Biology subjects

Kheradmand, F.

Publications and source records attributed to Kheradmand, F..

14 recordsLinked to original sources

bioRxiv2026

Mechanosignaling Promotes Macrophage Apoptosis Resistance in Pulmonary Fibrosis via Metabolic Reprogramming

The mechanisms underlying the progression of pulmonary fibrosis in idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases remain unclear. Increased extracellular matrix stiffness is a hallmark of fibrotic lung diseases. Monocyte-derived macrophages can promote fibrosis progression. However, there is limited understanding of how the mechanical properties of the fibrotic microenvironment influence macrophage phenotypes. Profibrotic macrophages are apoptosis-resistant, and this phenotype is modulated by enhanced mitochondrial bioenergetics. The objective of the study was to determine how lung tissue stiffness impacts macrophage phenotypes and fibrotic progression. We demonstrate that mechanoactivated macrophages exhibit apoptosis-resistance, increased expression of the antiapoptotic protein Bcl-xL and increased mitochondrial oxidative phosphorylation. Critically, the metabolic reprogramming observed in mechanoactivated macrophages is dependent on increased glutaminolysis. Inhibition of glutaminolysis attenuated apoptosis resistance in mechanoactivated macrophages. Moreover, inhibition of Bcl-xL in vivo protected mice against experimental pulmonary fibrosis. Lastly, mechanoactivated primary IPF macrophages produce more profibrotic cytokines and promote extracellular matrix production in precision-cut lung slices. We describe a mechanism for acquired macrophage apoptosis resistance dependent on metabolic reprogramming regulated by extracellular matrix stiffness. Our results identify mechanoactivated apoptosis-resistant macrophages as pro-fibrotic mediators, suggesting a novel therapeutic target in IPF and related fibrotic disorders.

molecular biology↗

bioRxiv2026

A Mixed T2/T17-Associated Systemic Immune Signature Links Airborne Pollutant Exposure to Persistent Respiratory Symptoms

Background: The systemic immune responses associated with persistent respiratory symptoms (PRS) after exposure to airborne environmental pollutants remain poorly understood. Objective: To identify immune disturbances associated with PRS, defined as persistent wheeze, cough, or breathlessness, we examined systemic immune responses and airway function in a cross-sectional cohort with detailed histories of airborne pollutant exposure. Methods: Never-smoking post-deployment Veterans with PRS (n=16) or without PRS (n=24) underwent chest computed tomography, pulmonary function testing, and oscillometry to assess structural and functional airway abnormalities. Peripheral blood mononuclear cells (PBMCs) were stimulated with anti-CD3/CD28 antibodies, lipopolysaccharide, or {beta}-glucan, and cytokine production was measured. Correlation analyses evaluated associations between cytokine responses and physiological measures of airway function. Results: Oscillometry, but not conventional pulmonary function testing or chest computed tomography, detected small-airway abnormalities in participants with PRS, including significantly greater frequency dependence of resistance and higher resonant frequency. Baseline PBMC cytokine concentrations were similar between groups. After stimulation, however, PBMCs from participants with PRS showed increased IL-17A production consistent with a type 17 (T17) response; innate stimulation also increased the type 2 (T2) cytokines IL-33 and IL-4. T2/T17 cytokine responses correlated positively with oscillometric measures of small-airway dysfunction. Conclusion: Individuals with PRS exhibited a stimulus-dependent systemic T2/T17 immune signature that was associated with early small-airway dysfunction. Clinical Implication: Stimulus-dependent systemic immune profiling, combined with oscillometry, may help identify early respiratory abnormalities in pollutant-exposed individuals whose conventional pulmonary tests remain normal.

immunology↗

bioRxiv2026

Tumor-infiltrating natural killer cell profiling for therapeutic stratification in patients with resectable non-small cell lung cancer

ObjectiveNeoadjuvant chemoimmunotherapy has improved outcomes in resectable non-small cell lung cancer (NSCLC), yet its real-world implementation is often challenged by surgical delays, immune-mediated fibrosis, and postoperative complications. Smokers with NSCLC, despite a high risk for surgical morbidity, show enhanced responses to neoadjuvant chemoimmunotherapy. This study aimed to identify smoking-associated immune cell determinants that could guide treatment strategies. MethodsSingle-cell RNA sequencing (scRNAseq) was performed on 61 lung tissues from non-smokers and smokers to identify smoking-related immune compositions. The scRNAseq data from 19 invasive lung adenocarcinomas were used to validate their presence in the tumor-immune microenvironment. Bulk RNA sequencing data from 102 resected NSCLC and 24 NSCLC patients treated with neoadjuvant chemoimmunotherapy followed by surgery were used for in silico cellular deconvolution and outcome analyses. ResultsAmong 135 lung cellular phenotypes, two natural killer (NK) cell subsets were strongly associated with smoking and chronic obstructive pulmonary disease (COPD) severity. "Stress-responsive" NK (NKSR) cells exhibited immature features and cytokine-responsive features, and "Adaptive and immunoregulatory NK" (NKAIR) cells showed mature features and elevated multiple immune checkpoint expression. High intratumoral NKSR cells correlated with improved survival after surgery, particularly in current smokers. Conversely, tumors with low NKSR and high NKAIR cells responded more favorably to neoadjuvant chemoimmunotherapy. ConclusionsIntratumoral NK cell phenotyping may aid in therapeutic stratification in patients with NSCLC. NKSR cell preservation predicts benefit from upfront surgery, while NKAIR cell enrichment indicates improved response to neoadjuvant chemoimmunotherapy. These NK cell profiles may help optimize treatment by balancing therapeutic benefit and risk. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/696292v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@168bc03org.highwire.dtl.DTLVardef@10fa947org.highwire.dtl.DTLVardef@132a92dorg.highwire.dtl.DTLVardef@100e4a4_HPS_FORMAT_FIGEXP M_FIG C_FIG Central Picture O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/696292v1_ufig2.gif" ALT="Figure 2"> View larger version (21K): org.highwire.dtl.DTLVardef@1a2d3b4org.highwire.dtl.DTLVardef@f8f84borg.highwire.dtl.DTLVardef@17510bcorg.highwire.dtl.DTLVardef@9da763_HPS_FORMAT_FIGEXP M_FIG C_FIG NK cell profiling for treatment stratification in resectable NSCLC Central MessageTumor-infiltrating NK cell profiling identifies distinct immune phenotypes that can inform personalized treatment strategies in resectable NSCLC. Perspective statementAbundance of intratumoral stress-responsive NK cells predicts favorable outcomes after upfront surgery, whereas enrichment of adaptive and immunoregulatory NK cells suggests greater benefit from neoadjuvant chemoimmunotherapy. These findings support incorporating NK-cell profiling into preoperative decision-making to optimize therapy selection and balance risks in the high-risk surgical population.

immunology↗

bioRxiv2025

Identification of a multi-omics factor predictive of long COVID in the IMPACC study

Following SARS-CoV-2 infection, [~]10-35% of COVID-19 patients experience long COVID (LC), in which often debilitating symptoms persist for at least three months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities. We utilized machine learning methods on biologic analytes and patient reported outcome surveys provided over 12 months after hospital discharge from >500 hospitalized COVID-19 patients in the IMPACC cohort to identify a multi-omics "recovery factor". IMPACC participants who experienced LC had lower recovery factor scores compared to participants without LC. Biologic characterization revealed increased levels of plasma proteins associated with inflammation, elevated transcriptional signatures of heme metabolism, and decreased androgenic steroids in LC patients. The recovery factor was also associated with altered circulating immune cell frequencies. Notably, recovery factor scores were predictive of LC occurrence in patients as early as hospital admission, irrespective of acute disease severity. Thus, the recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets.

systems biology↗

bioRxiv2024

Unraveling SARS-CoV-2 Host-Response Heterogeneity through Longitudinal Molecular Subtyping

Hospitalized COVID-19 patients exhibit diverse immune responses during acute infection, which are associated with a wide range of clinical outcomes. However, understanding these immune heterogeneities and their links to various clinical complications, especially long COVID, remains a challenge. In this study, we performed unsupervised subtyping of longitudinal multi-omics immunophenotyping in over 1,000 hospitalized patients, identifying two critical subtypes linked to mortality or mechanical ventilation with prolonged hospital stay and three severe subtypes associated with timely acute recovery. We confirmed that unresolved systemic inflammation and T-cell dysfunctions were hallmarks of increased severity and further distinguished patients with similar acute respiratory severity by their distinct immune profiles, which correlated with differences in demographic and clinical complications. Notably, one critical subtype (SubF) was uniquely characterized by early excessive inflammation, insufficient anticoagulation, and fatty acid dysregulation, alongside higher incidences of hematologic, cardiac, and renal complications, and an elevated risk of long COVID. Among the severe subtypes, significant differences in viral clearance and early antiviral responses were observed, with one subtype (SubC) showing strong early T-cell cytotoxicity but a poor humoral response, slower viral clearance, and greater risks of chronic organ dysfunction and long COVID. These findings provide crucial insights into the complex and context-dependent nature of COVID-19 immune responses, highlighting the importance of personalized therapeutic strategies to improve both acute and long-term outcomes.

immunology↗

bioRxiv2024

Chronic Viral Reactivation and Associated Host Immune Response and Clinical Outcomes in Acute COVID-19 and Post-Acute Sequelae of COVID-19

Chronic viral infections are ubiquitous in humans, with individuals harboring multiple latent viruses that can reactivate during acute illnesses. Recent studies have suggested that SARS- CoV-2 infection can lead to reactivation of latent viruses such as Epstein-Barr Virus (EBV) and cytomegalovirus (CMV), yet, the extent and impact of viral reactivation in COVID-19 and its effect on the host immune system remain incompletely understood. Here we present a comprehensive multi-omic analysis of viral reactivation of all known chronically infecting viruses in 1,154 hospitalized COVID-19 patients, from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, who were followed prospectively for twelve months. We reveal significant reactivation of Herpesviridae, Enteroviridae, and Anelloviridae families during acute stage of COVID-19 (0-40 days post- hospitalization), each exhibiting distinct temporal dynamics. We also show that viral reactivation correlated with COVID-19 severity, demographic characteristics, and clinical outcomes, including mortality. Integration of cytokine profiling, cellular immunophenotyping, metabolomics, transcriptomics, and proteomics demonstrated virus-specific host responses, including elevated pro-inflammatory cytokines (e.g. IL-6, CXCL10, and TNF), increased activated CD4+ and CD8+ T-cells, and upregulation of cellular replication genes, independent of COVID-19 severity and SARS-CoV-2 viral load. Notably, persistent Anelloviridae reactivation during convalescence ([≥]3 months post-hospitalization) was associated with Post-Acute Sequelae of COVID-19 (PASC) symptoms, particularly physical function and fatigue. Our findings highlight a remarkable prevalence and potential impact of chronic viral reactivation on host responses and clinical outcomes during acute COVID-19 and long term PASC sequelae. Our data provide novel immune, transcriptomic, and metabolomic biomarkers of viral reactivation that may inform novel approaches to prognosticate, prevent, or treat acute COVID- 19 and PASC.

immunology↗

bioRxiv2024

Tobacco smoke exposure is a driver of altered oxidative stress response and immunity in head and neck cancer

PurposeExposomes are critical drivers of carcinogenesis. However, how they modulate tumor behavior remains unclear. Extensive clinical data link cigarette smoke as a key exposome that promotes aggressive tumors, higher rates of metastasis, reduced response to chemoradiotherapy, and suppressed anti-tumor immunity. We sought to determine whether smoke itself can modulate aggressive tumor behavior in head and neck squamous cell carcinoma (HNSCC) through reprogramming the cellular reductive state. Experimental designUsing established human and murine HNSCC cell lines and syngeneic mouse models, we utilized conventional western blotting, steady state and flux metabolomics, RNA sequencing, quantitative proteomics and flow cytometry to analyze the impact of smoke exposure on HNSCC tumor biology. ResultsCigarette smoke persistently activated Nrf2 target genes essential for maintenance of the cellular reductive state and survival under conditions of increased oxidative stress in HNSCC regardless of HPV status. In contrast to e-cigarette vapor, conventional cigarette smoke mobilizes cellular metabolism toward oxidative stress adaptation, resulting in development of cross-resistance to cisplatin. In parallel, smoke exposure modulates both expression of PDL1 and the secretory phenotype of HNSCC cells through activation of NF-{kappa}B resulting in an altered tumor immune microenvironment (TIME) in syngeneic mouse models and altered PBMC differentiation that includes downregulated expression of antigen presentation and costimulatory genes in myeloid cells. ConclusionCigarette smoke exposome is a potent activator of the Nrf2 pathway and is a likely primary trigger for the tripartite phenotype of aggressive HNSCC consisting of: 1) reduced chemotherapy sensitivity, 2) enhanced metastatic potential and 3) suppressed anti-tumor immunity. Statement of significanceThe smoke exposome drives aggressive tumor behavior, treatment resistance and suppressed immunity through coordinated metabolic reprogramming. Successfully targeting this adaptation is critical to improving survival in smokers with head and neck cancer.

cancer biology↗

bioRxiv2024

MAGE-A4-Responsive Plasma Cells Promote Non-Small Cell Lung Cancer

Adaptive immunity is critical to eliminate malignant cells, while multiple tumor-intrinsic factors can alter this protective function. Melanoma antigen-A4 (MAGE-A4), a cancer-testis antigen, is expressed in several solid tumors and correlates with poor survival in non-small cell lung cancer (NSCLC), but its role in altering antitumor immunity remains unclear. We found that expression of MAGE-A4 was highly associated with the loss of PTEN, a tumor suppressor, in human NSCLC. Here we show that constitutive expression of human MAGE-A4 combined with the loss of Pten in mouse airway epithelial cells results in metastatic adenocarcinoma enriched in CD138+ CXCR4+ plasma cells, predominantly expressing IgA. Consistently, human NSCLC expressing MAGE-A4 showed increased CD138+ IgA+ plasma cell density surrounding tumors. The abrogation of MAGE-A4-responsive plasma cells (MARPs) decreased tumor burden, increased T cell infiltration and activation, and reduced CD163+CD206+ macrophages in mouse lungs. These findings suggest MAGE-A4 promotes NSCLC tumorigenesis, in part, through the recruitment and retention of IgA+ MARPs in the lungs.

immunology↗

bioRxiv2023

Downregulation of Let-7 miRNA promotes Tc17 differentiation and emphysema via de-repression of RORγt

Environmental air irritants including nanosized carbon black (nCB) can drive systemic inflammation, promoting chronic obstructive pulmonary disease (COPD) and emphysema development. The let-7 family of miRNAs is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests the let-7 family is downregulated in patients with COPD, however, whether this repression conveys a functional consequence on emphysema pathology has not been elucidated. Here we show that overall expression of the let-7 miRNA clusters, let-7b/let-7c2 and let-7a1/let-7f1/let-7d, are reduced in the lungs and T cells of smokers with emphysema as well as in mice with cigarette smoke (CS)- or nCB-elicited emphysema. We demonstrate that loss of the let-7b/let-7c2-cluster in T cells predisposed mice to exaggerated CS- or nCB-elicited emphysema. Furthermore, ablation of the let-7b/let-7c2-cluster enhanced CD8+IL17a+ T cells (Tc17) formation in emphysema development in mice. Additionally, transgenic mice overexpressing let-7 in T cells are resistant to Tc17 and CD4+IL17a+ T cells (Th17) development when exposed to nCB. Mechanistically, our findings reveal the master regulator of Tc17/Th17 differentiation, RAR-related orphan receptor gamma t (ROR{gamma}t), as a direct target of let-7 miRNA in T cells. Overall, our findings shed light on the let-7/ROR{gamma}t axis with let-7 acting as a molecular brake in the generation of Tc17 cells and suggests a novel therapeutic approach for tempering the augmented IL-17-mediated response in emphysema.

immunology↗

bioRxiv2022

Lung spatial profiling reveals a T cell signature in COPD patients with fatal SARS-CoV-2 infection

RationalePeople with pre-existing lung diseases like chronic obstructive pulmonary disease (COPD) are more likely to get very sick from SARS-CoV-2 disease 2019 (COVID-19), but an interrogation of the immune response to COVID-19 infection, spatial throughout the lung structure is lacking in patients with COPD. ObjectivesTo profile the immune microenvironment of lung parenchyma, airways, and vessels of never- and ever-smokers with or without COPD, whom all died of COVID-19, using spatial transcriptomic and proteomic profiling. FindingsThe parenchyma, airways, and vessels of COPD patients, compared to control lungs had: 1) significant enrichment for lung resident CD45RO+ memory T cells; 2) downregulation of genes associated with T cell antigen-priming and memory T cell differentiation; 3) higher expression of proteins associated with SARS-CoV-2 entry and major receptor ubiquitously across the ROIs and in particular the lung parenchyma, despite similar SARS-CoV-2 structural gene expression levels. ConclusionsThe lung parenchyma, airways, and vessels of COPD patients have increased T-lymphocytes with a blunted memory T cell response and a more invasive SARS-CoV-2 infection pattern, and may underlie the higher death toll observed with COVID-19.

immunology↗

bioRxiv2020

Paradoxical effects of cigarette smoke and COPD on SARS-CoV2 infection and disease

IntroductionHow cigarette smoke (CS) and chronic obstructive pulmonary disease (COPD) affect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severity is controversial. We investigated the protein and mRNA expression of SARS-CoV-2 entry receptor ACE2 and proteinase TMPRSS2 in lungs from COPD patients and controls, and lung tissue from mice exposed acutely and chronically to CS. Also, we investigated the effects of CS exposure on SARS-CoV-2 infection in human bronchial epithelial cells. MethodsIn Cohort 1, ACE2-positive cells were quantified by immunostaining in FFPE sections from both central and peripheral airways. In Cohort 2, we quantified pulmonary ACE2 protein levels by immunostaining and ELISA, and both ACE2 and TMPRSS2 mRNA levels by RT-qPCR. In C57BL/6 WT mice exposed to air or CS for up to 6 months, pulmonary ACE2 protein levels were quantified by triple immunofluorescence staining and ELISA. The effects of CS exposure on SARS-CoV-2 infection were evaluated after 72hr in vitro infection of Calu-3 cells. After SARS-CoV-2 infection, the cells were fixed for IF staining with dsRNA-specific J2 monoclonal Ab, and cell lysates were harvested for WB of viral nucleocapsid (N) protein. Supernatants (SN) and cytoplasmic lysates were obtained to measure ACE2 levels by ELISA. ResultsIn both human cohorts, ACE2 protein and mRNA levels were decreased in peripheral airways from COPD patients versus both smoker and NS controls, but similar in central airways. TMPRSS2 levels were similar across groups. Mice exposed to CS had decreased ACE2 protein levels in their bronchial and alveolar epithelia versus air-exposed mice exposed to 3 and 6 months of CS. In Calu3 cells in vitro, CS-treatment abrogated infection to levels below the limit of detection. Similar results were seen with WB for viral N protein, showing peak viral protein synthesis at 72hr. ConclusionsACE2 levels were decreased in both bronchial and alveolar epithelial cells from uninfected COPD patients versus controls, and from CS-exposed versus air-exposed mice. CS-pre-treatment did not affect ACE2 levels but potently inhibited SARS-CoV-2 replication in this in vitro model. These findings urge to further investigate the controversial effects of CS and COPD on SARS-CoV2 infection.

immunology↗

bioRxiv2020

NK cells and CTLs are required to clear solid tumor in a novel model of patient-derived-xenograft

Existing patient-derived-xenograft (PDX) mouse models of solid tumors lack a fully tumor-donor matched "syngeneic" and functional immune system. We developed such a model by engrafting lymphopenic recipient mice with a fresh undisrupted piece of solid tumor, whereby tumor-infiltrating lymphocytes (TIL) expanded in the recipient mice for several weeks. Tumors engrafted in about seventy to eighty percent of syngeneic-immune-system-PDX (SIS-PDX) mice, which harbored tumor-exhausted immune-effector and functional immune-regulatory cells persisting for at least six-months post-engraftment. Interleukin-15 (IL-15)-stimulation in addition to immune checkpoint inhibition (ICI), prevented resistance, resulting in complete or partial response to combined treatment. Further, the depletion of Cytotoxic T lymphocytes (CTLs) and/or Natural Killer (NK) cells from combined immunotherapy in SIS-PDX mice revealed that both cell types are required for the maximal response to tumor. Our novel SIS-PDX model provides a valuable resource for powerful mechanistic and therapeutic studies designed to eradicate solid tumors.

immunology↗

bioRxiv2019

A Transcriptome Fingerprinting Assay for Clinical Immune Monitoring

BackgroundWhile our understanding of the role that the immune system plays in health and disease is growing at a rapid pace, available clinical tools to capture this complexity are lagging. We previously described the construction of a third-generation modular transcriptional repertoire derived from genome-wide transcriptional profiling of blood of 985 subjects across 16 diverse immunologic conditions, which comprises 382 distinct modules.\n\nResultsHere we describe the use of this modular repertoire framework for the development of a targeted transcriptome fingerprinting assay (TFA). The first step consisted in down-selection of the number of modules to 32, on the basis of similarities in changes in transcript abundance and functional interpretation. Next down-selection took place at the level of each of the 32 modules, with each one of them being represented by four transcripts in the final 128 gene panel. The assay was implemented on both the Fluidigm high throughput microfluidics PCR platform and the Nanostring platform, with the list of assays target probes being provided for both. Finally, we provide evidence of the versatility of this assay to assess numerous immune functions in vivo by demonstrating applications in the context of disease activity assessment in systemic lupus erythematosus and longitudinal immune monitoring during pregnancy.\n\nConclusionsThis work demonstrates the utility of data-driven network analysis applied to large-scale transcriptional profiling to identify key markers of immune responses, which can be downscaled to a rapid, inexpensive, and highly versatile assay of global immune function applicable to diverse investigations of immunopathogenesis and biomarker discovery.

immunology↗

bioRxiv2019

A Novel Repertoire of Blood Transcriptome Modules Based on Co-expression Patterns Across Sixteen Disease and Physiological States

As the capacity for generating large scale data continues to grow the ability to extract meaningful biological knowledge from it remains a limitation. Here we describe the development of a new fixed repertoire of transcriptional modules. It is meant to serve as a stable reusable framework for the analysis and interpretation of blood transcriptome profiling data. It is supported by customized resources, which include analysis workflows, fingerprint grid plots data visualizations, interactive web applications providing access to a vast number of module-specific functional profiling reports, reference transcriptional profiles and give users the ability to visualize of changes in transcript abundance across the modular repertoire at different granularity levels. A use case focusing on a set of six modules comprising interferon-inducible genes is also provided. Altogether we hope that this resource will also serve as a framework for improving over time our collective understanding of the immunobiology underlying blood transcriptome profiling data.

immunology↗