Biology subjects

Sheikh, A.

Publications and source records attributed to Sheikh, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Turnip mosaic virus co-opts host RNA methylation to orchestrate plant infection

N6-methyladenosine (m6A) is a key RNA modification that regulates transcript stability and translation. However, its function in plant viruses remains largely unclear. Here, we show that the positive-sense single-stranded +ssRNA Turnip mosaic virus (TuMV) relies on the host m6A machinery to support efficient infection. Our findings uncover a previously unrecognized nuclear phase in the TuMV life cycle, during which viral RNA undergoes extensive methylation by host enzymes. We identify a complex and non-canonical methylation landscape on the TuMV genome, where canonical DRACH motifs are embedded within clusters of additional virus-specific non-canonical m6A sites. Notably, we also detect the presence of another RNA modification, m5C (5-methylcytosine), in close proximity to m6A-marked regions. This coordinated methylation landscape appears to be critical for efficient viral polyprotein synthesis. In its absence, the virus displays aberrant methylation and reduced infectivity as observed in m6A writer and reader mutants. Based on this, we propose a "seeding" model in which initial m6A deposition at canonical sites nucleates the formation of a broader network of m6A and m5C marks, likely guided by RNA structure rather than sequence motifs alone.

plant biology↗

bioRxiv2025

ETEC heat-labile toxin promotes β-catenin stabilization and transcriptional reprogramming to disrupt intestinal epithelial differentiation

Enterotoxigenic Escherichia coli (ETEC), defined by their production of heat-labile (LT) and heat-stable (ST) enterotoxins, are a common cause of acute diarrheal illness in children from low- and middle-income countries, and are also linked to long-term sequelae such as malnutrition, and growth impairment. While the mechanisms underlying toxin-mediated acute diarrhea are known, the molecular events involved in ETEC related sequelae remain unclear. Here, we demonstrate that the ETEC heat-labile toxin (LT) profoundly remodels intestinal epithelial composition and function through modulation of WNT/{beta}-catenin signaling. Using human ileal enteroids, we demonstrate that LT stabilizes {beta}-catenin independently of WNT ligands, promotes its nuclear accumulation, and enhances TCF/LEF-driven transcription. Single-cell transcriptomic analyses reveal that LT increases intestinal proliferation by enhancing cell cycle activity across all epithelial lineages, thus disrupting epithelial composition by expanding proliferative progenitor populations at the expense of absorptive enterocytes. Simultaneously, LT impairs epithelial maturation and suppresses transcriptional programs required for nutrient absorption and differentiation. Together, these findings identify LT as a potent driver of intestinal epithelial reprogramming, providing mechanistic insight into how ETEC infection may drive long-term consequences beyond acute diarrhea and may inform strategies to prevent major sequelae, including malnutrition, that affect millions of children worldwide.

microbiology↗

bioRxiv2025

Outer membrane vesicles from Bacteroides fragilis contain coding and non-coding small RNA species that modulate inflammatory signaling in intestinal epithelial cells.

Alterations to the community structure and function of the microbiome are associated with changes to host physiology, including immune responses. However, the contribution of microbe-derived RNAs carried by outer membrane vesicles (OMVs) to host immune responses remain unclear. This study investigated the role of OMVs and OMV-associated small RNA (sRNA) species from pathogenic and commensal Bacteroides fragilis (ETBF and NTBF respectively) in eliciting different immune responses from intestinal epithelial cells. To distinguish the differences in the sRNA profiles of the two strains and their OMVs, RNA-seq, qRT-PCR, and northern blotting were conducted to identify enrichment of discrete sRNA species in OMVs, which were also differentially expressed between the two strains. Specifically, both coding and non-coding RNAs were enriched in OMVs from NTBF and ETBF, with BF9343_RS22680 and BF9343_RS17870 being significantly enriched in ETBF OMVs compared to NTBF. To understand the effects of OMVs on pattern recognition receptors, reporter cells of Toll-like receptor (TLR) activation were treated with OMVs, demonstrating activation of TLRs 2, 3, and 7. Treatment of Caco-2 and HT29-MTX cells with OMVs demonstrated increased expression of IL-8. Surprisingly, we discovered that degradation of RNase-accessible RNAs within ETBF OMVs, but not NTBF OMVs, resulted in vesicles with enhanced capacity to stimulate IL-8 expression, indicating that these extravesicular RNAs exert an immunosuppressive effect. This suggests a dual role for OMV-associated RNAs in modulating host immune responses, with implications for both bacterial pathogenesis and therapeutic applications. Graphical Abstract

molecular biology↗

bioRxiv2025

m6A RNA methylation attenuates thermotolerance in Arabidopsis

Heat stress severely affects plant growth, causing significant crop yield losses. To counteract this, plants employ adaptive strategies, including chromatin and transcriptional regulation of heat stress-related genes. However, the role of RNA methylation in heat stress response remains unclear. This study identifies m6A RNA methylation as a negative regulator of thermotolerance in Arabidopsis. Loss of m6A modification enhances resilience to heat stress by increasing transcript levels of heat-responsive genes and stabilizing their mRNAs. Upon heat shock, plants transiently reduce m6A levels by modulating key methylation machinery genes. This m6A deficiency enriches the H3K4me3 histone mark at heat-responsive gene loci, boosting their transcription. The combined effect of m6A-regulated chromatin changes and mRNA stability facilitates the accumulation of heat shock proteins essential for cellular protection and stress response. These findings reveal an interplay between m6A RNA methylation and histone modifications, forming a regulatory network that fine-tunes gene expression during heat stress. This novel mechanism highlights m6A as a critical regulator of plant thermotolerance, offering a promising target for improving heat stress resilience in crops.

plant biology↗

bioRxiv2025

A novel bioinformatics approach reveals key transcription factors regulating type 1 diabetes-associated transcriptomes

We developed a novel bioinformatics pipeline that reveals key transcription factors (TFs) regulating type 1 diabetes transcriptomes by combining automated Python workflows, DESeq2-based differential expression analysis, motif enrichment, and genome-wide TF abundance profiling, a rare but powerful strategy that deepens our understanding of disease mechanisms. This approach not only uncovers TFs driving pathology but also quantifies TF abundance across multiple genomic loci, enabling rapid and precise monitoring of their occupancy. Analyzing 21 RNA sequencing datasets, including 13 from early-stage T1D patients and 8 matched controls, we identified nearly 6 000 differentially expressed genes; 1 900 met strict significance and fold-change criteria and 211 are previously uncharacterized transcripts that distinguish T1D from healthy samples. Pathway analysis highlighted disruptions in beta-cell signaling, ALK-linked drug responses, neurodegenerative processes, and cytoskeletal organization. Upstream motif analysis revealed enrichment of Myc/Max, AP-1, SP-1, TATA-box, and NF-{kappa}B binding sites in upregulated genes, confirming their central role in the T1D transcriptome. By placing TFs at the core of our discovery platform, this work uncovers novel molecular drivers of T1D and identifies actionable biomarkers and therapeutic targets for personalized treatment.

bioinformatics↗

bioRxiv2025

Parenteral Vaccination with recombinant EtpA glycoprotein impairs enterotoxigenic E. coli colonization

Enterotoxigenic E. coli (ETEC) cause hundreds of millions of cases of acute diarrheal illness in low-middle income regions, disproportionately in young children. To date there is no licensed, broadly protective vaccine to protect against these common but antigenically heterogeneous pathogens. One of the more highly conserved antigens of ETEC, EtpA, is an extracellular glycoprotein adhesin that preferentially binds to blood group A glycans on intestinal epithelia. EtpA contributes to increased severity of illness in blood group A individuals, elicits robust serologic and fecal antibody responses following infection, and has been associated with protection against subsequent infection. However, its utility as a protective antigen needs further examination. In the present studies we examined whether parenteral vaccination with recombinant EtpA (rEtpA) could afford protection against intestinal colonization in a murine model of ETEC infection. Here, we demonstrate that intramuscular vaccination with rEtpA when adjuvanted with double mutant LT (dmLT) primes IgG predominant mucosal antibody responses to ETEC challenge. Notably, however, both antibody levels and avidity, as well as protection were dependent on vaccination schedule. Likewise, by electron microscopy polyclonal epitope mapping (EMPEM) we observed a greater diversity of epitopes targeted by antibodies after a more protracted vaccination schedule. Next, we explored the utility of IM immunization with alum-adjuvanted rEtpA. This elicited strong serologic and fecal IgG responses. Although accompanied by negligible IgA mucosal responses, EtpA alum-adjuvanted IM vaccination nevertheless protected against ETEC intestinal colonization. Collectively, these data suggest that EtpA could expand the portfolio of antigens targeted in ETEC subunit vaccine development.

microbiology↗

bioRxiv2024

Neutrophils drive sexual dimorphism in experimental periodontitis

The motivating premise of this study is to improve the treatment of periodontal disease by elucidating sex-specific mechanisms of periodontal disease progression. Men and women experience inflammation in fundamentally different ways and understanding the sex-specific biology leading to inflammation and bone loss in the periodontium will inevitably improve patient outcomes. We therefore examined clinical and immunological differences in the progression of periodontal disease using the ligature-induced periodontitis model. Periodontitis was induced in male and female C57BL/6j mice by tying a 5-0 silk suture around the left maxillary second molar. The ligature was left on for 7 or 21 days at which point maxillae were characterized for bone loss by CT or immune infiltrate by flow cytometry. Neutrophil depletion was accomplished through systemic administration of a Ly6G antibody. Conditions were compared using two-way ANOVA with Tukeys multiple comparison correction from n[≥]5 animals. Ligature-induced periodontitis led to alveolar bone loss at both 7 and 21 days in both female and male mice. Males and females had approximately the same amount of linear bone loss 7 days post-ligature placement, while male mice had significantly more linear bone loss by day 21. Male mice had significantly more immune cells in their maxillae 7 days post ligature placement compared to female mice. Both male and female mice showed a shift in immune populations towards neutrophils, with no significant difference between males and females. Neutrophil counts were significantly elevated in male mice on day 7 but not day 21, while female mice did not have any statistically significant changes in neutrophil counts. Neutrophil depletion using a Ly6G antibody limited bone loss in male but not female mice relative to isotype antibody-treated controls. Analysis of single-cell sequencing data from human patients with periodontitis showed differences in neutrophil phenotypes that were also observed in a mouse model of periodontitis. Together, these data suggest a mechanistic role for neutrophil inflammation in sexual dimorphism in periodontitis.

pathology↗

bioRxiv2024

MyVivarium: A cloud-based lab animal colony management application with near-realtime ambient sensing

Management of research-animal colonies is vital for lab productivity in preclinical research. Labs often rely on inefficient paper-based or spreadsheet-based methods to manage animal colonies. Dedicated software-based solutions are generally expensive and many lack remote access. Currently available open-source alternatives are difficult to implement and deploy. These solutions also do not have the capability to track ambient variables that affect colony well-being. We built MyVivarium, an open-source database management web application to address these gaps. MyVivarium can be easily deployed to the cloud and sustained for a cost comparable to starting and maintaining a lab website. Using MyVivarium, lab members can collaboratively track individual animals within a database. Physical identities of cages map onto the database using QR codes, enabling quick and easy record-keeping on mobile devices. Lab administrators can assign tasks to users with reminders for experiments or cage maintenance. Finally, we designed a low-cost system to sense ambient humidity, temperature, vivarium worker activity, and room illuminance. These data are then sent to MyVivarium in realtime providing information relevant to colony well-being. Taken together, MyVivarium is a novel, open-source, cloud-based application template that provides a low-cost, simple, and efficient way to digitally manage research-animal colonies.

bioinformatics↗

bioRxiv2024

Host-derived CEACAM-laden vesicles engage enterotoxigenic E. coli for elimination and toxin neutralization.

Enterotoxigenic Escherichia coli (ETEC) cause hundreds of millions of diarrheal illnesses annually ranging from mildly symptomatic cases to severe, life-threatening cholera-like diarrhea. Although ETEC are associated with long-term sequelae including malnutrition, the acute diarrheal illness is largely self-limited. Recent studies indicate that in addition to causing diarrhea, the ETEC heat-labile toxin (LT) modulates the expression of many genes in intestinal epithelia, including carcinoembryonic cell adhesion molecules (CEACAMs) which ETEC exploit as receptors, enabling toxin delivery. Here however, we demonstrate that LT also enhances the expression of CEACAMs on extracellular vesicles (EV) shed by intestinal epithelia and that CEACAM-laden EV increase in abundance during human infections, mitigate pathogen-host interactions, scavenge free ETEC toxins, and accelerate ETEC clearance from the gastrointestinal tract. Collectively, these findings indicate that CEACAMs play a multifaceted role in ETEC pathogen-host interactions, transiently favoring the pathogen, but ultimately contributing to innate responses that extinguish these common infections. Significance statementEnterotoxigenic E. coli, characterized by the production of heat-labile (LT) and heat-stable (ST) toxins, are a very common cause of diarrhea in low-income regions responsible for hundreds of millions of infections each year, and the major cause of diarrhea in travelers to endemic areas. Although these infections may be severe and cholera-like, they are typically self-limited. These studies demonstrate that extracellular vesicles produced by host intestinal cells can capture the bacteria and its secreted toxins at a distance from the cell surface, potentially acting as molecular decoys to neutralize the enterotoxins and extinguish the infection.

microbiology↗

bioRxiv2024

Repeat modules and N-linked glycans define structure and antigenicity of a critical enterotoxigenic E. coli adhesin

Enterotoxigenic Escherichia coli (ETEC) cause hundreds of millions of cases of infectious diarrhea annually, predominantly in children from low-middle income regions. Notably, in children, as well as human volunteers challenged with ETEC, diarrheal severity is significantly increased severity in blood group A (bgA) individuals. EtpA, is a secreted glycoprotein adhesin that functions as a blood group A lectin to promote critical interactions between ETEC and blood group A glycans on intestinal epithelia for effective bacterial adhesion and toxin delivery. EtpA is highly immunogenic resulting in robust antibody responses following natural infection and experimental challenge of human volunteers with ETEC. To understand how EtpA directs ETEC-blood group A interactions and stimulates adaptive immunity, we mutated EtpA, mapped its glycosylation by mass-spectrometry (MS), isolated polyclonal (pAbs) and monoclonal antibodies (mAbs) from vaccinated mice and ETEC-infected human volunteers, and determined structures of antibody-EtpA complexes by cryo-electron microscopy. Both bgA and mAbs that inhibited EtpA-bgA interactions and ETEC adhesion, bound to the C-terminal repeat domain highlighting this region as crucial for ETEC pathogen-host interaction. MS analysis uncovered extensive and heterogeneous N-linked glycosylation of EtpA and cryo-EM structures revealed that mAbs directly engage these unique glycan containing epitopes. Finally, electron microscopy-based polyclonal epitope mapping revealed antibodies targeting numerous distinct epitopes on N and C-terminal domains, suggesting that EtpA vaccination generates responses against neutralizing and decoy regions of the molecule. Collectively, we anticipate that these data will inform our general understanding of pathogen-host glycan interactions and adaptive immunity relevant to rational vaccine subunit design. Author summaryEnterotoxigenic E. coli (ETEC), a leading cause of diarrhea disproportionately affecting young children in low-income regions, are a priority for vaccine development. Individuals possessing A blood-type are more susceptible to severe cholera-like disease. EtpA, a secreted, immunogenic, blood group A binding protein, is a current vaccine target antigen. Here, we determined the atomic structure of EtpA in complex with protective as well as non-protective monoclonal antibodies targeting two different domains of the protein, allowing us to pinpoint key regions involved in blood-group A antigen recognition and uncover the mechanism of antibody-based protection. In addition, we show through mass-spectrometry that EtpA is extensively and heterogeneously glycosylated at surface-exposed asparagine residues by a promiscuous and low-fidelity glycosyltransferase, EtpC, and that this unique form of bacterial glycosylation is critical for to development of protective immune responses. Lastly, polyclonal antibodies from vaccinated mice as well as monoclonal antibodies obtained from ETEC-infected human volunteers revealed that the highly antigenic surface of EtpA exhibits both protective and non-protective epitopes. These results greatly expand our understanding of ETEC pathogenesis, and the immune responses elicited by these common infections, providing valuable information to aid in the rational design and testing of subunit vaccines.

microbiology↗

bioRxiv2023

Therapeutic interventions on human xenografts promote systemic dissemination of oncogenes

We generated xenografts of human cancer cells in mice, and using immuno-FISH analysis detected multiple co-localizing signals of human DNA and eight human oncoproteins in brain cells. Signals increased dramatically five days after treatment with chemotherapy, localized radiotherapy or surgery, which could be minimized by concurrent treatment with cell-free chromatin deactivating agents. These results suggest that therapeutic interventions may potentially encourage metastatic spread which is preventable by deactivating cell-free chromatin.

cancer biology↗

bioRxiv2023

Microbe-induced plant drought tolerance by ABA-mediated root morphogenesis and epigenetic reprogramming of gene expression

The use of beneficial microbes to mitigate drought stress tolerance of plants is of great potential albeit little understood. We show here that a root endophytic desert bacterium, Pseudomonas argentinensis sp. SA190, enhances drought stress tolerance in Arabidopsis. Transcriptome and genetic analysis demonstrate that SA190-induced root morphogenesis and gene expression is mediated via the plant abscisic acid (ABA) pathway. Moreover, we demonstrate that SA190 primes the promoters of target genes in an epigenetic manner which is ABA-dependent. Application of the SA190 priming technology on crops is demonstrated for alfalfa in field trials, showing enhanced performance under desert agriculture conditions. In summary, a single beneficial root bacterial strain can help to perform agriculture under drought and water limiting conditions. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/522604v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@b0bd17org.highwire.dtl.DTLVardef@14e3262org.highwire.dtl.DTLVardef@cdd103org.highwire.dtl.DTLVardef@5526a0_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIBeneficial root endophyte Pseudomonas argentinensis sp. SA190 confers drought tolerance in plants C_LIO_LISA190 modulates the expression of genes under drought stress in an ABA-dependent manner C_LIO_LISA190 primes genes via H3K4me3 histone mark enrichment C_LIO_LISA190 alters host plant physiology by improving the plant water status C_LIO_LISA190 enhances crop performance in open field conditions with limited irrigation C_LI

plant biology↗

bioRxiv2022

Effects of Oxytocin Receptor Blockade on Dyadic Social Behavior in Monogamous and Non-Monogamous Eulemur

A prominent body of research spanning disciplines has been focused on the potential underlying role for oxytocin in the social signatures of monogamous mating bonds. Behavioral differences between monogamous and non-monogamous vole species, putatively mediated by oxytocinergic function, constitute a key source of support for this mechanism, but it is unclear to what extent this hormone-behavior linkage extends to the primate order. In a preregistered experiment, we test if oxytocin receptor blockade affects affiliative behavior in mixed-sex pairs of Eulemur, a genus of strepsirrhine primate containing both monogamous and non-monogamous species. Inconsistent with past studies in monogamous voles or monkeys, we do not find confirmatory evidence in Eulemur that monogamous pairs affiliate more than non-monogamous pairs, nor that oxytocin receptor blockade of one pair member selectively corresponds to reduced affiliative or scent-marking behavior in monogamous species. We do, however, find exploratory evidence of a pattern not previously investigated: simultaneously blocking oxytocin receptors in both members of a monogamous pair predicts lower rates of affiliative behavior relative to controls. Our study demonstrates the value of non-traditional animal models in challenging generalizations based on model organisms, and of methodological reform in providing a potential path forward for behavioral oxytocin research.

animal behavior and cognition↗

bioRxiv2022

Enterotoxigenic Escherichia coli heat-labile toxin drives enteropathic changes in small 1intestinal epithelia

Enterotoxigenic E. coli (ETEC), produce heat-labile (LT) and/or heat-stable (ST) enterotoxins, and are a common cause of diarrhea in children of resource-poor regions. ETEC have also been linked repeatedly to poorly understood sequelae including enteropathy, malnutrition, and growth impairment. While the cellular actions of ETEC enterotoxins leading to diarrhea are well-established, their potential contribution to subsequent pathology is unclear. LT stimulates cellular cAMP production to activate protein kinase A (PKA) which phosphorylates cellular ion channels that drive export of salt and water into the intestinal lumen resulting in diarrhea. However, as PKA exhibits broad kinase activity and its activated catalytic subunits modulate transcription of many genes, we interrogated the transcriptional profiles of LT-treated small intestinal epithelia. These studies demonstrated toxin-induced changes in hundreds of genes including those required for biogenesis and function of the brush border, the major site absorption of nutrients, and suppression of a key transcription factors, HNF4 and SMAD4, critical to differentiation of intestinal epithelia. Accordingly, LT treatment of intestinal epithelial cells significantly disrupted the absorptive microvillus architecture and altered transport of essential nutrients. In addition, challenge of neonatal mice with LT-producing ETEC recapitulated the architectural derangement of the brush border while maternal vaccination with LT prevented brush border disruption in ETEC-challenged neonatal mice. Finally, mice repeatedly challenged with toxigenic ETEC exhibited impaired growth recapitulating the multiplicative impact of recurring ETEC infections in children. These findings highlight impacts of ETEC enterotoxins beyond acute diarrheal illness and may inform approaches to mitigate and prevent major sequelae including malnutrition that impact millions of young children.

microbiology↗

bioRxiv2022

Linker histone H1 regulates defense priming and immunity in plants

Linker H1 histones play an important role in animal and human pathogenesis, but their function in plant immunity is poorly understood. Here, we analyzed mutants of the three canonical variants of Arabidopsis H1 histones, namely H1.1, H1.2 and H1.3. We observed that double h1.1h1.2 and triple h1.1h1.2h1.3 (3h1) mutants were resistant to Pseudomonas syringae and Botrytis cinerea infections. Transcriptome analysis of 3h1 mutant plants showed that histone H1s play a key role in regulating the expression of early and late defense genes upon pathogen challenge. Moreover, 3h1 mutant plants showed enhanced production of reactive oxygen species and activation of mitogen activated protein kinases upon pathogen-associated molecular pattern (PAMP) treatment. However, 3h1 mutant plants were insensitive to priming with flg22, a well-known bacterial PAMP (pathogen-associated molecular pattern) which induces enhanced resistance in WT plants. The defective defense response in 3h1 was correlated with the enhanced DNA methylation and reduced H3K56ac levels upon priming. Our data place H1 as a molecular gatekeeper in governing dynamic changes in the chromatin landscape of defense genes during plant pathogen interaction.

plant biology↗

bioRxiv2021

Enterotoxigenic Escherichia coli degrades the host MUC2 mucin barrier to facilitate critical pathogen-enterocyte interactions in human small intestine.

Enterotoxigenic Escherichia coli (ETEC) are a genetically diverse pathologic variant of E. coli defined by the production of heat-labile (LT) and/or heat-stable (ST) toxins. ETEC are estimated to cause hundreds of millions of cases of diarrheal illness annually. However, it is not clear that all strains are equally equipped to cause disease and asymptomatic colonization with ETEC is common in low-middle income regions lacking basic sanitation and clean water where ETEC are ubiquitous. Recent molecular epidemiology studies have revealed a significant association between strains which produce EatA, a secreted autotransporter protein, and the development of symptomatic infection. Here, we demonstrate that LT stimulates production of MUC2 mucin by goblet cells in human small intestine, enhancing the protective barrier between pathogens and enterocytes. In contrast, using explants of human small intestine as well as small intestinal enteroids, we show that EatA counters this host defense by engaging and degrading the MUC2 mucin barrier to promote bacterial access to target enterocytes and ultimately toxin delivery suggesting that EatA plays a crucial role in the molecular pathogenesis of ETEC. These findings may inform novel approaches to prevention of the acute diarrheal illness as well as the sequelae associated with ETEC and other pathogens that rely on EatA and similar proteases for efficient interaction with their human hosts.

microbiology↗

bioRxiv2021

Macrophages govern antiviral responses in human lung tissues protected from SARS-CoV-2 infection

The majority of SARS-CoV-2 infections among healthy individuals result in asymptomatic to mild disease. However, the immunological mechanisms defining effective lung tissue protection from SARS-CoV-2 infection remain elusive. Unlike mice solely engrafted with human fetal lung xenograft (fLX), mice co-engrafted with fLX and a myeloid-enhanced human immune system (HNFL mice) are protected against SARS-CoV-2 infection, severe inflammation, and histopathology. Effective control of viral infection in HNFL mice associated with significant macrophage infiltration, and the induction of a potent macrophage-mediated interferon response. The pronounced upregulation of the USP18-ISG15 axis (a negative regulator of IFN responses), by macrophages was unique to HNFL mice and represented a prominent correlate of reduced inflammation and histopathology. Altogether, our work shed light on unique cellular and molecular correlates of lung tissue protection during SARS-CoV-2 infection, and underscores macrophage IFN responses as prime targets for developing immunotherapies against coronavirus respiratory diseases. HIGHLIGHTSO_LIMice engrafted with human fetal lung xenografts (fLX-mice) are highly susceptible to SARS-CoV-2. C_LIO_LICo-engraftment with a human myeloid-enriched immune system protected fLX-mice against infection. C_LIO_LITissue protection was defined by a potent and well-balanced antiviral response mediated by infiltrating macrophages. C_LIO_LIProtective IFN response was dominated by the upregulation of the USP18-ISG15 axis. C_LI

microbiology↗

bioRxiv2021

IL-7 is essential for accumulation of antigen-specific CD8 T cells and to generate clonotype-specific effector responses during airway influenza/A infection.

Airborne diseases are the leading cause of infectious disease-related deaths in the world. In particular, the influenza virus activates a network of immune cells that leads to clearance or an overzealous response that can be fatal. Tight regulation of the cytokines that enable proper activation and function of immune cells is necessary to clear infections efficiently while minimizing damage to the host. Interleukin-7 (IL-7) is a cytokine known for its importance in T cell development and survival. How IL-7 shapes CD8 T cell responses during an acute viral infection is less understood. We had previously shown that IL-7 signaling deficient mice have reduced accumulation of influenza-specific CD8 T cells following infection. We sought to determine whether IL-7 affects early CD8 T cell expansion in the mediastinal lymph node and effector function in the lungs. Using IL-7R signaling deficient mice, we show that IL-7 is required for a normal sized mediastinal lymph node and the early clonal expansion of antigen-specific CD8 T cells therein. Bone marrow chimeric models and adoptive transfer of transgenic TCR CD8 T cells reveal a cell-intrinsic role for IL-7 in the accumulation of NP366-374 and PA224-233-specific CD8 T cells. We also found that IL-7 dictates terminal differentiation, degranulation and cytokine production in PA224-233-specific but not NP366-374-specific CD8 T cells. We further demonstrate that IL-7 is induced in the lung tissue by viral infection and we characterize multiple cellular sources that contribute to IL-7 production. Drugs that manipulate IL-7 signaling are currently under clinical trial for multiple conditions. Our findings on IL-7 and its effects on lower respiratory diseases will be important for expanding the utility of these therapeutics. Author SummaryInterleukin-7 plays an important role in development of immune cells such as lymphocytes. In recent years, its role in the immune system has been expanded beyond the development of immune cells to include revitalizing of lymphocytes during tumor and chronic viral response. We show here that IL-7 is required for accumulation and function of specialized lymphocytes in the lungs during an acute influenza infection.

immunology↗