Immune cell residency in the nasal mucosa may partially explain respiratory disease severity across the age range

AbstractPrevious studies focusing on the age disparity in COVID-19 severity have suggested that younger individuals mount a more robust innate immune response in the nasal mucosa after infection with SARS-CoV-2. However, it is unclear if this reflects increased immune activation or increased immune residence in the nasal mucosa. We hypothesized that immune residency in the nasal mucosa of healthy individuals may differ across the age range. We applied single-cell RNA-sequencing and measured the cellular composition and transcriptional profile of the nasal mucosa in 35 SARS-CoV-2 negative children and adults, ranging in age from 4 months to 65 years. We analyzed in total of ~ 30,000 immune and epithelial cells and found that age and immune cell proportion in the nasal mucosa are inversely correlated, with little evidence for structural changes in the transcriptional state of a given cell type across the age range. Orthogonal validation by epigenome sequencing indicate that it is especially cells of the innate immune system that underlie the age-association. Additionally, we characterize the predominate immune cell type in the nasal mucosa: a resident T cell like population with potent antiviral properties. These results demonstrate fundamental changes in the immune cell makeup of the uninfected nasal mucosa over the lifespan. The resource we generate here is an asset for future studies focusing on respiratory infection and immunization strategies.

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Geographic variation in hemocyte diversity and phagocytic propensity shows a diffuse genomic signature in the green veined white butterfly

10.1101/790782 ◽

2019 ◽

Author(s):

Naomi L.P. Keehnen ◽

Lisa Fors ◽

Peter Järver ◽

Anna-Lena Spetz ◽

Sören Nylin ◽

...

Keyword(s):

Genetic Variation ◽

Immune System ◽

Innate Immune System ◽

Immune Cell ◽

Innate Immune ◽

Glutamine Metabolism ◽

Cell Type ◽

Pieris Napi ◽

Allopatric Populations ◽

Complex Interactions

Insects rely on their innate immune system to successfully mediate complex interactions with their internal microbiota, as well as the microbes present in the environment. Given the variation in microbes across habitats, the challenges to respond to them is likely to result in local adaptation in the immune system. Here we focus upon phagocytosis, a mechanism by which pathogens and foreign particles are engulfed in order to be contained, killed and processed for antigen presentation. We investigated the phenotypic and genetic variation related to phagocytosis, in two allopatric populations of the butterfly Pieris napi. We found that the populations differ in their hemocyte composition, and overall phagocytic capability, driven by the increased phagocytic propensity of each cell type. However, no evidence for divergence in phagocytosis-related genes was observed, though an enrichment of genes involved in glutamine metabolism was found, which have recently been linked to immune cell differentiation in mammals.

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Immune cell residency in the nasal mucosa and COVID-19 severity across the age range

10.1101/2021.02.05.21251067 ◽

2021 ◽

Author(s):

Konner Winkley ◽

Dithi Banerjee ◽

Daniel Louiselle ◽

Rebecca Biswell ◽

Nyshele Posey ◽

...

Keyword(s):

Nasal Mucosa ◽

Immune Cell ◽

Severe Disease ◽

Experimental Studies ◽

Cell Subset ◽

Upper Airway ◽

Influenza B ◽

Respiratory Pathogens ◽

Disease Spectrum ◽

Age Range

SummarySevere coronavirus disease of 2019 (COVID-19) positively correlates with age (Centers for Disease Control), develops after progression of infection from the upper airway to the lower respiratory tract (LRT), and can worsen into acute respiratory distress syndrome (ARDS) (Shi et al., 2020). Why children seem to be less likely to develop severe disease remains unclear. As the nasal mucosa (NM) is the first site of contact and defense for respiratory pathogens such as SARS-CoV-2 before dissemination to the LRT (Casadei and Salinas, 2019), we hypothesized that differences in this tissue across the age range may help explain the disparity in COVID-19 severity. To this end, we profiled NM samples across the lifespan in health and disease. We find that global transcriptomic changes including the expression of SARS-CoV-2 and coronavirus-associated receptors and factors are not correlated with age or the novel virus type, since pediatric NM cells mount similar antiviral response to both SARS-CoV-2 or Influenza B. Rather, we find immune cell residency in NM decreases dramatically with age especially cells of the innate immune system. This includes a resident-memory-like T cell subset with antiviral properties. These observations give plausible biological explanation to the observed clinical differences in disease spectrum and provide a foundation for future experimental studies.

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Faculty Opinions recommendation of TRAIL-R as a negative regulator of innate immune cell responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1022999.265647 ◽

2004 ◽

Author(s):

Stephen Philip Schoenberger

Keyword(s):

Immune Cell ◽

Innate Immune ◽

Innate Immune Cell ◽

Negative Regulator ◽

Cell Responses

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Faculty Opinions recommendation of Innate immune cell networking in hepatitis C virus infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718484653.793497073 ◽

2014 ◽

Author(s):

Philip Rosenthal

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Virus Infection ◽

Immune Cell ◽

Innate Immune ◽

Innate Immune Cell ◽

Hepatitis C Virus Infection

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Cortical structural differences in major depressive disorder correlate with cell type-specific transcriptional signatures

Nature Communications ◽

10.1038/s41467-021-21943-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jiao Li ◽

Jakob Seidlitz ◽

John Suckling ◽

Feiyang Fan ◽

Gong-Jun Ji ◽

...

Keyword(s):

Gene Expression ◽

Major Depressive Disorder ◽

Depressive Disorder ◽

Structural Changes ◽

Brain Regions ◽

Cell Type ◽

Major Depressive ◽

Structural Differences ◽

Neuroimaging Data ◽

Cell Type Specific

AbstractMajor depressive disorder (MDD) has been shown to be associated with structural abnormalities in a variety of spatially diverse brain regions. However, the correlation between brain structural changes in MDD and gene expression is unclear. Here, we examine the link between brain-wide gene expression and morphometric changes in individuals with MDD, using neuroimaging data from two independent cohorts and a publicly available transcriptomic dataset. Morphometric similarity network (MSN) analysis shows replicable cortical structural differences in individuals with MDD compared to control subjects. Using human brain gene expression data, we observe that the expression of MDD-associated genes spatially correlates with MSN differences. Analysis of cell type-specific signature genes suggests that microglia and neuronal specific transcriptional changes account for most of the observed correlation with MDD-specific MSN differences. Collectively, our findings link molecular and structural changes relevant for MDD.

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Immune classification of clear cell renal cell carcinoma

Scientific Reports ◽

10.1038/s41598-021-83767-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sumeyye Su ◽

Shaya Akbarinejad ◽

Leili Shahriyari

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Renal Cell ◽

Cd4 T Cells ◽

Immune Cell ◽

Clear Cell ◽

P Value ◽

Cell Type ◽

Primary Tumors ◽

Immune Cell Type

AbstractSince the outcome of treatments, particularly immunotherapeutic interventions, depends on the tumor immune micro-environment (TIM), several experimental and computational tools such as flow cytometry, immunohistochemistry, and digital cytometry have been developed and utilized to classify TIM variations. In this project, we identify immune pattern of clear cell renal cell carcinomas (ccRCC) by estimating the percentage of each immune cell type in 526 renal tumors using the new powerful technique of digital cytometry. The results, which are in agreement with the results of a large-scale mass cytometry analysis, show that the most frequent immune cell types in ccRCC tumors are CD8+ T-cells, macrophages, and CD4+ T-cells. Saliently, unsupervised clustering of ccRCC primary tumors based on their relative number of immune cells indicates the existence of four distinct groups of ccRCC tumors. Tumors in the first group consist of approximately the same numbers of macrophages and CD8+ T-cells and and a slightly smaller number of CD4+ T cells than CD8+ T cells, while tumors in the second group have a significantly high number of macrophages compared to any other immune cell type (P-value $$<0.01$$ < 0.01 ). The third group of ccRCC tumors have a significantly higher number of CD8+ T-cells than any other immune cell type (P-value $$<0.01$$ < 0.01 ), while tumors in the group 4 have approximately the same numbers of macrophages and CD4+ T-cells and a significantly smaller number of CD8+ T-cells than CD4+ T-cells (P-value $$<0.01$$ < 0.01 ). Moreover, there is a high positive correlation between the expression levels of IFNG and PDCD1 and the percentage of CD8+ T-cells, and higher stage and grade of tumors have a substantially higher percentage of CD8+ T-cells. Furthermore, the primary tumors of patients, who are tumor free at the last time of follow up, have a significantly higher percentage of mast cells (P-value $$<0.01$$ < 0.01 ) compared to the patients with tumors for all groups of tumors except group 3.

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Antibody Conjugation of Fluorescent Nanodiamonds for Targeted Innate Immune Cell Activation

ACS Applied Nano Materials ◽

10.1021/acsanm.1c00256 ◽

2021 ◽

Author(s):

Lorena P. Suarez-Kelly ◽

Steven H. Sun ◽

Casey Ren ◽

Isaac V. Rampersaud ◽

David Albertson ◽

...

Keyword(s):

Cell Activation ◽

Immune Cell ◽

Innate Immune ◽

Innate Immune Cell ◽

Immune Cell Activation ◽

Antibody Conjugation ◽

Fluorescent Nanodiamonds

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Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade

Nature Communications ◽

10.1038/s41467-021-23731-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Sebastian R. Nielsen ◽

Jan E. Strøbech ◽

Edward R. Horton ◽

Rene Jackstadt ◽

Anu Laitala ◽

...

Keyword(s):

Cd8 T Cells ◽

Immune Cell ◽

Immune Checkpoint Blockade ◽

Ductal Adenocarcinoma ◽

Cancer Growth ◽

Cancer Therapies ◽

Cell Type ◽

Clinical Prognosis ◽

Tumor Associated Neutrophils ◽

Poor Clinical Prognosis

AbstractPancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical prognosis. However, despite recent advances in understanding neutrophil biology in cancer, therapies targeting tumor-associated neutrophils are lacking. Here, we demonstrate, using pre-clinical mouse models of PDAC, that lorlatinib attenuates PDAC progression by suppressing neutrophil development and mobilization, and by modulating tumor-promoting neutrophil functions within the TME. When combined, lorlatinib also improves the response to anti-PD-1 blockade resulting in more activated CD8 + T cells in PDAC tumors. In summary, this study identifies an effect of lorlatinib in modulating tumor-associated neutrophils, and demonstrates the potential of lorlatinib to treat PDAC.

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The Transcriptional Regulator CpsY Is Important for Innate Immune Evasion in Streptococcus pyogenes

Infection and Immunity ◽

10.1128/iai.00925-16 ◽

2016 ◽

Vol 85 (3) ◽

Cited By ~ 2

Author(s):

Luis A. Vega ◽

Kayla M. Valdes ◽

Ganesh S. Sundar ◽

Ashton T. Belew ◽

Emrul Islam ◽

...

Keyword(s):

Streptococcus Pyogenes ◽

Immune Evasion ◽

Immune Cell ◽

Group A Streptococcus ◽

Transcriptional Regulator ◽

Innate Immune ◽

Content Type ◽

Human Host

ABSTRACTAs an exclusively human pathogen,Streptococcus pyogenes(the group A streptococcus [GAS]) has specifically adapted to evade host innate immunity and survive in multiple tissue niches, including blood. GAS can overcome the metabolic constraints of the blood environment and expresses various immunomodulatory factors necessary for survival and immune cell resistance. Here we present our investigation of one such factor, the predicted LysR family transcriptional regulator CpsY. The encoding gene,cpsY, was initially identified as being required for GAS survival in a transposon-site hybridization (TraSH) screen in whole human blood. CpsY is homologous with transcriptional regulators ofStreptococcus mutans(MetR),Streptococcus iniae(CpsY), andStreptococcus agalactiae(MtaR) that regulate methionine transport, amino acid metabolism, resistance to neutrophil-mediated killing, and survivalin vivo. Our investigation indicated that CpsY is involved in GAS resistance to innate immune cells of its human host. However, GAS CpsY does not manifest thein vitrophenotypes of its homologs in other streptococcal species. GAS CpsY appears to regulate a small set of genes that is markedly different from the regulons of its homologs. The differential expression of these genes depends on the growth medium, and CpsY modestly influences their expression. The GAS CpsY regulon includes known virulence factors (mntE,speB,spd,nga[spn],prtS[SpyCEP], andsse) and cell surface-associated factors of GAS (emm1,mur1.2,sibA[cdhA], andM5005_Spy0500). Intriguingly, the loss of CpsY in GAS does not result in virulence defects in murine models of infection, suggesting that CpsY function in immune evasion is specific to the human host.

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