Biology subjects

Sun, J.

Publications and source records attributed to Sun, J..

At least 487 records · Page 27Linked to original sources

bioRxiv2020

Undinarchaeota illuminate the evolution of DPANN archaea

Introductory paragraphThe evolution and diversification of Archaea is central to the history of life on Earth. Cultivation-independent approaches have revealed the existence of at least ten archaeal lineages whose members have small cell and genome sizes and limited metabolic capabilities and together comprise the tentative DPANN archaea. However, the phylogenetic diversity of DPANN and the placement of the various lineages of this group in the archaeal tree remain debated. Here, we reconstructed additional metagenome assembled genomes (MAGs) of a thus far uncharacterized archaeal phylum-level lineage UAP2 (Candidatus Undinarchaeota) affiliating with DPANN archaea. Comparative genome analyses revealed that members of the Undinarchaeota have small estimated genome sizes and, while potentially being able to conserve energy through fermentation, likely depend on partner organisms for the acquisition of vitamins, amino acids and other metabolites. Phylogenomic analyses robustly recovered Undinarchaeota as a major independent lineage between two highly supported clans of DPANN: one clan comprising Micrarchaeota, Altiarchaeota and Diapherotrites, and another encompassing all other DPANN. Our analyses also suggest that DPANN archaea may have exchanged core genes with their hosts by horizontal gene transfer (HGT), adding to the difficulty of placing DPANN in the archaeal tree. Together, our findings provide crucial insights into the origins and evolution of DPANN archaea and their hosts.

evolutionary biology↗

bioRxiv2020

Tissue-resident CD4+ T helper cells assist protective respiratory mucosal B and CD8+ T cell memory responses

The roles of CD4+ T helper cells (TH) in shaping localized memory B and CD8+ T cell immunity in the mucosal tissues are largely unexplored. Here, we report that lung TH cells provide local assistance for the optimal development of tissue-resident memory B (BRM) and CD8+ T (TRM) cells following the resolution of primary influenza virus infection. We identify a population of tissue-resident CD4+ TH (aka TRH) cells that co-exhibit follicular T helper (TFH) and TRM cell features and mediate local help of CD4+ T cells to B and CD8+ T cells. Optimal TRH cell formation requires lung B cells and transcription factors involved in TFH or TRM development. Further, we show that TRH cells deliver local help to B and CD8 T cells through CD40L and IL-21-dependent mechanisms. Our data have uncovered a new tissue-resident TH cell population that is specialized in assisting the development of mucosal protective B and CD8+ T cell responses in situ.

immunology↗

bioRxiv2020

mTOR-driven widespread exon skipping renders multifaceted gene regulation and proteome complexity

The mammalian target of rapamycin (mTOR) pathway is crucial in cell proliferation. Previously, we reported transcriptome-wide 3’-untranslated region (UTR) shortening by alternative polyadenylation upon mTOR activation and its impact on the proteome. Here, we further interrogated the mTOR-activated transcriptome and found that hyperactivation of mTOR promotes transcriptome-wide exon-skipping/exclusion, producing short isoform transcripts from genes. This widespread exon skipping confers multifarious regulations in the mTOR-controlled functional proteomics: alternative splicing (AS) in the 5’-UTR controls translation efficiency while AS in coding regions widely affects the protein length and functional domains. They also alter the half-life of proteins and affect the regulatory post-translational modifications. Among the RNA processing factors differentially regulated by mTOR signaling, we found that SRSF3 mechanistically facilitates exon skipping in the mTOR-activated transcriptome. This study reveals a role of mTOR in AS regulation and demonstrates that widespread AS is a multifaceted modulator of the mTOR-regulated functional proteome.Competing Interest StatementThe authors have declared no competing interest.View Full Text

biochemistry↗

bioRxiv2020

Vitamin D receptor protects against dysbiosis and tumorigenesis via the JAK/STAT pathway in intestine

BackgroundVitamin D exerts regulatory roles via vitamin D receptor (VDR) in mucosal immunity, host defense, and inflammation involving host factors and microbiome. Human Vdr gene variation shapes the microbiome and VDR deletion leads to dysbiosis. Low VDR expression and diminished vitamin D/VDR signaling are observed in colon cancer. Nevertheless, how intestinal epithelial VDR is involved in tumorigenesis through gut microbiota remains unknown. We hypothesized that intestinal VDR protects mice against dysbiosis via modulating the JAK/STAT pathway in tumorigenesis. To test our hypothesis, we used an azoxymethane/Dextran Sulfate Sodium-induced cancer model in intestinal VDR conditional knockout (VDR{Delta}IEC) mice, cell cultures, stem-cell derived colonoids, and human colon cancer samples. ResultsVDR{Delta}IEC mice have higher numbers of tumors with location shifted from distal to proximal colon. Fecal microbiota analysis showed that VDR deletion leads to bacterial profile shift from normal to susceptible carcinogenesis. We found enhanced bacterial staining in mouse and human tumors. Microbial metabolites from VDR{Delta}IEC mice showed elevated secondary bile acids, consistent with the observations in human CRC. We further identified that VDR protein bound to the Jak2 promoter, suggesting that VDR transcriptionally regulated Jak2. The JAK/STAT pathway is critical in intestinal and microbial homeostasis. Fecal samples from VDR{Delta}IEC mice activate the STAT3 activation in human and mouse organoids. Lack of VDR led to hyperfunction of Jak2 in respond to intestinal dysbiosis. A JAK/STAT inhibitor abolished the microbiome-induced activation of STAT3. ConclusionWe provide insights into the mechanism of VDR dysfunction leading to dysbiosis and tumorigenesis. It indicates a new target -- microbiome and VDR for prevention of cancer.

cancer biology↗

bioRxiv2020

Nucleoporin 153 links nuclear pore complex to chromatin architecture by mediating CTCF and cohesin binding at cis-regulatory elements and TAD boundaries

The nuclear pore complex (NPC) components, nucleoporins (Nups), have been proposed to mediate spatial and temporal organization of chromatin during gene regulation. Nevertheless, we have little understanding on the molecular mechanisms that underlie Nup-mediated chromatin structure and transcription in mammals. Here, we show that Nucleoporin 153 (NUP153) interacts with the chromatin architectural proteins, CTCF and cohesin, and mediates their binding across cis-regulatory elements and TAD boundaries in mouse embryonic stem (ES) cells. NUP153 depletion results in altered CTCF and cohesin occupancy and differential gene expression. This function of NUP153 is most prevalent at the developmental genes that show bivalent chromatin state. To dissect the functional relevance of NUP153-mediated CTCF and cohesin binding during transcriptional activation or silencing, we utilized epidermal growth factor (EGF)-inducible immediate early genes (IEGs). We found that NUP153 binding at the cis-regulatory elements controls CTCF and cohesin binding and subsequent POL II pausing during the transcriptionally silent state. Furthermore, efficient and timely transcription initiation of IEGs relies on NUP153 and occurs around the nuclear periphery suggesting that NUP153 acts as an activator of IEG transcription. Collectively, these results uncover a key role for NUP153 in chromatin architecture and transcription by mediating CTCF and cohesin binding in mammalian cells. We propose that NUP153 links NPCs to chromatin architecture allowing developmental genes and IEGs that are poised to respond rapidly to developmental cues to be properly modulated.

cell biology↗

bioRxiv2020

Arabidopsis ERF4 and MYB52 Transcription Factors Play Antagonistic Roles in Regulating Homogalacturonan De-methylesterification in Seed Coat Mucilage

The Arabidopsis (Arabidopsis thaliana) seed coat mucilage is a specialized cell wall with pectin as its major component. Pectin is synthesized in the Golgi apparatus with homogalacturonan fully methylesterified, but it must undergo de-methylesterification by pectin methylesterase (PME) after being secreted into the cell wall. This reaction is critical for pectin maturation, but the mechanisms of its transcriptional regulation remain largely unknown. Here, we show that the Arabidopsis ERF4 transcription factor positively regulates pectin de-methylesterification during seed development and directly suppresses the expression of PME INHIBITOR13 (PMEI13), 14, 15 and SUBTILISIN-LIKE SERINE PROTEASE 1.7 (SBT1.7). The erf4 mutant seeds showed repartitioning of mucilage between soluble and adherent layers as a result of decreased PME activity and increased degree of pectin methylesterification. ERF4 physically associates with and antagonizes MYB52 in activating PMEI6, 14 and SBT1.7 and MYB52 also antagonizes ERF4 activity in the regulation of downstream targets. Gene expression studies revealed that ERF4 and MYB52 have opposite effects on pectin de-methylesterification. Genetic analysis indicated that the erf4-2 myb52 double mutant seeds show mucilage phenotype similar to wild-type. Taken together, this study demonstrates that ERF4 and MYB52 antagonize each others activity to maintain the appropriate degree of pectin methylesterification, expanding our understanding of how pectin de-methylesterification is fine-tuned by the ERF4-MYB52 transcriptional complex in the seed mucilage. One-sentence summaryArabidopsis ERF4 and MYB52 transcription factors interact and play antagonistic roles in regulating homogalacturonan de-methylesterification related genes in the seed coat mucilage.

plant biology↗

bioRxiv2020

Contrasting population structure and demographic history of cereal aphids in different environmental and agricultural landscapes

Genetic diversity of populations has important ecological and evolutionary consequences, which are fundamental to improve the sustainability of agricultural production. Studies of how differences in agricultural management and environment influence the population structure of insect pests are fundamental to predict outbreaks and optimise control programmes. Here, we have studied the population genetic diversity and evolution of Sitobion avenae and Sitobion miscanthi (previously mistaken for S. avenae), which are among the most relevant aphid pests of cereals across Europe and China, respectively. We have used a genomic approach that allows the identification of weak geographic structure and migration patterns at scales that were previously not discernible. In the present study, we show that the population structure in present day populations are different from that described in previous studies, which suggests that they have evolved recently possibly as a response to human-induced changes in agriculture. In the UK, S. avenae is predominantly anholocyclic and, as a result of the evolution of insecticide resistance, a superclone is now dominant across the geographic distribution in the country and the genetic diversity is low. In China, S. miscanthi populations are mostly holocyclic, with one sexual stage in autumn to produce overwintering eggs, and there are six genetically differentiated subpopulations and high genetic differentiation between geographic locations, which suggests that further taxonomical research is needed. Unlike in the case of S. avenae in England, there is no evidence for insecticide resistance and there is no predominance of a single lineage in S. miscanthi in China.

evolutionary biology↗

bioRxiv2020

Salmonella Enteritidis Effector AvrA suppresses autophagy by reducing Beclin-1 protein

Autophagy is a cellular process to clear pathogens. Salmonella enterica serovar Enteritidis (S.E) has emerged as one of the most important food-borne pathogens. However, major studies still focus on Salmonella enterica serovar Typhimurium. Here, we reported that AvrA, a S. Enteritidis effector, inhibited autophagy to promote bacterial survival in the host. We found that AvrA regulates the conversion of LC3 I into LC3 II and the enrichment of lysosomes. Beclin-1, a key molecular regulator of autophagy, was decreased after AvrA expressed strain colonization. In S.E-AvrA--infected cells, we found the increases of protein levels of p-JNK and p-c-Jun and the transcription level of AP-1. AvrA-reduction of Beclin-1 protein expression is through the JNK pathway. The JNK inhibitor abolished the AvrA-reduced Beclin-1 protein expression. Moreover, we identified that the AvrA mutation C186A abolished its regulation of Beclin-1 expression. In addition, AvrA protein interacted with Beclin-1. In organoids and infected mice, we explored the physiologically related effects and mechanism of AvrA in reducing Beclin-1 through the JNK pathway, thus attenuating autophagic responses. ImportanceSalmonella Enteritidis is an important pathogen with a public health concern and farm production risk, yet the host-pathogen interactions that govern the survival of S. Enteritidis infections are incompletely understood. Anti-bacterial autophagy provides potent cell-autonomous immunity against bacterial colonization. Here, we report that a new role for effector AvrA of S. Enteritidis in the reduction of Beclin-1 protein expression through the JNK pathway and the attenuation of the autophagic response in intestinal epithelial cells. This finding not only indicates an important role of S. Enteritidis effector in reducing host protein as a strategy to suppress autophagy, but also suggests manipulating autophagy as a new strategy to treat infectious diseases.

microbiology↗

bioRxiv2020

Quantitative single cell heterogeneity profiling of patient derived tumor initiating gliomaspheres reveals unique signatures of malignancy and response

BackgroundGlioblastoma is a deadly brain tumor with median patient survival of 14.6 months. At the core of this malignancy are rare, highly heterogenous malignant stem-like tumor initiating cells. Aberrant signaling across the EGFR-PTEN-AKT-mTOR signal transduction pathways are common oncogenic drivers in these cells. Though gene-level clustering has determined the importance of the EGFR signaling pathway as a treatment indicator, multiparameter protein-level analyses are necessary to discern functional attributes of signal propagation. Multiparameter single cell analyses is emerging as particularly useful in identifying such attributes. MethodsSingle cell targeted proteomic analysis of EGFR-PTEN-AKT-mTOR proteins profiled heterogeneity in a panel of fifteen patient derived gliomaspheres. A microfluidic cell array chip tool served as a low cost methodology to derive high quality quantitative single cell analytical outputs. Chip design specifications produced extremely high signal-to-noise ratios and brought experimental efficiencies of cell control and minimal cell use to accommodate experimentation with these rare and often slow-growing cell populations. Quantitative imaging software generated datasets to observe similarities and differences within and between cells and patients. Bioinformatic self-organizing maps (SOMs) and hierarchical clustering stratified patients into malignancy and responder groups which were validated by phenotypic and statistical analyses. ResultsFifteen patient dissociated gliomaspheres produced 59,464 data points from 14,866 cells. Forty-nine molecularly defined signaling phenotypes were identified across samples. Bioinformatics resolved two clusters diverging on EGFR expression (p = 0.0003) and AKT/TORC1 activation (p = 0.08 and p = 0.09 respectively). TCGA status of a subset showed genetic heterogeneity with proneural, classical and mesenchymal subtypes represented in both clusters. Phenotypic validation measures indicated drug responsive phenotypes to EGFR blocking were found in the EGFR expressing cluster. EGFR expression in the subset of drug-treated lines was statistically significant (p<.05). The EGFR expressing cluster was of lower tumor initiating potential in comparison to the AKT/TORC1 activated cluster. Though not statistically significant, EGFR expression trended with improved patient prognosis while AKT/TORC1 activated samples trended with poorer outcomes. ConclusionsQuantitative single cell heterogeneity profiling resolves signaling diversity into meaningful non-obvious phenotypic groups suggesting EGFR is decoupled from AKT/TORC1 signalling while identifying potentially valuable targets for personalized therapeutic approaches for deadly tumor-initiating cell populations.

cancer biology↗

bioRxiv2020

CRL5-dependent regulation of Arl4c and Arf6 controls hippocampal morphogenesis.

The small GTPase Arl4c participates in the regulation of cell migration, cytoskeletal rearrangements, and vesicular trafficking in epithelial cells. The Arl4c signaling cascade starts by the recruitment of the Arf-GEF cytohesins to the plasma membrane, which in turn engage the small GTPase Arf6. In the nervous system, Arf6 regulates dendrite outgrowth in vitro and neuronal migration in the developing cortex. However, the role of Arl4c-cytohesin-Arf6 signaling during brain development and particularly during hippocampal development remain elusive. Here, we report that the E3 ubiquitin ligase Cullin 5/Rbx2 (CRL5) controls the stability of Arl4c and its signaling effectors to regulate hippocampal morphogenesis. Rbx2 knock out causes hippocampal pyramidal neuron mislocalization and formation of multiple apical dendrites. The same phenotypes were observed when Cullin 5 was knocked down in pyramidal neurons by in utero electroporation. We used quantitative mass spectrometry to show that Arl4c, Cytohesin-1/3, and Arf6 accumulate in the telencephalon when Rbx2 is absent. Arl4c expression is post-transcriptionally regulated, with a peak in expression at early postnatal stages, and is localized at the plasma membrane and on intracellular vesicles in hippocampal pyramidal neurons. Furthermore, we show that depletion of Arl4c rescues the phenotypes caused by Cullin 5 knock down in the hippocampus, whereas depletion of Arf6 exacerbates over-migration. Finally, we show that Arl4c and Arf6 are necessary for the dendritic outgrowth of pyramidal neurons to the most superficial strata of the hippocampus. Overall, we identified CRL5 as a key regulator of hippocampal development and uncovered Arl4c and Arf6 as novel CRL5-regulated signaling effectors that control pyramidal neuron migration and dendritogenesis.

developmental biology↗

bioRxiv2020

Nα-acetylation of EsxA is required for mycobacterial cytosolic translocation and virulence

Mycobacterium tuberculosis virulence factors, EsxA and EsxB, are secreted as a heterodimer (EsxA:B) and play an essential role in mycobacterial phagosomal escape and cytosolic translocation. Current studies support a model that EsxA must dissociate from its chaperon EsxB at low pH in order for EsxA to interact with host membranes. However, the mechanism of the heterodimer separation is not clear. In the present study, we have obtained evidence that the N-acetylation of Thr2 on EsxA, a post-translational modification that is present in mycobacteria, but absent in E. coli, is required for the heterodimer separation. The point mutations at Thr2 without N-acetylation inhibited the heterodimer separation and hence prevented EsxA from interacting with the membranes, which resulted in attenuated mycobacterial cytosolic translocation and virulence. Molecular dynamic simulation showed that at low pH the N-acetylated Thr2 made direct and frequent "bind-and-release" contacts with EsxB, which generates a dragging force to pull EsxB away from EsxA.

biochemistry↗

bioRxiv2020

MSIsensor-pro: fast, accurate and matched-normal-sample-free detection of microsatellite instability

We developed MSIsensor-pro (https://github.com/xjtu-omics/msisensor-pro), an open-source single sample microsatellite instability (MSI) scoring method for research and clinical applications. MSIsensor-pro introduces a multinomial distribution model to quantify polymerase slippages for each tumor sample and a discriminative sites selection method to enable MSI detection without matched normal samples. For samples of various sequencing depths and tumor purities, MSIsensor-pro significantly outperformed the current leading methods in terms of both accuracy and computational cost.

bioinformatics↗

bioRxiv2019

IRAK1-mediated coincidence detection of microbial signals licenses inflammasome activation

The innate immune system signals through various higher order signaling complexes called supramolecular organizing centers (SMOCs), which typically organize components of a single pathway. While innate immune signaling pathways have been largely characterized using single receptor stimuli, responses to pathogens require the coordinated engagement of multiple pathways. Here, we report an IRAK1-containing SMOC formed specifically when multiple receptors are activated, which recruits select components of the TLR, MAPK and inflammasome pathways. This allows for signal flux redistribution from TLRs to inflammasomes and facilitates inflammasome licensing through an MKK7-JNK axis, which is defective in Irak1-/- mice. Furthermore, this defect in Irak1-/- mice manifests in increased susceptibility to inflammasome-sensitive pathogens and diminished IL1 production from inflammasomes after co-TLR priming. Thus, IRAK1 SMOCs form a multi-pathway coordinating hub for coincidence detection of microbial signals, which may be employed by innate immune cells as a threat assessment and thresholding mechanism for inflammasome activation.

immunology↗

bioRxiv2019

NADPH diaphorase neuronal dystrophy in gracile nucleus, cuneatus nucleus and spinal trigeminal nucleus in aged rat

NADPH-diaphorase (N-d) activity is commonly used to identify NOS-ergic neurons. In our previous study, N-d positive neuritic dystrophy and spheroid termed aging-related N-d Body is discovered in the lumbosacral spinal cord in the normal aging rats. Histological studies also reveal that N-d positive neurodegenerative changes occur in the gracile nucleus. We re-examined N-d activity in gracile nucleus in aged rat. We found N-d positive neuritic dystrophy and spheroid also occurred in the cuneatus nucleus and spinal trigeminal nucleus. Besides regular coronal section, longitudinal oriented dystrophic neurites were detected in the sagittal and horizontal section in gracile nucleus and dorsal column. We fziurther examined the medullary oblongata with regular classical histology including Golgi staining, immunocytochemistry of NOS and phosphorylated tau protein, neuronal tracing method with wheat germ agglutinin conjugated alexa-fluor-488 through sciatic nerve, and spinal cord transection at thoracic level. Most of N-d positive neuritic dystrophy and spheroid did not showed colocalization with NOS or phosphorylated tau protein. Neuronal tracing and spinal cord transection revealed that N-d dystrophic neurites in gracile nucleus originated from terminal of sensory projection from spinal cord and peripheral somatic input. The results suggested that aging-related N-d dystrophy in the gracile nucleus was unique morphological feature. In conclusion, it was postulated that the N-d dystrophy as a morphological marker of aging degenerative damage in normal aged organisms.

neuroscience↗

bioRxiv2019

Developing a DeSipher method for conformational change detection of membrane receptor complex at residue resolution

While one dimensional 1H nuclear magnetic resonance (1D 1H-NMR) spectroscopy is one of the most important and convenient method for measuring conformation change in biomacromolecules, characterization of protein dynamics in large membrane protein complexes by 1D 1H-NMR remains challenging, due to the difficulty of spectra assignment, low signal-to-noise ratio (S/N) and the need for large amount of protein. Here we report the site-specific incorporation of 4-trimethylsilyl phenylalanine (TMSiPhe) into proteins, through genetic code expansion in Escherichia coli cells, and the measurement of multiple conformational states in membrane protein complex by 1D 1H-NMR. The unique up-field 1H-NMR chemical shift of TMSiPhe, highly efficient and specific incorporation of TMSiPhe enabled facile assignment of the TMSiPhe 1H-NMR signal, and characterization of multiple conformational state in a 150 kilodalton (kD) membrane protein complex, using only 5 M of protein and 20 min spectra accumulation time. This highly efficient and convenient methods should be broadly applicable for the investigation of dynamic conformation change of protein complexes.

biochemistry↗

bioRxiv2019

In vitro pancreatic islet cluster expansion facilitated by hormones and chemicals

Tissue regeneration, such as pancreatic islet tissue propagation in vitro, could serve as a promising strategy for diabetes therapy and personalized drug testing. However, such a protocol has not been realized yet. Propagation could be divided by two steps, which are: (1) expansion in vitro and (2) repeat passaging. Even the in vitro expansion of the islet has not been achieved to date. Here, we describe a method to enable the expansion of islet clusters isolated from pregnant mice or wild-type rats by employing a combination of specific regeneration factors and chemical compounds in vitro. The expanded islet clusters expressed insulin, glucagon and somatostatin, which are markers corresponding to pancreatic {beta} cells, cells and {delta} cells, respectively. These different types of cells grouped together, were spatially organized and functioned similarly to primary islets. Further mechanistic analysis revealed that forskolin in our recipe contributed to renewal and regeneration, whereas exendin4 was essential for preserving islet cell identity. Our results provide a novel method for the in vitro expansion of islet clusters, which is an important step forward in developing future protocols and medium used for islet tissue propagation in vitro. Such method is important for future regenerative diabetes therapies and personalized medicine using large amounts of pancreatic islets derived from the same person.

cell biology↗

bioRxiv2019

Deficiency of Norepinephrine Transmission In Brain Contributed To Seizure-Induced Respiratory Arrest In the DBA/1 Mouse SUDEP Model

ObjectiveSudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in patients in patients with intractable epilepsy. However, the pathogenesis of SUDEP seems to be poorly understood. Our previous findings showed that the incidence of seizure-induced respiratory arrest (S-IRA) was markedly reduced by atomoxetine in a murine SUDEP model. Because the central NE -1 receptor (NE-1R) plays a vital role in regulating respiratory function, we hypothesized that the suppression of S-IRA by atomoxetine was mediated by NE/NE-1R interactions that can be reversed by NE-1R antagonism. MethodsWe examined whether atomoxetine-mediated suppression of S-IRA evoked by either acoustic stimulation or pentylenetetrazole (PTZ) in DBA/1 mice can be reversed by intraperitoneal (IP) and intracerebroventricular (ICV) administration of prazosin, a selective antagonist of NE-1R. The content and activity of tyrosine hydroxylase (TH), a rate-limiting enzyme for NE synthesis, in the lower brainstem was measured by ELISA. Electroencephalograms (EEG) were obtained by using the PTZ-evoked SUDEP model. ResultsAtomoxetine-mediated suppression of S-IRA evoked by either acoustic stimulation or PTZ was significantly reversed by low doses of IP and ICV prazosin. Neither repetitive acoustic stimulation nor S-IRA reduced TH levels in lower brainstem. However, the enzyme activity of TH levels in lower brainstem was significantly increased by mechanical ventilation with DBA/1 mice ,which makes dead DBA/1 mice suffered from S-IRA and SUDEP recover. EEG data showed that although the protective effect of atomoxetine was reversed by prazosin, neither drug affected EEG activity. SignificanceThese data suggest that deficient synthesis of NE and norepinephrinergic neurotransmission contributes to S-IRA and that the NE-1R is a potential therapeutic target for the prevention of SUDEP.

neuroscience↗

bioRxiv2019

A common pattern of influenza A virus single cell gene expression heterogeneity governs the innate antiviral response to infection

Viral infection outcomes are governed by the complex and dynamic interplay between the infecting virus population and the host response. It is increasingly clear that both viral and host cell populations are highly heterogeneous, but little is known about how this heterogeneity influences infection dynamics or viral pathogenicity. To dissect the interactions between influenza A virus (IAV) and host cell heterogeneity, we examined the combined host and viral transcriptomes of thousands of individual, single virion-infected cells. We observed complex patterns of viral gene expression and the existence of multiple distinct host transcriptional responses to infection at the single cell level. Our analyses reveal that viral NS segment gene expression diverges from that of the rest of the viral genome within a subset of infected cells, and that this unique pattern of NS segment expression can play a dominant role in shaping the host cell response to infection. Finally, we show that seasonal human H1N1 and H3N2 strains differ significantly in patterns of host anti-viral gene transcriptional heterogeneity at the single cell level. Altogether, these data reveal a common pattern of viral gene expression heterogeneity across human IAV subtypes that can serve as a major determinant of antiviral gene activation.

microbiology↗