Meta-analysis of host transcriptional responses to SARS-CoV-2 infection reveals their manifestation in human tumors

AbstractA deeper understanding of the molecular biology of SARS-CoV-2 infection, including the host response to the virus, is urgently needed. Commonalities exist between the host immune response to viral infections and cancer. Here, we defined transcriptional signatures of SARS-CoV-2 infection involving hundreds of genes common across lung adenocarcinoma cell lines (A549, Calu-3) and normal human bronchial epithelial cells (NHBE), with additional signatures being specific to one or both adenocarcinoma lines. Cross-examining eight transcriptomic databases, we found that host transcriptional responses of lung adenocarcinoma cells to SARS-CoV-2 infection shared broad similarities with host responses to multiple viruses across different model systems and patient samples. Furthermore, these SARS-CoV-2 transcriptional signatures were manifested within specific subsets of human cancer, involving ~ 20% of cases across a wide range of histopathological types. These cancer subsets show immune cell infiltration and inflammation and involve pathways linked to the SARS-CoV-2 response, such as immune checkpoint, IL-6, type II interferon signaling, and NF-κB. The cell line data represented immune responses activated specifically within the cancer cells of the tumor. Common genes and pathways implicated as part of the viral host response point to therapeutic strategies that may apply to both SARS-CoV-2 and cancer.

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Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1613601113 ◽

2016 ◽

Vol 113 (42) ◽

pp. E6409-E6417 ◽

Cited By ~ 80

Author(s):

David G. McFadden ◽

Katerina Politi ◽

Arjun Bhutkar ◽

Frances K. Chen ◽

Xiaoling Song ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Mouse Models ◽

Cancer Progression ◽

Large Scale ◽

Human Cancer ◽

Genetically Engineered ◽

Model Systems ◽

Driver Mutations ◽

Genetic Profile ◽

Genetically Engineered Mouse Models

Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

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A functional spleen contributes to afucosylated IgG in humans

Scientific Reports ◽

10.1038/s41598-021-03196-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Iwona Wojcik ◽

David E. Schmidt ◽

Lisa A. de Neef ◽

Minke A. E. Rab ◽

Bob Meek ◽

...

Keyword(s):

Immune Responses ◽

Viral Infections ◽

Immune Cell ◽

Lymphoid Organ ◽

Immune Effector ◽

Adaptive Immune ◽

Wide Range ◽

Humoral Responses ◽

First Time

AbstractAs a lymphoid organ, the spleen hosts a wide range of immune cell populations, which not only remove blood-borne antigens, but also generate and regulate antigen-specific immune responses. In particular, the splenic microenvironment has been demonstrated to play a prominent role in adaptive immune responses to enveloped viral infections and alloantigens. During both types of immunizations, antigen-specific immunoglobulins G (IgGs) have been characterized by the reduced amount of fucose present on N-linked glycans of the fragment crystallizable (Fc) region. These glycans are essential for mediating the induction of immune effector functions. Therefore, we hypothesized that a spleen may modulate humoral responses and serve as a preferential site for afucosylated IgG responses, which potentially play a role in immune thrombocytopenia (ITP) pathogenesis. To determine the role of the spleen in IgG-Fc glycosylation, we performed IgG subclass-specific liquid chromatography–mass spectrometry (LC–MS) analysis of Fc glycosylation in a large cohort of individuals splenectomized due to trauma, due to ITP, or spherocytosis. IgG-Fc fucosylation was consistently increased after splenectomy, while no effects for IgG-Fc galactosylation and sialylation were observed. An increase in IgG1- and IgG2/3-Fc fucosylation level upon splenectomy has been reported here for the first time, suggesting that immune responses occurring in the spleen may be particularly prone to generate afucosylated IgG responses. Surprisingly, the level of total IgG-Fc fucosylation was decreased in ITP patients compared to healthy controls. Overall, our results suggest a yet unrecognized role of the spleen in either the induction or maintenance of afucosylated IgG responses by B cells.

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SNX20AR/MiRNA-301a-3p/SNX20 Axis Associated With Cell Proliferation and Immune Infiltration in Lung Adenocarcinoma

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.744363 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yixiao Yuan ◽

Xiulin Jiang ◽

Lin Tang ◽

Juan Wang ◽

Qianqian Liu ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Lung Adenocarcinoma ◽

Cancer Progression ◽

Immune Cell ◽

Human Cancer ◽

Dna Hypermethylation ◽

Over Expression ◽

Immune Infiltration ◽

And Migration

Lung cancer is the most common tumor with severe morbidity and high mortality. Increasing evidence has demonstrated that SNX20 plays crucial roles in the progression of human cancer. However, the functions and mechanism of SNX20 in LUAD are still barely known. Here, we employ the TCGA, GEO and CCLE databases to examine the expression of SNX20 in human varies cancer, the results shown that SNX20 is down-regulated in lung Adenocarcinoma, SNX20 level was significantly positive correlated with poor prognosis and lung cancer immune cell infiltration. We found that over-expression of SNX20 significantly restrain NSCLC cell proliferation and migration. Subsequently, we discover a network regulating SNX20 in LUAD, further study found that the decreased of the SNX20 likely caused by DNA hypermethylation. Furthermore, we identified that SNX20AR/miRNA-301a-3p mediated decreased of SNX20 correlated with lung cancer progression and cancer immune infiltration in LUAD. Our findings suggested that ncRNAs play a crucial role in the regulatory network of SNX20. Collectively, our findings demonstrate the suppressor roles of the SNX20AR/miRNA-301a-3p/SNX20 axis in Lung Adenocarcinoma, represent that SNX20 have the potential of as an effective therapeutic target in future.

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Simple and effective bacterial-based intratumoral cancer immunotherapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002688 ◽

2021 ◽

Vol 9 (9) ◽

pp. e002688

Author(s):

Christina S E Carroll ◽

Erin R Andrew ◽

Laeeq Malik ◽

Kathryn F Elliott ◽

Moira Brennan ◽

...

Keyword(s):

Immune System ◽

Tumor Growth ◽

Cancer Immunotherapy ◽

Cancer Patients ◽

Immune Cell ◽

Human Cancer ◽

Intratumoral Injection ◽

Ct Scans ◽

Antitumor Effects ◽

Wide Range

BackgroundWe describe intratumoral injection of a slow-release emulsion of killed mycobacteria (complete Freund’s adjuvant (CFA)) in three preclinical species and in human cancer patients.MethodsEfficacy and safety were tested in mammary tumors in mice, in mastocytomas in mice and dogs, and in equine melanomas. In mice, survival, tumor growth, and tumor infiltration by six immune cell subsets (by flow cytometry) were investigated and analyzed using Cox proportional hazards, a random slopes model, and a full factorial model, respectively. Tumor growth and histology were investigated in dogs and horses, as well as survival and tumor immunohistochemistry in dogs. Tumor biopsies were taken from human cancer patients on day 5 (all patients) and day 28 (some patients) of treatment and analyzed by histology. CT scans are provided from one patient.ResultsSignificantly extended survival was observed in mouse P815 and 4T1 tumor models. Complete tumor regressions were observed in all three non-human species (6/186 (3%) of mouse mastocytomas; 3/14 (21%) of canine mastocytomas and 2/11 (18%) of equine melanomas). Evidence of systemic immune responses (regression of non-injected metastases) was also observed. Analysis of immune cells infiltrating mastocytoma tumors in mice showed that early neutrophil infiltration was predictive of treatment benefit. Analysis of the site of mastocytoma regression in dogs weeks or months after treatment demonstrated increased B and T cell infiltrates. Thus, activation of the innate immune system alone may be sufficient for regression of some injected tumors, followed by activation of the acquired immune system which can mediate regression of non-injected metastases. Finally, we report on the use of CFA in 12 human cancer patients. Treatment was well tolerated. CT scans showing tumor regression in a patient with late-stage renal cancer are provided.ConclusionOur data demonstrate that intratumoral injection of CFA has major antitumor effects in a proportion of treated animals and is safe for use in human cancer patients. Further trials in human cancer patients are therefore warranted. Our novel treatment provides a simple and inexpensive cancer immunotherapy, immediately applicable to a wide range of solid tumors, and is suitable to patients in developing countries and advanced care settings.

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COVID-19 associated central nervous system manifestations, mental and neurological symptoms: a systematic review and meta-analysis

Reviews in the Neurosciences ◽

10.1515/revneuro-2020-0108 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Saber Soltani ◽

Alireza Tabibzadeh ◽

Armin Zakeri ◽

Amir Mohammad Zakeri ◽

Tayebeh Latifi ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Viral Infections ◽

Psychological Symptoms ◽

Meta Analysis ◽

Olfactory Dysfunction ◽

Neurological Symptoms ◽

Online Databases ◽

Pooled Prevalence ◽

Wide Range

Abstract The ongoing pandemic of Coronavirus disease 2019 (COVID-19) has infected more than 27 million confirmed cases and 8,90,000 deaths all around the world. Verity of viral infections can infect the nervous system; these viral infections can present a wide range of manifestation. The aim of the current study was to systematically review the COVID-19 associated central nervous system manifestations, mental and neurological symptoms. For that we conducted a comprehensive systematic literature review of four online databases, including Web of Science, PubMed, Scopus and Embase. All relevant articles that reported psychiatric/psychological symptoms or disorders in COVID-19 without considering time and language restrictions were assessed. All the study procedures were performed based on the PRISMA criteria. Due to the screening, 14 studies were included. The current study result indicated that, the pooled prevalence of CNS or mental associated disorders with 95% CI was 50.68% (6.68–93.88). The most prevalence symptoms were hyposmia/anosmia/olfactory dysfunction (number of study: 10) with 36.20% (14.99–60.51). Only one study reported numbness/paresthesia and dysphonia. Pooled prevalence of numbness/paresthesia and dysphonia was 5.83% (2.17–12.25) and 2.39% (10.75–14.22). The pooled prevalence of depression and anxiety was 3.52% (2.62–4.54) and 13.92% (9.44–19.08). Our findings demonstrate that COVID-19 has a certain relation with neurological symptoms. The hypsomia, anosmia or olfactory dysfunction was most frequent symptom. Other symptoms were headache or dizziness, dysgeusia or ageusia, dysphonia and fatigue. Depression, anxiety, and confusion were less frequent symptoms.

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Monocytic THP-1 Cells Diverge Significantly From Their Native Counterparts: A Comparative Examination of The Chromosomal Conformations And Transcriptomes

10.21203/rs.3.rs-483700/v1 ◽

2021 ◽

Author(s):

Yulong Liu ◽

Hua Li ◽

Daniel M Czajkowsky ◽

Zhifeng Shao

Keyword(s):

Cell Lines ◽

Chromatin Structure ◽

Immune Cell ◽

Leukemia Cell ◽

Model Systems ◽

Leukemia Cell Line ◽

Primary Cells ◽

Monocytic Leukemia ◽

Altered Expression ◽

Wide Range

Abstract Immortalized cell lines have long been used as model systems to systematically investigate biological processes under controlled and reproducible conditions, providing insights that have greatly advanced cellular biology and medical sciences. Recently, the widely used monocytic leukemia cell line, THP-1, was comprehensively examined to understand mechanistic relationships between the 3D chromatin structure and transcription during the trans-differentiation of monocytes to macrophages. To corroborate these observations in primary cells, we analyze in situ Hi-C and RNA-seq data of human primary monocytes and their differentiated macrophages in comparison to that obtained from the monocytic/macrophagic THP-1 cells. Surprisingly, we find significant differences between the primary cells and the THP-1 cells at all levels of chromatin structure, from loops to topologically associated domains to compartments. Importantly, the compartment-level differences correlate significantly with transcription: those genes that are in A-compartments in the primary cells but are in B-compartments in the THP-1 cells exhibit a higher level of expression in the primary cells than in the THP-1 cells, and vice versa. Overall, the genes in these different compartments are enriched for a wide range of pathways, and, at least in the case of the monocytic cells, their altered expression in certain pathways in the THP-1 cells argues for a less immune cell-like phenotype, suggesting that immortalization or prolonged culturing of THP-1 caused a divergence of these cells from their native counterparts. It is thus essential to reexamine phenotypic details observed in cell lines with their native counterparts so as to ensure a proper understanding of functional cell states in vivo.

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Effects of Citrus Fruit Juices and Their Bioactive Components on Inflammation and Immunity: A Narrative Review

Frontiers in Immunology ◽

10.3389/fimmu.2021.712608 ◽

2021 ◽

Vol 12 ◽

Author(s):

Elizabeth A. Miles ◽

Philip C. Calder

Keyword(s):

Oxidative Stress ◽

Immune System ◽

Vitamin C ◽

Orange Juice ◽

Immune Cell ◽

Meta Analysis ◽

Citrus Fruit ◽

Fruit Juices ◽

Model Systems ◽

Markers Of Inflammation

The immune system provides defence to the host against pathogenic organisms. A weak immune system increases susceptibility to infections and allows infections to become more severe. One component of the immune response is inflammation. Where inflammation is excessive or uncontrolled it can damage host tissues and cause pathology. Limitation of oxidative stress is one means of controlling inflammation. Citrus fruit juices are a particularly good source of vitamin C and folate, which both have roles in sustaining the integrity of immunological barriers and in supporting the function of many types of immune cell including phagocytes, natural killer cells, T-cells and B-cells. Vitamin C is an antioxidant and reduces aspects of the inflammatory response. Important bioactive polyphenols in citrus fruit juices include hesperidin, narirutin and naringin. Hesperidin is a glycoside of hesperetin while narirutin and naringin are glycosides of naringenin. Hesperidin, hesperetin, naringenin, naringin and narirutin have all been found to have anti-inflammatory effects in model systems, and human trials of hesperidin report reductions in inflammatory markers. In humans, orange juice was shown to limit the post-prandial inflammation induced by a high fat-high carbohydrate meal. Consuming orange juice daily for a period of weeks has been reported to reduce markers of inflammation, including C-reactive protein, as confirmed through a recent meta-analysis. A newly emerging topic is whether polyphenols from orange juice have direct anti-viral effects. In summary, micronutrients and other bioactives present in citrus fruit juices have established roles in controlling oxidative stress and inflammation and in supporting innate and acquired immune responses. Trials in humans demonstrate that orange juice reduces inflammation; its effects on innate and acquired immunity require further exploration in well-designed trials in appropriate population sub-groups such as older people.

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Biomarkers of inflammation and the etiology of sepsis

Biochemical Society Transactions ◽

10.1042/bst20190029 ◽

2020 ◽

Vol 48 (1) ◽

pp. 1-14 ◽

Cited By ~ 5

Author(s):

Inge Grondman ◽

Andrei Pirvu ◽

Anca Riza ◽

Mihai Ioana ◽

Mihai G. Netea

Keyword(s):

Host Response ◽

Viral Infections ◽

Immune Cell ◽

Inflammatory Responses ◽

Treatment Options ◽

Specific Treatment ◽

Adverse Outcomes ◽

Preclinical Research ◽

Related Factors ◽

Life Threatening

Sepsis is characterized as a life-threatening organ dysfunction syndrome that is caused by a dysregulated host response to infection. The main etiological causes of sepsis are bacterial, fungal, and viral infections. Last decades clinical and preclinical research contributed to a better understanding of pathophysiology of sepsis. The dysregulated host response in sepsis is complex, with both pathogen-related factors contributing to disease, as well as immune-cell mediated inflammatory responses that can lead to adverse outcomes in early or advanced stages of disease. Due to its heterogenous nature, clinical diagnosis remains challenging and sepsis-specific treatment options are still lacking. Classification and early identification of patient subgroups may aid clinical decisions and improve outcome in sepsis patients. The initial clinical presentation is rather similar in sepsis of different etiologies, however, inflammatory profiles may be able to distinguish between different etiologies of infections. In this review, we summarize the role and the discriminating potency of host-derived inflammatory biomarkers in the context of the main etiological types of sepsis.

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The mutational landscape of EGFR-, MYC-, and Kras- driven genetically-engineered mouse models of lung adenocarcinoma

10.1101/048058 ◽

2016 ◽

Cited By ~ 1

Author(s):

David G. McFadden ◽

Katerina Politi ◽

Arjun Bhutkar ◽

Frances K. Chen ◽

Xiaoling Song ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Mouse Models ◽

Human Cancer ◽

Genetically Engineered ◽

Model Systems ◽

Driver Mutations ◽

Genetic Profile ◽

Genetically Engineered Mouse Models ◽

Synonymous Mutations ◽

Mutant Egfr

Genetically-engineered mouse models (GEMMs) of cancer are increasingly being utilized to assess putative driver mutations identified by large scale sequencing of human cancer genomes. In order to accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant EGFR, mutant Kras or by overexpression of MYC. Tumors from EGFR- and Kras- driven models exhibited respectively 0.02 and 0.07 non-synonymous mutations/megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras- driven models both exhibited recurrent whole chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared to human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

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Functional consequences of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals

10.1101/170712 ◽

2017 ◽

Cited By ~ 2

Author(s):

Jonathan R. I. Coleman ◽

Julien Bryois ◽

Héléna A. Gaspar ◽

Philip R. Jansen ◽

Jeanne Savage ◽

...

Keyword(s):

Pyramidal Neurons ◽

Association Studies ◽

Meta Analysis ◽

Neuronal Cell ◽

Cell Types ◽

Model Systems ◽

Genome Wide Association Studies ◽

Ca1 Region ◽

Wide Range ◽

Neural Underpinnings

AbstractVariance in IQ is associated with a wide range of health outcomes, and 1% of the population are affected by intellectual disability. Despite a century of research, the fundamental neural underpinnings of intelligence remain unclear. We integrate results from genome-wide association studies (GWAS) of intelligence with brain tissue and single cell gene expression data to identify tissues and cell types associated with intelligence. GWAS data for IQ (N = 78,308) were meta-analyzed with an extreme-trait cohort of 1,247 individuals with mean IQ ∼170 and 8,185 controls. Genes associated with intelligence implicate pyramidal neurons of the somatosensory cortex and CA1 region of the hippocampus, and midbrain embryonic GABAergic neurons. Tissue-specific analyses find the most significant enrichment for frontal cortex brain expressed genes. These results suggest specific neuronal cell types and genes may be involved in intelligence and provide new hypotheses for neuroscience experiments using model systems.

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