scholarly journals 521. Similarities and Differences in Transcriptomic Host Response between SARS-CoV-2 and Other Viral Infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S326-S327
Author(s):  
Simone A Thair ◽  
Yudong He ◽  
Yehudit Hasin-Brumshtein ◽  
Suraj Sakaram ◽  
Rushika R Pandya ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Nk Cells ◽  
Pathway Analysis ◽  
Host Response ◽  
Viral Infections ◽  
Cell Types ◽  
Gene Signature ◽  
Gene Signatures ◽  
Similarities And Differences

Abstract Background COVID-19 is a pandemic caused by the SARS-CoV-2 virus that shares and differs in clinical characteristics of known viral infections. Methods We obtained RNAseq profiles of 62 prospectively enrolled COVID-19 patients and 24 healthy controls (HC). We collected 23 independent studies profiling 1,855 blood samples from patients covering six viruses (influenza, RSV, HRV, Ebola, Dengue and SARS-CoV-1). We studied host whole-blood transcriptomic responses in COVID-19 compared to non-COVID-19 viral infections to understand similarities and differences in host response. Gene signature threshold was absolute effect size ≥1, FDR ≤ 0.05%. Results Differential gene expression of COVID-19 vs HC are highly correlated with non-COVID-19 vs HC (r=0.74, p< 0.001). We discovered two gene signatures: COVID-19 vs HC (2002 genes) (COVIDsig) and non-COVID-19 vs HC (635 genes) (nonCOVIDsig). Pathway analysis of over-expressed signature genes in COVIDsig or nonCOVIDsig identified similar pathways including neutrophil activation, innate immune response, immune response to viral infection and cytokine production. Conversely, for under-expressed genes, pathways indicated repression of lymphocyte differentiation and activation (Fig1). Intersecting the two gene signatures found two genes significantly oppositely regulated (ACO1, ATL3). We derived a third gene signature using COCONUT to compare COVID-19 to non-COVID-19 viral infections (416 genes) (Fig2). Pathway analysis did not result in significant enrichment, suggesting identification of novel biology (Fig1). Statistical deconvolution of bulk transcriptomic data found M1 macrophages, plasmacytoid dendritic cells, CD14+ monocytes, CD4+ T cells and total B cells changed in the same direction across COVID-19 and non-COVID-19 infections. Cell types that increased in COVID-19 relative to non-COVID-19 were CD56bright NK cells, M2 macrophages and total NK cells. Those that decreased in non-COVID-19 relative to COVID-19 were CD56dim NK cells & memory B cells and eosinophils (Fig3). Figure 1 Figure 2 Figure 3 Conclusion The concordant and discordant responses mapped here provide a window to explore the pathophysiology of COVID-19 vs other viral infections and show clear differences in signaling pathways and cellularity as part of the host response to SARS-CoV-2. Disclosures Simone A. Thair, PhD, Inflammatix, Inc. (Employee, Shareholder) Yudong He, PhD, Inflammatix Inc. (Employee) Yehudit Hasin-Brumshtein, PhD, Inflammatix (Employee, Shareholder) Suraj Sakaram, MS in Biochemistry and Molecular Biology, Inflammatix (Employee, Other Financial or Material Support, stock options) Rushika R. Pandya, MS, Inflammatix Inc. (Employee, Shareholder) David C. Rawling, PhD, Inflammatix Inc. (Employee, Shareholder) Purvesh Khatri, PhD, Inflammatix Inc. (Shareholder) Timothy Sweeney, MD, PHD, Inflammatix, Inc. (Employee, Shareholder)

scholarly journals Transcriptomic Similarities and Differences in Host Response between SARS-CoV-2 and Other Viral Infections

2020 ◽  
Author(s):  
Simone A. Thair ◽  
Yudong D. He ◽  
Yehudit Hasin-Brumshtein ◽  
Suraj Sakaram ◽  
Rushika Pandya ◽  
...  
Keyword(s):  
Immune Response ◽  
Nk Cells ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Host Response ◽  
Cell Activation ◽  
Viral Infections ◽  
Healthy Controls ◽  
Similarities And Differences ◽  
Highly Correlated

AbstractCOVID-19 is a pandemic that shares certain clinical characteristics with other acute viral infections. Here, we studied the whole-blood transcriptomic host response to SARS-CoV-2 and compared it with other viral infections to understand similarities and differences in host response. Using RNAseq we profiled peripheral blood from 24 healthy controls and 62 prospectively enrolled patients with community-acquired lower respiratory tract infection by SARS-Cov-2 within the first 24 hours of hospital admission. We also compiled and curated 23 independent studies that profiled 1,855 blood samples from patients with one of six viruses (influenza, RSV, HRV, ebola, Dengue, and SARS-CoV-1). We show gene expression changes in peripheral blood in patients with COVID-19 versus healthy controls are highly correlated with changes in response to other viral infections (r=0.74, p<0.001). However, two genes, ACO1 and ATL3, show significantly opposite changes between conditions. Pathway analysis in patients with COVID-19 or other viral infections versus healthy controls identified similar pathways including neutrophil activation, innate immune response, immune response to viral infection, and cytokine production for over-expressed genes. Conversely, for under-expressed genes, pathways indicated repression of lymphocyte differentiation and T cell activation. When comparing transcriptome profiles of patients with COVID-19 directly with those with other viral infections, we found 114 and 302 genes were over- or under-expressed, respectively, during COVID-19. Pathways analysis did not identify any significant pathways in these genes, suggesting novel responses to further study. Statistical deconvolution using immunoStates found that M1 macrophages, plasmacytoid dendritic cells, CD14+ monocytes, CD4+ T cells, and total B cells showed change consistently in the same direction across all viral infections including COVID-19. Those that increased in COVID-19 but decreased in non-COVID-19 viral infections were CD56bright NK cells, M2 macrophages, and total NK cells. The concordant and discordant responses mapped out here provide a window to explore the pathophysiology of COVID-19 versus other viral infections and show clear differences in signaling pathways and cellularity as part of the host response to SARS-CoV-2.

scholarly journals Kawasaki Disease Patient Stratification and Pathway Analysis Based on Host Transcriptomic and Proteomic Profiles

2021 ◽  
Vol 22 (11) ◽  
pp. 5655
Author(s):  
Heather Jackson ◽  
Stephanie Menikou ◽  
Shea Hamilton ◽  
Andrew McArdle ◽  
Chisato Shimizu ◽  
...  
Keyword(s):  
Kawasaki Disease ◽  
Pathway Analysis ◽  
Host Response ◽  
Viral Infections ◽  
Disease Patient ◽  
Inflammatory Disorder ◽  
Comprehensive Picture ◽  
Clustering And Classification ◽  
Infection And Inflammation ◽  
Proteomic Responses

The aetiology of Kawasaki disease (KD), an acute inflammatory disorder of childhood, remains unknown despite various triggers of KD having been proposed. Host ‘omic profiles offer insights into the host response to infection and inflammation, with the interrogation of multiple ‘omic levels in parallel providing a more comprehensive picture. We used differential abundance analysis, pathway analysis, clustering, and classification techniques to explore whether the host response in KD is more similar to the response to bacterial or viral infections at the transcriptomic and proteomic levels through comparison of ‘omic profiles from children with KD to those with bacterial and viral infections. Pathways activated in patients with KD included those involved in anti-viral and anti-bacterial responses. Unsupervised clustering showed that the majority of KD patients clustered with bacterial patients on both ‘omic levels, whilst application of diagnostic signatures specific for bacterial and viral infections revealed that many transcriptomic KD samples had low probabilities of having bacterial or viral infections, suggesting that KD may be triggered by a different process not typical of either common bacterial or viral infections. Clustering based on the transcriptomic and proteomic responses during KD revealed three clusters of KD patients on both ‘omic levels, suggesting heterogeneity within the inflammatory response during KD. The observed heterogeneity may reflect differences in the host response to a common trigger, or variation dependent on different triggers of the condition.

scholarly journals Phenotype of recovering lymphoid cell populations after marrow transplantation.

1985 ◽  
Vol 161 (6) ◽  
pp. 1483-1502 ◽  
Author(s):  
K A Ault ◽  
J H Antin ◽  
D Ginsburg ◽  
S H Orkin ◽  
J M Rappeport ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Nk Cells ◽  
Cell Types ◽  
Lymphoid Cells ◽  
The Other ◽  
Hla Dr ◽  
T Cell Antigens ◽  
Leu 7

Four patients who received bone marrow transplants were studied sequentially during the posttransplant period to define the pattern of recovering lymphoid cell types. Three patients received T cell-depleted, HLA-matched marrow, and one received untreated marrow from an identical twin. Blood lymphoid cells were labeled with 25 different pairs of monoclonal antibodies. In each sample, one antibody was conjugated to fluorescein and one to phycoerythrin, thus allowing simultaneous assessment of the expression of the two markers using the fluorescence activated cell sorter. A total of 14 antibodies were used, routinely including HLE, Leu-M3, Leu-4, Leu-1, Leu-5, Leu-9, Leu-6, Leu-2, Leu-3, HLA-DR, Leu-7, Leu-11, Leu-15, and Leu-12. Other antibodies were used to further define some populations. This study has allowed us to define six distinct cell types that have appeared in all four patients by day 90 posttransplantation, and which account for 90-100% of all circulating lymphoid cells. These cell types are (a) T helper cells expressing Leu-1, Leu-4, Leu-9, Leu-5, Leu-3, and variable amounts of HLA-DR; (b) T suppressor cells expressing Leu-1, Leu-4, Leu-9, Leu-5, Leu-2, and variable amounts of HLA-DR; (c) B cells expressing Leu-12, B1, HLA-DR, IgD, and IgM, but none of the T cell antigens; (d) an unusual B cell phenotype (Leu-1 B) expressing all of the B cell markers, and also having low amounts of Leu-1, but none of the other T cell antigens; (e) natural killer (NK) cells expressing Leu-11, Leu-15, Leu-5 but none of the other T cell or B cell markers; (f) NK cells expressing Leu-11, Leu-15, Leu-5, and low levels of Leu-2. Both NK types also express Leu-7 on some, but not all cells. The relative frequencies of these cell types varied among the patients and with time, but the striking findings were the presence of relatively few mature T cells, large numbers of NK cells, and the preponderance of the unusual Leu-1 B cell over conventional B cells in all three patients who developed B cells. Sorting experiments confirmed the NK activity of the major NK cell phenotypes, and DNA analysis confirmed that all of the cells studied were of donor origin. In addition, analysis of Ig genes in one patient showed that the Leu-1 B cells were not clonally rearranged.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals CD69 Deficiency Enhances the Host Response to Vaccinia Virus Infection through Altered NK Cell Homeostasis

2016 ◽  
Vol 90 (14) ◽  
pp. 6464-6474 ◽  
Author(s):  
Laura Notario ◽  
Elisenda Alari-Pahissa ◽  
Antonio de Molina ◽  
Pilar Lauzurica
Keyword(s):  
Immune Response ◽  
Infection Control ◽  
Vaccinia Virus ◽  
Nk Cells ◽  
Natural Killer ◽  
Host Response ◽  
Nk Cell ◽  
Innate Immune ◽  
Cell Numbers

ABSTRACTDuring the host response to viral infection, the transmembrane CD69 protein is highly upregulated in all immune cells. We have studied the role of CD69 in the murine immune response to vaccinia virus (VACV) infection, and we report that the absence of CD69 enhances protection against VACV at both short and long times postinfection in immunocompetent and immunodeficient mice. Natural killer (NK) cells were implicated in the increased infection control, since the differences were greatly diminished when NK cells were depleted. This role of NK cells was not based on an altered NK cell reactivity, since CD69 did not affect the NK cell activation threshold in response to major histocompatibility complex class I NK cell targets or protein kinase C activation. Instead, NK cell numbers were increased in the spleen and peritoneum of CD69-deficient infected mice. That was not just secondary to better infection control in CD69-deficient mice, since NK cell numbers in the spleens and the blood of uninfected CD69−/−mice were already augmented. CD69-deficient NK cells from infected mice did not have an altered proliferation capacity. However, a lower spontaneous cell death rate was observed for CD69−/−lymphocytes. Thus, our results suggest that CD69 limits the innate immune response to VACV infection at least in part through cell homeostatic survival.IMPORTANCEWe show that increased natural killer (NK) cell numbers augment the host response and survival after infection with vaccinia virus. This phenotype is found in the absence of CD69 in immunocompetent and immunodeficient hosts. As part of the innate immune system, NK lymphocytes are activated and participate in the defense against infection. Several studies have focused on the contribution of NK cells to protection against infection with vaccinia virus. In this study, it was demonstrated that the augmented early NK cell response in the absence of CD69 is responsible for the increased protection seen during infection with vaccinia virus even at late times of infection. This work indicates that the CD69 molecule may be a target of therapy to augment the response to poxvirus infection.

scholarly journals A crucial role for Jagunal homolog 1 in humoral immunity and antibody glycosylation in mice and humans

2020 ◽  
Vol 218 (1) ◽  
Author(s):  
Astrid Hagelkruys ◽  
Gerald Wirnsberger ◽  
Johannes Stadlmann ◽  
Miriam Wöhner ◽  
Marion Horrer ◽  
...  
Keyword(s):  
Immune Response ◽  
Endoplasmic Reticulum ◽  
B Cells ◽  
Er Stress ◽  
Rare Disease ◽  
Humoral Immunity ◽  
Viral Infections ◽  
Loss Of Function ◽  
Humoral Immune ◽  
Specific Antigens

Jagunal homolog 1 (JAGN1) has been identified as a critical regulator of neutrophil biology in mutant mice and rare-disease patients carrying JAGN1 mutations. Here, we report that Jagn1 deficiency results in alterations in the endoplasmic reticulum (ER) of antibody-producing cells as well as decreased antibody production and secretion. Consequently, mice lacking Jagn1 in B cells exhibit reduced serum immunoglobulin (Ig) levels at steady state and fail to mount an efficient humoral immune response upon immunization with specific antigens or when challenged with viral infections. We also demonstrate that Jagn1 deficiency in B cells results in aberrant IgG N-glycosylation leading to enhanced Fc receptor binding. Jagn1 deficiency in particular affects fucosylation of IgG subtypes in mice as well as rare-disease patients with loss-of-function mutations in JAGN1. Moreover, we show that ER stress affects antibody glycosylation. Our data uncover a novel and key role for JAGN1 and ER stress in antibody glycosylation and humoral immunity in mice and humans.

Simultaneous Monitoring of Drug Responses on Distinct Hematopoietic Cell Populations Allow Assessment of Direct and Indirect Cytotoxic Effects of Targeted Therapies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3515-3515
Author(s):  
Muntasir M Majumder ◽  
Aino Maija Leppä ◽  
Caroline A Heckman
Keyword(s):  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
Research Funding ◽  
Plasma Cells ◽  
Cell Types ◽  
Cell Populations ◽  
Specific Cell ◽  
Drug Responses ◽  
Nk T Cells

Abstract Introduction Off-target cytotoxicity resulting in severe side effects and compromising patient survival often hampers the development of new cancer therapeutics. Understanding the complete drug response landscape of different cell populations is crucial to identify drugs that selectively eradicate the malignant cell population, but spare healthy cells. Here, we developed a high content, no wash, multi-parametric flow cytometry based assay that enables testing of blood cancer patient samples and simultaneously monitors the effects of several drugs on 11 hematopoietic cell types. The assay can be used to i) dissect malignant from healthy cell responses and predict off-target effects; ii) assess drug effects on immune cell subsets; iii) identify drugs that can potentially be repositioned to new blood cancer indications. Methods Mononuclear cells were prepared from bone marrow aspirates of 7 multiple myeloma (MM) and 3 acute myeloid leukemia (AML) patients plus the peripheral blood from a healthy donor, which were collected following informed consent and in compliance with the Declaration of Helsinki. Optimal cell density, antibody dilutions, incubation time, and wash versus no wash assay conditions for the selected antibody panels were determined. Cells were incubated at a density of 2 million cells/ml in either 96- or 384-well plates for 3 days. The antibodies were tested in two panels to study the effects of 6 drugs in 5 dilutions (1-10000 nM) (clofarabine, bortezomib, dexamethasone, navitoclax, venetoclax and omipalisib) on 11 cell populations, namely hematopoietic stem cells (HSCs) (CD34+CD38-), common progenitor cells (CPCs) (CD34+CD38+), monocytes (CD14+), B cells (CD45+CD19+), cytotoxic T cells (CD45+CD3+CD8+), T helper cells (CD45+CD3+CD4+), NK-T cells (CD45+CD3+CD56+), NK cells (CD45+CD56+CD3-), clonal plasma cells (CD138+CD38+), other plasma cells (CD138+CD38-) and granulocytes (CD45+, SSC++). Annexin-V and 7AAD were used to distinguish live cell populations from apoptotic and dead cells. After 1 h incubation with antibodies, the plates were read with the iQue Screener PLUS instrument (Intellicyt). Counts for each population were used to generate four parameter nonlinear regression fitted dose response curves with GraphPad Prism 7. Three samples were tested in duplicate to assess reproducibility. Results To decrease the complexity of the assay, we tested all antibodies under wash and no wash conditions, and found that results from both conditions were comparable. To minimize the amount of sample needed as well as maximize the number of drugs tested and cell populations that can be detected, we set up the assay in both 96- and 384-well plates. The assay was highly reproducible when samples were tested in replicate and was scalable to a 384-well format without compromising sensitivity to detect rare populations such as plasma cells. Due to the differentiation of immature cells to specialized cell types, the drug responses of specific populations tended to drift. HSCs (CD34+CD38-) were shown to be refractory to the tested drugs compared to CPCs characterized as (CD34+CD38+) and other cell types. Interestingly, the proteasome inhibitor bortezomib was cytotoxic to all cell populations except for CD138+CD38- plasma cells. Clofarabine, a nucleoside analog used to treat ALL, effectively targeted CPC, NK and B cells, while HSCs and plasma cells were resistant. The glucocorticoid and immunosuppressive drug dexamethasone specifically targeted B and NK cells compared to T cell populations (CD8+, CD4+), while NK-T cells were modestly sensitive. The cell population response patterns were similar in samples derived from MM, AML and healthy individuals, highlighting that the drug responses are highly cell type specific. Summary Using a high content, multi-parametric assay, we could rapidly assess the effect of several drugs on specific cell populations in individual patient samples. Our results demonstrate that many drugs preferentially affect different hematological cell lineages. Although heterogeneity was observed between individual patients, the pattern of cytotoxic response exhibited by specific cell types was consistent among samples derived from MM, AML and healthy donors. The assay will be useful to identify drugs with maximal on-target and minimal off-target specificity, and can potentially be used to guide treatment decision and predict patient response Disclosures Heckman: Celgene: Research Funding; Pfizer: Research Funding.

scholarly journals Initiation of autoimmunity to the p53 tumor suppressor protein by complexes of p53 and SV40 large T antigen.

1994 ◽  
Vol 179 (4) ◽  
pp. 1243-1252 ◽  
Author(s):  
X Dong ◽  
K J Hamilton ◽  
M Satoh ◽  
J Wang ◽  
W H Reeves
Keyword(s):  
Immune Response ◽  
T Cells ◽  
B Cells ◽  
Tumor Suppressor ◽  
Viral Infections ◽  
T Antigen ◽  
Tumor Suppressor Protein ◽  
Large T Antigen ◽  
P53 Tumor Suppressor Protein ◽  
Self Antigen

Antinuclear antibodies (ANAs) reactive with a limited spectrum of nuclear antigens are characteristic of systemic lupus erythematosus (SLE) and other collagen vascular diseases, and are also associated with certain viral infections. The factors that initiate ANA production and determine ANA specificity are not well understood. In this study, high titer ANAs specific for the p53 tumor suppressor protein were induced in mice immunized with purified complexes of murine p53 and the Simian virus 40 large T antigen (SVT), but not in mice immunized with either protein separately. The autoantibodies to p53 in these mice were primarily of the IgG1 isotype, were not cross-reactive with SVT, and were produced at titers up to 1:25,000, without the appearance of other autoantibodies. The high levels of autoantibodies to p53 in mice immunized with p53/SVT complexes were transient, but low levels of the autoantibodies persisted. The latter may have been maintained by self antigen, since the anti-p53, but not the SVT, response in these mice could be boosted by immunizing with murine p53. Thus, once autoimmunity to p53 was established by immunizing with p53/SVT complexes, it could be maintained without a requirement for SVT. These data may be explained in at least two ways. First, altered antigen processing resulting from the formation of p53/SVT complexes might activate autoreactive T helper cells specific for cryptic epitopes of murine p53, driving anti-p53 autoantibody production. Alternatively, SVT-responsive T cells may provide intermolecular-intrastructural help to B cells specific for murine p53. In a second stage, these activated B cells might themselves process self p53, generating p53-responsive autoreactive T cells. The induction of autoantibodies during the course of an immune response directed against this naturally occurring complex of self and nonself antigens may be relevant to the generation of specific autoantibodies in viral infections, and may also have implications for understanding the pathogenesis of ANAs in SLE. In particular, our results imply that autoimmunity can be initiated by a "hit and run" mechanism in which the binding of a viral antigen to a self protein triggers an immune response that subsequently can be perpetuated by self antigen.

Inhibition of NKG2D expression in NK cells by cytokines secreted in response to human cytomegalovirus infection

Blood ◽  
2010 ◽  
Vol 115 (25) ◽  
pp. 5170-5179 ◽  
Author(s):  
Aura Muntasell ◽  
Giuliana Magri ◽  
Daniela Pende ◽  
Ana Angulo ◽  
Miguel López-Botet
Keyword(s):  
Immune Response ◽  
Nk Cells ◽  
Human Cytomegalovirus ◽  
Viral Infections ◽  
Nk Cell ◽  
Cell Cytotoxicity ◽  
Down Regulation ◽  
Nkg2d Ligands ◽  
Nkg2d Expression ◽  
Nk Cell Cytotoxicity

Abstract The NKG2D receptor activates natural killer (NK) cell cytotoxicity and cytokine production on recognition of self-molecules induced by cellular stress under different conditions such as viral infections. The importance of NKG2D in the immune response to human cytomegalovirus (HCMV) is supported by the identification of several viral molecules that prevent the expression of NKG2D ligands by infected cells. In this study we report that, paradoxically, a significant, selective, and transient reduction of NKG2D expression on NK cells is detected during HCMV infection of peripheral blood mononuclear cells if needed. Antagonizing type I interferon (IFN), interleukin-12 (IL-12), and IFNγ prevented HCMV-induced down-regulation of surface NKG2D. Moreover, treatment of purified NK cells with recombinant IFNβ1 and IL-12 mimicked the effect, supporting a direct role of these cytokines in regulating NKG2D surface expression in NK cells. The loss of NKG2D expression selectively impaired NK-cell cytotoxicity against cells expressing NKG2D ligands but preserved the response triggered through other activating receptors. These results support that down-regulation of NKG2D expression on NK cells by cytokines with a key role in antiviral immune response may constitute a physiologic mechanism to control NK-cell reactivity against normal cells expressing NKG2D ligands in the context of inflammatory responses to viral infections.

scholarly journals A single-cell atlas reveals shared and distinct immune responses and metabolism during SARS-CoV-2 and HIV-1 infections

2022 ◽  
Author(s):  
Tony Pan ◽  
Guoshuai Cao ◽  
Erting Tang ◽  
Yu Zhao ◽  
Pablo Penaloza-MacMaster ◽  
...  
Keyword(s):  
Immune Responses ◽  
Single Cell ◽  
Immune Cells ◽  
Viral Infections ◽  
Rho Gtpase ◽  
Cell Types ◽  
Disease Biology ◽  
Similarities And Differences ◽  
Different Cell Types ◽  
Hiv 1

SARS-CoV-2 and HIV-1 are RNA viruses that have killed millions of people worldwide. Understanding the similarities and differences between these two infections is critical for understanding disease progression and for developing effective vaccines and therapies, particularly for 38 million HIV-1+ individuals who are vulnerable to SARS-CoV-2 co-infection. Here, we utilized single-cell transcriptomics to perform a systematic comparison of 94,442 PBMCs from 7 COVID-19 and 9 HIV-1+ patients in an integrated immune atlas, in which 27 different cell types were identified using an accurate consensus single-cell annotation method. While immune cells in both cohorts show shared inflammation and disrupted mitochondrial function, COVID-19 patients exhibit stronger humoral immunity, broader IFN-I signaling, elevated Rho GTPase and mTOR pathway activities, and downregulated mitophagy. Our results elucidate transcriptional signatures associated with COVID-19 and HIV-1 that may reveal insights into fundamental disease biology and potential therapeutic targets to treat these viral infections.

Evidence That Novel NK-NK Cell Subset Regulation Exists With Regard To Effects In Tumor and Viral Models

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1038-1038
Author(s):  
Ethan G Aguilar ◽  
Can M Sungur ◽  
Anthony E Zamora ◽  
William J Murphy
Keyword(s):  
Immune Response ◽  
Nk Cells ◽  
Mhc Class I ◽  
Viral Infections ◽  
Nk Cell ◽  
Class I ◽  
Inhibitory Receptors ◽  
The Individual

Abstract Natural killer (NK) cells are lymphocytes of the innate immune system and are classically associated with cytotoxic responses to both virally infected as well as neoplastic cells. Activation of NK cells to exhibit their cytotoxicity is dependent on signaling through a number of activating and inhibitory receptors. In mice, one such family of inhibitory receptors is the C-type lectin-like Ly49 family. In humans, the killer immunoglobulin-like receptors (KIRs) serve as the primary family of inhibitory receptors and are functional analogs of the Ly49s. Despite markedly different structures, the Ly49s and KIRs display similar binding capabilities and bind primarily to distinct MHC class I haplotypes, which plays an important role in regulating NK cell function. NK cells that express inhibitory receptors that are specific for the MHC class I haplotype of the individual are termed “licensed” and have been shown to have increased functionality in terms of cytotoxicity and cytokine production. In contrast, NK cells that express inhibitory receptors that are unable to bind to the MHC class I haplotype of the individual are termed “unlicensed” and have been shown to be hyporesponsive. We have recently reported on the role of NK licensing on the immune response to viral infections such as MCMV. In addition, we have previously described how regulatory T cells can regulate NK cell activity in vivo. However, there are limited data examining the interaction and regulation between the different NK subsets based on differences in licensing. We hypothesized that different NK cell subsets, based on licensing, can regulate each other in the context of anti-tumor and anti-viral responses. Here we first provide in vitro data providing evidence to support the hypothesis of NK-NK regulation based on licensing. In vitro killing assays using MCMV infected fibroblasts, or C1498 (murine acute myeloid leukemia) cells as targets and using different combinations of murine NK Ly49 subsets as effectors were used to assess this NK-NK regulation. To further test our hypothesis, in vivo experiments were also performed using a mouse leukemia model as well as an MCMV model. Mice were injected with C1498 cells and then given hematopoietic stem cell transplantation (HSCT). The mice were then depleted of all NK cells or either licensed or unlicensed subsets by antibody depletion once a week, and monitored for survival. Mice that were depleted of the unlicensed population survived significantly longer compared with the other depleted groups, suggesting a negative regulation of the anti-tumor response by the unlicensed population resulting in greater tumor burden and death in the presence of the unlicensed population. This negative regulation by the unlicensed population is further supported by another experiment where mice were infected with MCMC following total NK or subset depletion and monitored for ten days throughout the course of the immune response to MCMV. Mice that were depleted of their unlicensed population displayed a significantly larger expansion of the licensed population of NK cells, without reciprocal greater expansion of the unlicensed population upon licensed NK cell depletion. More specifically, depletion of the unlicensed population resulted in an expansion of the Ly49H+NK cells which have previously been shown to be the primary effector population during MCMV infection. Thus, the unlicensed NK cells are playing a role in down-regulating the anti-viral response by limiting the expansion of the effector licensed population. Our data highlight a role for the murine NK subsets to negatively regulate the immune response of the effector licensed NK population in the context of anti-tumor and anti-viral responses. This new insight into the regulatory role of NK cells may have clinical benefit for patients receiving bone marrow transplants during cancer treatment to enhance graft vs. tumor effects, and to combat opportunistic viral infections that may manifest in the immune compromised environment of the BMT patient. Disclosures: No relevant conflicts of interest to declare.

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