Biology subjects

Zhang, A.

Publications and source records attributed to Zhang, A..

At least 163 records · Page 9Linked to original sources

bioRxiv2023

A maize lipid droplet-associated protein is modulated by a virus to promote viral multiplication and infection

Pathogen infection induces massive reprogramming of host primary metabolism. Lipid and fatty acid metabolism is generally disrupted by pathogens and co-opted for their proliferation. Lipid droplets (LDs) that play important roles in regulating cellular lipid metabolism are utilized by a variety of pathogens in mammalian cells. However, the function of LDs during pathogenic infection in plants remains unknown. We show here that infection by rice black streaked dwarf virus (RBSDV) affects the lipid metabolism of maize, which causes elevated accumulation of C18 polyunsaturated fatty acids (PUFAs) leading to viral proliferation and symptom development. Overexpression of one of the two novel LD-associated proteins (LDAPs) of maize (ZmLDAP1 and ZmLDAP2) induces LD clustering. The core capsid protein P8 of RBSDV interacts with ZmLDAP2 and prevents its degradation through the ubiquitin-proteasome system mediated by a UBX domain-containing protein, PUX10. In addition, silencing of the ZmLDAP2 down-regulates expression of fatty acid desaturase genes in maize, leading to a decrease in C18 PUFAs levels and suppression of RBSDV accumulation. Our findings reveal that the plant virus recruits LDAP to regulate cellular fatty acid metabolism to promote viral multiplication and infection. These results expand the knowledge of the LD functions and viral infection mechanism in plants. One Sentence SummaryRice black streaked dwarf virus recruits a lipid droplet-associated protein to regulate cellular fatty acid metabolism for promoting viral multiplication and infection.

pathology↗

bioRxiv2023

Structural insights into ion conduction by novel cation channel, TMEM87A, in Golgi apparatus

TMEM87 family is evolutionarily conserved eukaryotic transmembrane proteins residing in the Golgi1. TMEM87 members play a role in retrograde transport in Golgi and are also proposed mechanosensitive ion channel implicated in cancer and heart disease2-7. In an accompanying study, TMEM87A is described as a voltage-gated, pH-sensitive, non-selective cation channel whose genetic ablation in mice disrupts Golgi morphology, alters glycosylation and protein trafficking, and impairs hippocampal memory. Despite the pivotal functions of TMEM87s in Golgi, underlying molecular mechanisms of channel gating and ion conduction have remained unknown. Here, we present a high-resolution cryo-electron microscopy structure of human TMEM87A (hTMEM87A). Compared with typical ion channels, the architecture of hTMEM87A is unique: a monomeric cation channel consisting of a globular extracellular/luminal domain and a seven-transmembrane domain (TMD) with close structural homology to channelrhodopsin. The central cavity within TMD is occupied by endogenous phosphatidylethanolamine, which seals a lateral gap between two TMs exposed to the lipid bilayer. By combining electrophysiology and molecular dynamics analysis, we identify a funnel-shaped electro-negative luminal vestibule that effectively attracts cations, and phosphatidylethanolamine occludes ion conduction. Our findings suggest that a conformational switch of highly conserved positively-charged residues on TM3 and displacement of phosphatidylethanolamine are opening mechanisms for hTMEM87A, providing an unprecedented insight into the molecular basis for voltage-gated ion conduction in Golgi.

biophysics↗

bioRxiv2022

In situ genetically targeted chemical assembly of polymers on living neuronal membranes

Multicellular biological systems, most notably living neural networks, exhibit highly complex physical organization properties that pose challenges for building cell-specific and biocompatible interfaces. We developed a novel approach to genetically program cells to chemically assemble artificial structures that modify the electrical properties of neurons in situ, opening up the possibility of minimally-invasive cell-specific interfaces with neural circuits in living animals. However, the efficiency and biocompatibility of this approach were challenged by limited membrane targeting of the constructed material. Here, we report a method with significantly improved molecular construct properties, which expresses highly localized enzymes targeted to the plasma membrane of primary neurons with minimal intracellular retention. Polymers synthesized in situ by this approach form dense clusters on the targeted cell membrane, and neurons remain viable after polymerization. This platform can be readily extended to incorporate a broad range of materials onto the surface membranes of specific cells within complex tissues, using chemistry that may further enable the next generation of interfaces with living biological systems.

bioengineering↗

bioRxiv2022

Genetically-encoded photosensitizers enable light-controlled polymerization on living neuronal membranes

The ability to record, stimulate, and modify brains of living animals would unlock numerous research opportunities and create potential clinical interventions, but it is difficult to interface with a living neural network without damaging it. We previously reported a novel approach to building neural interfaces, namely: genetically programming cells to build artificial structures to modify the electrical properties of neurons in situ, which opens up the possibility of modifying neural circuits in living animals without surgery. However, the spatiotemporal resolution, efficiency, and biocompatibility of this approach were still limited and lacked selectivity on cell membrane. Here, we demonstrate an approach using genetically-targeted photosensitizers to instruct living cells to synthesize functional materials directly on the plasma membrane under the control of light. Polymers synthesized by this approach were selectively deposited on the membrane of targeted live neurons. This platform can be readily extended to incorporate a broad range of light-controlled reactions onto specific cells, which may enable researchers to grow seamless, dynamic interfaces directly in living animals.

bioengineering↗

bioRxiv2022

Haploid-resolved and chromosome-scale genome assembly in hexa-autoploid sweetpotato (Ipomoea batatas (L.) Lam)

Sweetpotato (Ipomoea batatas (L.) Lam) is the worlds seventh most important food crop by production quantity. Cultivated sweetpotato is a hexaploid (2n = 6x = 90), and its genome (B1B1B2B2B2B2) is quite complex due to polyploidy, self-incompatibility, and high heterozygosity. Here we established a haploid-resolved and chromosome-scale de novo assembly of autohexaploid sweetpotato genome sequences. Before constructing the genome, we created chromosome-scale genome sequences in I. trifida using a highly homozygous accession, Mx23Hm, with PacBio RSII and Hi-C reads. Haploid-resolved genome assembly was performed for a sweetpotato cultivar, Xushu18 by hybrid assembly with Illumina paired-end (PE) and mate-pair (MP) reads, 10X genomics reads, and PacBio RSII reads. Then, 90 chromosome-scale pseudomolecules were generated by aligning the scaffolds onto a sweetpotato linkage map. De novo assemblies were also performed for chloroplast and mitochondrial genomes in I. trifida and sweetpotato. In total, 34,386 and 175,633 genes were identified on the assembled nucleic genomes of I. trifida and sweetpotato, respectively. Functional gene annotation and RNA-Seq analysis revealed locations of starch, anthocyanin, and carotenoid pathway genes on the sweetpotato genome. This is the first report of chromosome-scale de novo assembly of the sweetpotato genome. The results are expected to contribute to genomic and genetic analyses of sweetpotato.

genomics↗

bioRxiv2022

Study of Pinelliae Rhizoma hepatotoxicity based on complex network algorithm improvement

Important protein identification methods based on centrality have reached a high level of accuracy. However, there is a need to improve centrality algorithms because they currently consider the nature of protein-protein interaction (PPI) network topology but not protein properties. To improve the centrality algorithm, we introduce the weighted PageRank algorithm, which represents node importance, and the protein interaction combined_score, which represents PPI network edge importance in the STRING database to construct a weighted PPI network. We constructed yeast protein networks for simulations to validate the improved algorithm. Finally, we studied the hepatotoxicity of Pinelliae Rhizoma by applying the PageRank and Edge Clustering (PEC) algorithm. Our study shows that the PageRank and Edge Clustering algorithm can pre-screen important targets and has superior accuracy, sensitivity, and specificity to other centrality algorithms.

pharmacology and toxicology↗

bioRxiv2022

Modular cell type organization of cortical areas revealed by in situ sequencing

The cortex is composed of neuronal types with diverse gene expression that are organized into specialized cortical areas. These areas, each with characteristic cytoarchitecture (Brodmann 1909; Vogt and Vogt 1919; Von Bonin 1947), connectivity (Zingg et al. 2014; Harris et al. 2019), and neuronal activity (Schwarz et al. 2008; Ferrarini et al. 2009; He et al. 2009; Meunier et al. 2010; Bertolero et al. 2015), are wired into modular networks (Zingg et al. 2014; Harris et al. 2019; Huang et al. 2020). However, it remains unclear whether cortical areas and their modular organization can be similarly defined by their transcriptomic signatures and how such signatures are established in development. Here we used BARseq, a high-throughput in situ sequencing technique, to interrogate the expression of 104 cell type marker genes in 10.3 million cells, including 4,194,658 cortical neurons over nine mouse forebrain hemispheres at cellular resolution. De novo clustering of gene expression in single neurons revealed transcriptomic types that were consistent with previous single-cell RNAseq studies(Yao et al. 2021a; Yao et al. 2021b). Gene expression and the distribution of fine-grained cell types vary along the contours of cortical areas, and the composition of transcriptomic types are highly predictive of cortical area identity. Moreover, areas with similar compositions of transcriptomic types, which we defined as cortical modules, overlap with areas that are highly connected, suggesting that the same modular organization is reflected in both transcriptomic signatures and connectivity. To explore how the transcriptomic profiles of cortical neurons depend on development, we compared the cell type distributions after neonatal binocular enucleation. Strikingly, binocular enucleation caused the cell type compositional profiles of visual areas to shift towards neighboring areas within the same cortical module, suggesting that peripheral inputs sharpen the distinct transcriptomic identities of areas within cortical modules. Enabled by the high-throughput, low-cost, and reproducibility of BARseq, our study provides a proof-of-principle for using large-scale in situ sequencing to reveal brain-wide molecular architecture and to understand its development.

neuroscience↗

bioRxiv2022

A CMOS-based highly scalable flexible neural electrode interface

Perception, thoughts, and actions are encoded by the coordinated activity of large neuronal populations spread over large areas. Using thin film electrocorticography (ECoG) arrays, this cortical activity has been used to decode speech and individual finger movements, enabling neuroprosthetics, and to localize epileptic foci. However, the connectorization of these multi-thousand channel thin-film arrays to external circuitry is challenging; current state-of-the-art methods are complex, bulky, and unscalable. We address this shortcoming by developing an electrode connector based on an ultra-conformable thin film electrode array that self-assembles onto hard silicon chip sensors, such as microelectrode arrays (MEAs) or camera sensors enabling large channel counts at high density. The interconnects are formed using microfabricated electrode pads suspended by thin support arms, termed flex2chip. Capillary-assisted assembly drives the pads to deform towards the chip surface, and van der Waals forces maintain this deformation, establishing mechanical and Ohmic contact onto individual pixels. We demonstrate a 2200-channel array with a channel density of 272 channels / mm2 connected to the MEA through the flex2chip interconnection method. Thin film electrode arrays connected through the flex2chip successfully measured extracellular action potentials ex vivo. Furthermore, in a transgenic mouse model for absence epilepsy, Scn8a+/-, we observed highly variable propagation trajectories at micrometer scales, even across the duration of a single spike- and-wave discharge (SWD).

bioengineering↗

bioRxiv2022

Extreme diversity of mycoviruses present in four strains of Rhizoctonia cerealis, the pathogen of wheat sharp eyespot

Rhizoctonia cerealis is the pathogen of wheat sharp eyespot, which occurs throughout temperate wheat growing regions of the world. In this project, the genomes of viruses from four strains of R. cerealis were analyzed based on Illumina high-throughput RNA-Seq data. Ribosomal RNA-depleted total RNA and purified dsRNA from cultivated mycelia of each isolate were used for cDNA library construction and sequencing. After filtering out reads that mapped to the fungal genome, viral genomes were assembled using the remaining reads from the rRNA-depleted and dsRNA-Seq data. In total, 131 viral genome sequences containing complete ORFs, belonging to 117 viruses, were obtained. Based on phylogenetic analysis, some of them were identified as novel members of the families Curvulaviridae, Endornaviridae, Hypoviridae, Mitoviridae, Mymonaviridae and Phenuiviridae, while others were unclassified viruses. We compared the integrity and reliability of the viral sequences obtained by the two sequencing methods and, for the first time, estimated the density of some viruses in host cells. Most of these viruses from R. cerealis were sufficiently different from those deposited in databases. We propose the establishment of a new family, Rhizoctobunyaviridae, and two new genera, Rhizoctobunyavirus and Iotahypovirus. We further clarified the distribution and co-infection of these viruses in the four R. cerealis strains. In conclusion, the diversity of mycoviruses in R. cerealis is extremely rich. We report a series of novel viruses and provide important insight into virus evolution.

microbiology↗

bioRxiv2022

Decoding Age-specific Changes in Brain Functional Connectivity Using a Sliding-window Based Clustering Method

Functional magnetic resonance imaging (fMRI) permits detailed study of human brain function. Understanding the age-specific development of neural circuits in the typically developing brain may help us generate new hypotheses for developmental psychopathologies. Functional connectivity (FC), defined as the statistical associations between two brain regions, has been widely used in estimating functional networks from fMRI data. Previous research has shown that the evolution of FC does not follow a linear trend, particularly from childhood to young adulthood. Thus, this work aims to detect the nuanced FC changes with age from the non-linear curves and identify age-period-specific FC development patterns. We proposed a sliding-window based clustering approach to identify refined age interval of FC development. We used resting-state fMRI (rs-fMRI) data from the human connectome project-development (HCP-D), which recruited children, adolescents, and young adults aged from 5 to 21 years. Our analyses revealed different developmental patterns of resting-state FC by sex. In general, females matured earlier than males, but males had a faster development rate during age 100 -120 months. We identified four developmental phases: network construction in late childhood, segregation and integration construction in adolescence, network pruning in young adulthood, and a unique phase in males -- U-shape development. In addition, we investigated the sex effect on the slopes of FC-age correlation. Males had higher slopes during late childhood and young adulthood. These results inform trajectories of normal FC development, information that can in the future be used to pinpoint when development might go awry in neurodevelopmental disorders. HighlightO_LIPropose a novel sliding-window-based framework to identify refined age intervals of functional connectivity (FC) development. C_LIO_LIIdentify four developmental phases: network construction in late childhood, segregation and integration in adolescence, network pruning in young adulthood, and a unique phase in males -- U-shape development. C_LIO_LICharacterize the representative FC pattern for each developmental phase based on global network statistics, modular connectivity, and hub ROIs. C_LIO_LIReveal sex differences in developmental timing, rate, and patterns of resting-state FC. C_LI

neuroscience↗

bioRxiv2022

Chromosome 9p21.3 Coordinates Cell Intrinsic and Extrinsic Tumor Suppression

Somatic chromosomal deletions are prevalent in cancer, yet their functional contributions remain ill-defined. Among the most prominent of these events are deletions of chromosome 9p21.3, which disable a cell intrinsic barrier to tumorigenesis by eliminating the CDKN2A/B tumor suppressor genes. However, half of 9p21.3 deletions encompass a cluster of 16 type I interferons (IFNs) whose co-deletions have not been functionally characterized. To dissect how 9p21.3 and other genomic deletions impact cancer, we developed MACHETE (Molecular Alteration of Chromosomes with Engineered Tandem Elements), a genome engineering strategy that enables flexible modeling of megabase-sized deletions. Generation of 9p21.3-syntenic deletions in a mouse model of pancreatic cancer revealed that concomitant loss of Cdkn2a/b and the IFN cluster led to immune evasion and metastasis compared to Cdkn2a/b-only deletions. Mechanistically, IFN co-deletion disrupted type I IFN signaling, altered antigen-presenting cells, and facilitated escape from CD8+ T cell surveillance in a cell extrinsic manner requiring loss of interferon epsilon (Ifne). Our results establish co-deletions of the IFN cluster as a pervasive route to tumor immune evasion and metastasis, revealing how deletions can disable physically linked cell intrinsic and extrinsic tumor suppression. Our study establishes a framework to dissect the functions of genomic deletions in cancer and beyond.

cancer biology↗

bioRxiv2022

Diversity and task-dependence of task representations in V1 during freely-moving decisions

Neurons in primary visual cortex (area V1) are strongly driven by both sensory stimuli and non-sensory events. However, although the representation of sensory stimuli has been well characterized, much less is known about the representation of non-sensory events. Here, we characterize the specificity and organization of non-sensory representations in rat V1 during a freely-moving visual decision task. We find that single neurons encode diverse combinations of task features simultaneously and across task epochs. Despite heterogeneity at the level of single neuron response patterns, both visual and non-visual task variables could be reliably decoded from small neural populations (5-40 units) throughout a trial. Interestingly, in animals trained to make an auditory decision following passive observation of a visual stimulus, some but not all task features could also be decoded from V1 activity. Our results support the view that even in V1-- the earliest stage of the cortical hierarchy--bottom-up sensory information is combined with top-down non-sensory information in a task-dependent manner.

neuroscience↗

bioRxiv2022

Genomic analyses provide new insights into the evolutionary history and reproduction of the Paleogene relictual Kingdonia (Circaeasteraceae, Ranunculales)

Asexual lineages are perceived to be short-lived on evolutionary timescales due to accumulation of deleterious mutations. Hence reports for exceptional cases of putative ancient asexual species usually raise doubts about whether such species are recently derived or engage in some undocumented sexual reproduction. However, there have been few studies to solve the mystery. The monotypic Kingdonia dating to the early Eocene, contains only K. uniflora that has no known definitive evidence for sexual reproduction nor records for having closely related congeneric sexual species, seeming to have persisted under strict asexuality for long periods of time. In this study, we use population genomic analyses to test for reproduction mode and infer the evolutionary process and mechanisms facilitating the survival of the species. Our results indicate the presence of three differentiating genetic lineages within the species and support that asexual reproduction in K. uniflora indicated by high allelic heterozygosity had occurred prior to the lineage differentiation ([~]0.5 mya). We also detected DNA recombination events in some populations, in line with occurrence of unseen and unevenly distributed sexual reproduction among populations. However the observation of high linkage disequilibrium, relatively high ratio of{pi} N/{pi}S (nonsynonymous versus synonymous nucleotide diversity), together with high allelic heterozygosity suggest the sexual reproduction is infrequent. Furthermore, we found that genes containing SNPs with elevated Fst values are significantly enriched in functions associated with seed development, suggesting differentiation in genes regulating seed development is likely to be the key reason of the uneven distribution of sexual reproduction in K. uniflora. Evidence from our study supports predominate asexual reproduction in K. uniflora, but unseen sexual reproduction must have played a key role to ensure the long-term survival of the lineage in general. Uneven distribution of sexual reproduction in the species may be a key factor underlying the observed genetic differentiation between populations. This study provides novel insights into the reproduction and evolution of Kingdonia, a relict lineage evolved in the Paleogene and known for asexual reproduction, and demonstrate the power of data from population genome sequencing in resolving long-standing evolutionary questions.

genomics↗

bioRxiv2022

Distributed information encoding and decoding using self-organized spatial patterns

Dynamical systems often generate distinct outputs according to different initial conditions, and one can infer the corresponding input configuration given an output. This property captures the essence of information encoding and decoding. Here, we demonstrate the use of self-organized patterns, combined with machine learning, to achieve distributed information encoding and decoding. Our approach exploits a critical property of many natural pattern-formation systems: in repeated realizations, each initial configuration generates similar but not identical output patterns due to randomness in the patterning process. However, for sufficiently small randomness, different groups of patterns that arise from different initial configurations can be distinguished from one another. Modulating the pattern generation and machine learning model training can tune the tradeoff between encoding capacity and security. We further show that this strategy is applicable to non-biological dynamical systems and scalable by implementing the encoding and decoding of all characters of the standard English keyboard. Significance StatementSelf-organized patterns are ubiquitous in biology. They arise from interactions in and between cells, and with the environment. These patterns are often used as a composite phenotype to distinguish cell states and environment conditions. Conceptually, pattern generation under an initial condition is encoding; discerning the initial condition from the pattern represents decoding. Inspired by these examples, we develop a scheme, integrating mathematical modeling and machine learning, to use self-organization for secure and accurate information encoding and decoding. We show that this strategy is applicable to non-biological dynamical systems. We further demonstrate the scalability of the scheme by generating a complete mapping of the standard English keyboard, allowing encoding of English text. Our work serves as an example of nature-inspired computation.

systems biology↗

bioRxiv2022

The salivary and nasopharyngeal microbiomes are associated with SARS-CoV-2 infection and disease severity

Oral and upper respiratory microbiota play important roles in modulating host immune responses to viral infection. As emerging evidence suggests the host microbiome may be involved in the pathophysiology of COVID-19, we aimed to investigate associations between the oral and nasopharyngeal microbiome and COVID-19 severity. We collected saliva (n = 78) and nasopharyngeal swab (n = 66) samples from a COVID-19 cohort and characterized the microbiomes using 16S ribosomal RNA gene sequencing. We also examined associations between the salivary and nasopharyngeal microbiome and age, COVID-19 symptoms, and blood cytokines. SARS-CoV-2 infection status, but not COVID-19 severity, was associated with community-level differences in the oral and nasopharyngeal microbiomes. Salivary and nasopharyngeal microbiome alpha diversity negatively correlated with age and were associated with fever and diarrhea. Several bacterial genera were differentially abundant by COVID-19 severity, including oral Bifidobacterium, Lactobacillus, and Solobacterium, all of which were depleted in patients with severe COVID-19. Nasopharyngeal Paracoccus was depleted while nasopharyngeal Proteus, Cupravidus, and Lactobacillus were increased in patients with severe COVID-19. Further analysis revealed that the abundance of oral Bifidobacterium was negatively associated with plasma concentrations of known COVID-19 biomarkers interleukin 17F (IL-17F) and monocyte chemoattractant protein-1 (MCP-1). In conclusion, our results suggest COVID-19 disease severity is associated with the relative abundance of certain bacterial taxa.

microbiology↗

bioRxiv2022

Tissue libraries enable rapid determination of conditions that preserve antibody labeling in cleared mouse and human tissue

Difficulty achieving complete, specific, and homogenous staining is a major bottleneck preventing the widespread use of tissue clearing techniques to image large volumes of human tissue. In this manuscript, we describe a procedure to rapidly design immunostaining protocols for antibody labeling of cleared brain tissue. We prepared libraries of .5-1.0 mm thick tissue sections that are fixed, pre-treated, and cleared via similar, but different procedures to optimize staining conditions for a panel of antibodies. Results from a library of mouse tissue correlate well with results from a similarly prepared library of human brain tissue, suggesting mouse tissue is an adequate substitute for protocol optimization. These data show that procedural differences do not influence every antibody-antigen pair in the same way, and minor changes can have deleterious effects, therefore, optimization should be conducted for each target. The approach outlined here will help guide researchers to successfully label a variety of targets, thus removing a major hurdle to accessing the rich 3D information available in large, cleared human tissue volumes.

cell biology↗

bioRxiv2022

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell therapy

Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a compelling tumor-associated cell surface antigen for therapeutic targeting in solid tumors. We identified broad expression of STEAP1 (87% positive) in lethal metastatic prostate cancer, even more so than prostate-specific membrane antigen (PSMA, 60% positive) which is a clinically established diagnostic and therapeutic target. Second-generation chimeric antigen receptor (CAR) T cells were engineered for reactivity against STEAP1 and demonstrated substantial antitumor activity in metastatic human prostate cancer models in immunodeficient mice. Adoptive transfer of STEAP1 CAR T cells was associated with prolonged peripheral persistence and either disease eradication or substantial tumor growth inhibition with progressive disease demonstrating antigen loss. As STEAP1 CAR T cells were also highly active in antigen density conditions as low as [~]1,500 molecules/cell, we generated a human STEAP1 (hSTEAP1) knock-in (KI) mouse to evaluate the potential for on-target off-tumor toxicities. hSTEAP1-KI mice demonstrated a pattern of systemic hSTEAP1 expression akin to that observed in humans with the greatest expression found in the prostate gland. Mouse-in-mouse studies of STEAP1 CAR T cell therapy in immunocompetent hSTEAP1-KI mice engrafted with disseminated mouse prostate cancer showed preliminary safety without evidence of gross toxicity, cytokine storm, or architectural disruption and increased T cell infiltration at sites of systemic hSTEAP1 expression. Tumor responses and extension of survival were appreciated but antigen loss was identified in recurrent and progressive disease. In summary, we report the extent of STEAP1 expression in treatment-refractory metastatic prostate cancer, the generation of a STEAP1 CAR T cell therapy with promising potency and safety in preclinical studies of advanced prostate cancer, and antigen escape as a mechanism of resistance to effective STEAP1 CAR T cell therapy.

cancer biology↗

bioRxiv2022

Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence

Acute Respiratory Distress Syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, has no cure. Hypoxemia is a defining feature, yet its impact on inflammation is often neglected. Patients with ARDS are monocytopenic early in the onset of the disease. Endotoxin or Streptococcus pneumoniae acute lung injury (ALI) in the context of hypoxia replicates this finding, through hypoxia-driven suppression of type I interferon signalling. This results in failed lung monocyte-derived interstitial macrophages (IM) niche expansion and unchecked neutrophilic inflammation. Administration of colony stimulating factor 1 (CSF1) rescues the monocytopenia, alters the circulating classical monocyte phenotype in hypoxic endotoxin-driven ALI and enables lung IM population expansion, thus limiting lung injury in endotoxin- and virally-induced hypoxic ALI. Hypoxia directly alters immune dynamics to the detriment of the host and manipulation of this aberrant response offers new therapeutic strategies for ARDS.

cell biology↗