characterise 699 isolates, primarily C. neoformans from HIV-infected patients, from 5 countries in Asia and Africa. We found that 91% of our clinical isolates belonged to one of three highly clonal sub-clades of VNIa, which we have termed VNIa-4, VNIa-5 and VNIa-93. Parsimony analysis revealed frequent, long distance transmissions of C. neoformans; international transmissions took place on 13% of VNIa-4 branches, and intercontinental transmissions on 7% of VNIa-93 branches. The median length of within sub-clade internal branches was 3-6 SNPs, while terminal branches were 44.5-77.5 SNPs. The short median internal branches were partly driven by the large number (12-15% of internal branches) of polytomies in the within-sub-clade trees. To simultaneously explain our observation of no apparent molecular clock, short internal branches and frequent polytomies we hypothesise that C. neoformans VNIa spends much of its time in the environment in a quiescent state, while, when it is sampled, it has almost always undergone an extended period of growth. Infections with VNIa-93 were associated with a significantly reduced risk of death by 10 weeks compared with infections with VNIa-4 (Hazard Ratio = 0.45, p = 0.003). We detected a recombination in the mitochondrial sequence of VNIa-5, suggesting that mitochondria could be involved in the propensity of this sub-clade to infect HIV-uninfected patients. These data highlight the insight into the biology and epidemiology of pathogenic fungi which can be gained from WGS data.

microbiology↗

bioRxiv2018

Circulation of Foot-and-Mouth Disease Virus in Africa and identification of the underlying constraints using Phylogeographic methods

Foot and mouth disease (FMD) is endemic in sub-Saharan Africa and can lead to important and continuous economic losses for affected countries. Due to the complexity of the disease epidemiology and the lack of data there is a need to use inferential computational approaches to fill the gaps in our understanding of the circulation of FMD virus on this continent. Using a phylogeographic approach we reconstructed the circulation of FMD virus serotypes A, O and SAT2 in Africa and evaluated the influence of potential environmental and anthropological predictors of virus diffusion. Our results show that over the last hundred year the continental circulation of the tree serotypes was mainly driven by livestock trade. Whilst our analyses show that the serotypes A and O were introduced in Africa trough livestock trades, the SAT2 serotype probably originates from African wildlife population. The circulation of serotype O in eastern Africa is impacted by both indirect transmission through persistence in the environment and anthropological activities such as cattle movements.

evolutionary biology↗

bioRxiv2018

Development and analytical validation of an enzyme-linked immunosorbent assay based on baculovirus recombinant LipL32 protein antigen for the accurate detection of canine leptospirosis

Leptospira infects a wide range of companion, domestic and wild animal species, shedding the spirochetes into the environment via urine. Dogs become infected by direct or indirect contact with wild or domestic infected animal reservoirs increasing the risk of zoonotic transmission of the disease. The microscopic agglutination test has been used as the gold standard for the diagnosis of leptospirosis but has low sensitivity and is technically complex. Several ELISA tests have been developed based on recombinant proteins of Leptospira for the diagnosis of leptospirosis with similar or higher specificity and sensitivity levels than the microscopic agglutination test. Here, we developed and analytically validated an ELISA test based on recombinant LipL32 protein of Leptospira expressed in baculovirus. The LipL32 protein was successfully adapted in an indirect ELISA using dog plasma samples. Optimization of the ELISA resulted in a P/N ratio of 7.18 using only 5 ng of rLipL32 per well. Inter-assay and intra-assay variation showed a CV of 3.96% and 6.98% respectively, suggesting that the ELISA-LipL32 is highly reproducible. When tested with field samples, concordance of the ELISA-LipL32 with a real-time PCR, positive concordance was 100%. Our results indicate that the ELISA-LipL32 has the potential to be used by veterinarians and public health investigators as a safe, rapid, inexpensive and reliable method for the early diagnosis of Leptospira infection in dogs. Additional studies are still required for clinical validation on field samples under different epidemiological scenarios.

developmental biology↗

bioRxiv2018

Both rare and common genetic variants contribute to autism in the Faroe Islands

The number of genes associated with autism is increasing, but few studies have been performed on epidemiological cohorts and in isolated populations. Here, we investigated 357 individuals from the Faroe Islands including 36 individuals with autism, 136 of their relatives and 185 non-autism controls. Data from SNP array and whole exome sequencing revealed that individuals with autism compared to controls had a higher burden of copy-number variants (p < 0.05), higher inbreeding status (p < 0.005) and higher load of homozygous deleterious variants (p < 0.01). Our analysis supports the role of several genes/loci associated with autism (e.g. NRXN1, ADNP, 22q11 deletion) and identified new truncating (e.g. GRIK2, ROBO1, NINL and IMMP2L) or recessive deleterious variants (e.g. KIRELL3 and CNTNAP2) affecting autism-risk genes. It also revealed three genes involved in synaptic plasticity, RIMS4, KALRN and PLA2G4A, carrying de novo deleterious variants in individuals with autism without intellectual disability. In summary, our analysis provides a better understanding of the genetic architecture of autism in isolated populations by highlighting the role of both common and rare gene variants and pointing at new autism-risk genes. It also indicates that more knowledge about how multiple genetic hits affect neuronal function will be necessary to fully understand the genetic architecture of autism.

genetics↗

bioRxiv2018

Testing Causal Bidirectional Influences between Physical Activity and Depression using Mendelian Randomization

BackgroundBurgeoning evidence from randomized controlled trials and prospective cohort studies suggests that physical activity protects against depression, pointing to a potential modifiable target for prevention. However, the direction of this inverse association is not clear: physical activity may reduce risk for depression, and/or depression may result in decreased physical activity. Here, we used bidirectional two-sample Mendelian randomization (MR) to test causal influences between physical activity and depression.\n\nMethodsFor genetic instruments, we selected independent top SNPs associated with major depressive disorder (MDD, N = 143,265) and two physical activity phenotypes--self-reported (N = 377,234) and objective accelerometer-based (N = 91,084)--from the largest available, non-overlapping genome-wide association results. We used two sets of genetic instruments: (1) only SNPs previously reported as genome-wide significant, and (2) top SNPs meeting a more relaxed threshold (p < 1x10-7). For each direction of influence, we combined the MR effect estimates from each instrument SNP using inverse variance weighted (IVW) meta-analysis, along with other standard MR methods such as weighted median, MR-Egger, and MR-PRESSO.\n\nResultsWe found evidence for protective influences of accelerometer-based activity on MDD (IVW odds ratio (OR) = 0.74 for MDD per 1 SD unit increase in average acceleration, 95% confidence interval (CI) = 0.59-0.92, p =.006) when using SNPs meeting the relaxed threshold (i.e., 10 versus only 2 genome-wide significant SNPs, which provided insufficient data for sensitivity analyses). In contrast, we found no evidence for negative influences of MDD on accelerometer-based activity (IVW b = 0.04 change in average acceleration for MDD versus control status, 95% CI = -0.43-0.51, p =.87). Furthermore, we did not see evidence for causal influences between self-reported activity and MDD, in either direction and regardless of instrument SNP criteria.\n\nDiscussionWe apply MR for the first time to examine causal influences between physical activity and MDD. We discover that objectively measured--but not self-reported--physical activity is inversely associated with MDD. Of note, prior work has shown that accelerometer-based physical activity is more heritable than self-reported activity, in addition to being more representative of actual movement. Our findings validate physical activity as a protective factor for MDD and point to the importance of objective measurement of physical activity in epidemiological studies in relation to mental health. Overall, this study supports the hypothesis that enhancing physical activity is an effective prevention strategy for depression.

genetics↗

bioRxiv2018

RNASeq analysis of Aedes albopictus mosquitoes during chikungunya virus infection

Chikungunya virus (CHIKV), preferentially transmitted by Aedes mosquitoes, is an emerging pathogen around the world and causes significant morbidity in patients. A single amino acid mutation in the envelope protein of CHIKV has led to shift in vector preference towards Aedes albopictus, an invasive mosquito. Previous studies have shown that after infection, mosquitoes mount an antiviral immune response. However, molecular interactions during the course of infection at different tissues and time-points remain largely uncharacterised. Here we performed whole transcriptome analysis on dissected midguts and head/thorax of CHIKV (Indian Ocean strain) infected Aedes albopictus to identify differentially expressed genes compared with uninfected controls. For this, RNA was extracted at two days post-infection (D2) from pooled midguts and eight days post-infection (D8) from heads and the anterior 1/3rd of the thorax. We identified 25 and 96 differentially expressed genes from the D2 and D8 samples respectively (p-value <0.05). Custom de novo transcriptomes were assembled for the reads that did not align with the reference genome and an additional 225 and 4771 differentially expressed genes from D2 and D8, respectively, were identified. Twenty-two of the identified transcripts, possibly involved in immunity, were validated by qRT-PCR. Interestingly, we also detected changes in viral diversity, as shown by number of mutations in the viral genome, with increase in number of mutations in the midgut compared with mammalian host (Vero cell culture), followed by reduction in the number of mutations in head and thorax at D8, indicating a possible genomic bottleneck. Taken together, these results will help in understanding Aedes Albopictus interactions with CHIKV and can be utilised to reduce the impact of this viral infection.\n\nAuthor SummaryChikungunya virus has caused several outbreaks around the world in the last decade. Once a relatively unknown virus, it now causes seasonal infections in tropical and some temperate regions. This change in epidemiology is attributed to vector switch from Aedes aegypti to Aedes albopictus, an invasive pest leading to spread and causing infections in temperate regions. Although recent research has identified mosquito factors influencing infections, our understanding of interaction between chikungunya virus and its vector is limited. Using whole transcriptome sequencing of chikungunya infected mosquitoes, we identified differentially expressed genes in the midgut and head and thorax, over the course of mosquito infection. We also detected changes in the viral genome during mosquito infection and a possible genetic bottleneck event with reduction in viral variants at the head and thorax region of mosquito in the later stages of infection. These results will lead to improving our understanding of mosquito-virus interactions with Aedes albopictus as a vector and in turn lead to development of novel disease control strategies.

microbiology↗

bioRxiv2018

Varicose veins of lower extremities: insights from the first large-scale genetic study

Varicose veins of lower extremities (VVs) are a common multifactorial vascular disease. Genetic factors underlying VVs development remain largely unknown. Here we report the first large-scale study of VVs performed on a freely available genetic data of 408,455 European-ancestry individuals. We identified 7 reliably associated loci that explain 10% of the SNP-based heritability, and prioritized the most likely causal genes CASZ1, PPP3R1, EBF1, STIM2, and HFE. Genetic correlation analysis confirmed known epidemiological associations and found genetic overlap with various traits including fluid intelligence score, educational attainment, smoking, and pain. Finally, we observed causal effects of height, weight, both fat and fat-free mass, and plasma levels of MICB and CD209 proteins.

genomics↗

bioRxiv2018

Pathogen diversity drives the evolution of promiscuous peptide binding of human MHC-II alleles

Major histocompatibility complex (MHC) molecules mediate the adaptive immune response against pathogens. Certain MHC alleles are generalists: they present an exceptionally large variety of antigenic peptides. However, the functional implications of such elevated epitope binding promiscuity in the MHC molecules are largely unknown. According to what we term the pathogen-driven promiscuity hypothesis, exposure to a broad range of pathogens favors the evolution of highly promiscuous MHC variants. Consistent with this hypothesis, we found that in pathogen-rich geographical regions, humans are more likely to carry promiscuous MHC class II DRB1 alleles, and the switch between high and low promiscuity levels has occurred repeatedly and in a rapid manner during human evolution. We also show that selection for promiscuous peptide binding shapes MHC genetic diversity. In sum, our study offers a conceptually novel mechanism to explain the global distribution of allelic variants of a key human immune gene by demonstrating that pathogen pressure maintains promiscuous MHC class II alleles. More generally, our work highlights the hitherto neglected role of epitope binding promiscuity in immune defense, with implications for medical genetics and epidemiology.

evolutionary biology↗

bioRxiv2018

Differential morphological changes in response to environmental stimuli in a fungal plant pathogen

During their life cycles, pathogens have to adapt to many biotic and abiotic environmental stresses to maximize their overall fitness. Morphological transitions are one of the least understood of the many strategies employed by fungal plant pathogens to adapt to constantly changing environments, even though different morphotypes may play important biological roles. We characterized the responses of the wheat pathogen Zymoseptoria tritici to a series of environmental stresses in order to understand the effects of changing environments on fungal morphology and adaptation. We found that all tested stresses induced morphological changes, but different responses were found among four different strains. A transcription analysis showed that morphogenesis and virulence factors are co-regulated. We discovered that Z. tritici forms chlamydospores and demonstrated that these structures are better able to survive extreme cold, heat and drought than other cell types. We also show that blastospores (the \"yeast-like\" form of the pathogen typically found only in laboratory conditions) can form from germinated pycnidiospores on the surface of wheat leaves, suggesting that this morphotype can play an important role in the natural history of Z. tritici. Our findings illustrate how changing environmental conditions can affect cellular morphology and lead to the formation of new morphotypes, with each morphotype having a potential impact on both pathogen survival and disease epidemiology.

microbiology↗

bioRxiv2018

APP-induced patterned neurodegeneration exacerbated by APOE4 in C. elegans

Genetic and epidemiological studies have found that variations in the amyloid precursor protein (APP) and the apoliopoprotein E (APOE) genes represent major modifiers of the progressive neurodegeneration in Alzheimers disease (AD). An extra copy or gain-of-function mutations in APP lower age of AD onset. Compared to the other isoforms (APOE3 and APOE2), the {varepsilon}4 allele of APOE (APOE4) hastens and exacerbates early and late onset forms of AD. Convenient in vivo models to study how APP and APOE4 interact at the cellular and molecular level to influence neurodegeneration are lacking. Here, we show that the nematode C. elegans can model important aspects of AD including age-related, patterned neurodegeneration that is exacerbated by APOE4. Specifically, we found that APOE4, but not APOE3, acts with APP to hasten and expand the pattern of cholinergic neurodegeneration caused by APP. Molecular mechanisms underlying how APP and APOE4 synergize to kill some neurons while leaving others unaffected may be uncovered using this convenient worm model of neurodegeneration.

neuroscience↗