scholarly journals Spatially distributed infection increases viral load in a computational model of SARS-CoV-2 lung infection

2021 ◽  
Vol 17 (12) ◽  
pp. e1009735
Author(s):  
Melanie E. Moses ◽  
Steven Hofmeyr ◽  
Judy L. Cannon ◽  
Akil Andrews ◽  
Rebekah Gridley ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Load ◽  
T Cell ◽  
Epithelial Cells ◽  
Computational Model ◽  
Temporal Dynamics ◽  
T Cell Response ◽  
Cell Immune Response ◽  
Viral Loads ◽  
Viral Spread

A key question in SARS-CoV-2 infection is why viral loads and patient outcomes vary dramatically across individuals. Because spatial-temporal dynamics of viral spread and immune response are challenging to study in vivo, we developed Spatial Immune Model of Coronavirus (SIMCoV), a scalable computational model that simulates hundreds of millions of lung cells, including respiratory epithelial cells and T cells. SIMCoV replicates viral growth dynamics observed in patients and shows how spatially dispersed infections can lead to increased viral loads. The model also shows how the timing and strength of the T cell response can affect viral persistence, oscillations, and control. By incorporating spatial interactions, SIMCoV provides a parsimonious explanation for the dramatically different viral load trajectories among patients by varying only the number of initial sites of infection and the magnitude and timing of the T cell immune response. When the branching airway structure of the lung is explicitly represented, we find that virus spreads faster than in a 2D layer of epithelial cells, but much more slowly than in an undifferentiated 3D grid or in a well-mixed differential equation model. These results illustrate how realistic, spatially explicit computational models can improve understanding of within-host dynamics of SARS-CoV-2 infection.

scholarly journals Spatially distributed infection increases viral load in a computational model of SARS-CoV-2 lung infection

2021 ◽  
Author(s):  
Melanie E. Moses ◽  
Steve Hofmeyr ◽  
Judy L Cannon ◽  
Akil Andrews ◽  
Rebekah Gridley ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Computational Model ◽  
Computational Models ◽  
Temporal Dynamics ◽  
Growth Dynamics ◽  
T Cell Response ◽  
Viral Loads ◽  
Viral Spread ◽  
Spatially Distributed

A key question in SARS-CoV-2 infection is why viral loads and patient outcomes vary dramatically across individuals. Because spatial-temporal dynamics of viral spread and immune response are challenging to study in vivo, we developed Spatial Immune Model of Coronavirus (SIMCoV), a scalable computational model that simulates billions of lung cells, including respiratory epithelial cells and T cells. SIMCoV replicates viral growth dynamics observed in patients and shows that spatially dispersed infections lead to increased viral loads. The model shows how the timing and strength of the T cell response can affect viral persistence, oscillations, and control. When the branching airway structure is explicitly represented, we find that virus spreads faster than in a 2D layer of epithelial cells, but much more slowly than in an undifferentiated 3D grid or in a well-mixed ODE model. These results illustrate how realistic spatially explicit computational models can improve understanding of within-host dynamics of SARS-CoV-2 infection.

scholarly journals Brd4 Regulates the Homeostasis of CD8+ T-Lymphocytes and Their Proliferation in Response to Antigen Stimulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhilin Peng ◽  
Yiwen Zhang ◽  
Xiancai Ma ◽  
Mo Zhou ◽  
Shiyu Wu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Cell Immune Response ◽  
Type I ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Antigen Stimulation

CD8+ T cells are major components of adaptive immunity and confer robust protective cellular immunity, which requires adequate T-cell numbers, targeted migration, and efficient T-cell proliferation. Altered CD8+ T-cell homeostasis and impaired proliferation result in dysfunctional immune response to infection or tumorigenesis. However, intrinsic factors controlling CD8+ T-cell homeostasis and immunity remain largely elusive. Here, we demonstrate the prominent role of Brd4 on CD8+ T cell homeostasis and immune response. By upregulating Myc and GLUT1 expression, Brd4 facilitates glucose uptake and energy production in mitochondria, subsequently supporting naïve CD8+ T-cell survival. Besides, Brd4 promotes the trafficking of naïve CD8+ T cells partially through maintaining the expression of homing receptors (CD62L and LFA-1). Furthermore, Brd4 is required for CD8+ T cell response to antigen stimulation, as Brd4 deficiency leads to a severe defect in clonal expansion and terminal differentiation by decreasing glycolysis. Importantly, as JQ1, a pan-BRD inhibitor, severely dampens CD8+ T-cell immune response, its usage as an anti-tumor agent or latency-reversing agent for human immunodeficiency virus type I (HIV-1) should be more cautious. Collectively, our study identifies a previously-unexpected role of Brd4 in the metabolic regulation of CD8+ T cell-mediated immune surveillance and also provides a potential immunomodulation target.

scholarly journals Metabolic control of T cell immune response through glycans in inflammatory bowel disease

2018 ◽  
Vol 115 (20) ◽  
pp. E4651-E4660 ◽  
Author(s):  
Ana M. Dias ◽  
Alexandra Correia ◽  
Márcia S. Pereira ◽  
Catarina R. Almeida ◽  
Inês Alves ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Disease Severity ◽  
Ex Vivo ◽  
Cell Activity ◽  
Cell Receptor ◽  
T Cell Response ◽  
Cell Immune Response ◽  
T Helper 1 ◽  
Glycosylation Pathway

Mucosal T lymphocytes from patients with ulcerative colitis (UC) were previously shown to display a deficiency in branched N-glycosylation associated with disease severity. However, whether this glycosylation pathway shapes the course of the T cell response constituting a targeted-specific mechanism in UC remains largely unknown. In this study, we demonstrated that metabolic supplementation of ex vivo mucosal T cells from patients with active UC with N-acetylglucosamine (GlcNAc) resulted in enhancement of branched N-glycosylation in the T cell receptor (TCR), leading to suppression of T cell growth, inhibition of the T helper 1 (Th1)/Th17 immune response, and controlled T cell activity. We further demonstrated that mouse models displaying a deficiency in the branched N-glycosylation pathway (MGAT5−/−, MGAT5+/−) exhibited increased susceptibility to severe forms of colitis and early-onset disease. Importantly, the treatment of these mice with GlcNAc reduced disease severity and suppressed disease progression due to a controlled T cell-mediated immune response at the intestinal mucosa. In conclusion, our human ex vivo and preclinical results demonstrate the targeted-specific immunomodulatory properties of this simple glycan, proposing a therapeutic approach for patients with UC.

scholarly journals Cellular Immune Responses to BNT162b2 mRNA COVID-19 Vaccine in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 638-638
Author(s):  
Gilad Itchaki ◽  
Lior Rokach ◽  
Ohad Benjamini ◽  
Osnat Bairey ◽  
Adi Sabag ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Response ◽  
Research Funding ◽  
T Cell Response ◽  
Lymphocytic Leukemia ◽  
Cell Immune Response ◽  
P Value ◽  
Igg Antibodies ◽  
Cellular Immune

Abstract Background: Patients with chronic lymphocytic leukemia (CLL) are known to have a suboptimal immune response of both humoral and cellular arms. Recently, a BNT162b2 mRNA COVID-19 vaccine was introduced with a high efficacy of 95% in immunocompetent individuals. Approximately half of the patients with CLL fail to mount a humoral response to the vaccine, as detected by anti-spike antibodies. Currently, there is no data available regarding T-cell immune responses following the vaccine of these patients. Aim of the study: To investigate T-cell response determined by interferon gamma (IFNγ) secretion in patients with CLL following BNT162b mRNA Covid-19 vaccine, in comparison with serologic response. Methods: CLL patients from 3 medical centers in Israel were included in the study. All patients received two 30-μg doses of BNT162b2 vaccine (Pfizer), administered intramuscularly 3 weeks apart. For evaluation of SARS-CoV-2 Spike-specific T-cell responses, blood samples were stimulated ex-vivo with Spike protein and secreted IFNγ was quantified (ELISA DuoSet, R&D Systems, Minneapolis, Minnesota, USA). T-cell immune response was considered to be positive for values above 25 pg/ml of Spike-specific response. T-cell subpopulations were characterized by flow cytometry (CD3, CD4, CD8). Anti-spike antibody tests were performed using the Architect AdviseDx SARS-CoV-2 IgG II (Abbot, Lake Forest, Illinois, USA). Statistical analysis was performed using Mann-Whitney test for continuous variables while the Wald Chi-square test was used for comparing categorical variables. Results: 83 patients with CLL were tested for T-cell response. Blood samples were collected after a median time of 139 days post administration of the second dose of vaccine (IQ range 134-152). Out of 83 patients, 68 were eligible for the analysis (with positive internal control). Median age of the cohort was 68 years (56-72); and 44 (65%) were males. 19 (28%) patients were treatment-naïve, most of whom were Binet stage A or B. 31 (46%) patients were on therapy: 17 with a BTK-inhibitor, and 13 with a venetoclax-based regimen. 29 (42%) patients were previously treated with anti-CD20, 13 of whom in the 12 months period prior to vaccination. T cell immune response to the vaccine was evident in 22 (32%) patients. CIRS Score>6 and specifically hypertension were statistically significantly associated with a lower T-cell response (univariate analysis, p-value<0.05). Variables that were associated with the development of T-cell response were presence of del(13q), IgM ≥ 40 mg/dL, and IgA ≥ 80 mg/dL (p-value 0.05-0.1). There was no significant difference with regards to age, gender, other CLL-specific prognostic markers, treatment, and T-cell subpopulation distribution according to flow cytometry (Table 1). The presence of T-cell response highly correlated with both the detection of anti-spike IgG antibodies following the second dose (p=0.0239) and at the time of T-cell testing (n=66, p=0.048, Table 2). While 50% of patients who tested positive for anti-spike IgG antibodies also developed positive T-cell response, only 17% of patients who did not develop T-cell response, tested positive for anti-spike antibodies. Importantly, 24% of the patients who tested negative for anti-spike IgG antibodies, developed positive T cell response. Moreover, the level of the T-cell response (log transformed) correlated linearly with (log transformed) anti-spike IgG titer (adjusted r=0.26 and p =0.026 according to Pearson correlation, Figure 1). Conclusion: We show that cellular immune response to the BNT162b2 mRNA COVID-19 vaccine, is blunted in most CLL patients and that there is a correlation between T-cell response and serologic response to the vaccine. These results need to be validated in a larger cohort. Figure 1 Figure 1. Disclosures Itchaki: AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Benjamini: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tadmor: AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

scholarly journals Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination

2015 ◽  
Vol 112 (10) ◽  
pp. 3050-3055 ◽  
Author(s):  
Rama S. Akondy ◽  
Philip L. F. Johnson ◽  
Helder I. Nakaya ◽  
Srilatha Edupuganti ◽  
Mark J. Mulligan ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Yellow Fever ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Virus Load

CD8 T cells are a potent tool for eliminating intracellular pathogens and tumor cells. Thus, eliciting robust CD8 T-cell immunity is the basis for many vaccines under development. However, the relationship between antigen load and the magnitude of the CD8 T-cell response is not well-described in a human immune response. Here we address this issue by quantifying viral load and the CD8 T-cell response in a cohort of 80 individuals immunized with the live attenuated yellow fever vaccine (YFV-17D) by sampling peripheral blood at days 0, 1, 2, 3, 5, 7, 9, 11, 14, 30, and 90. When the virus load was below a threshold (peak virus load < 225 genomes per mL, or integrated virus load < 400 genome days per mL), the magnitude of the CD8 T-cell response correlated strongly with the virus load (R2∼ 0.63). As the virus load increased above this threshold, the magnitude of the CD8 T-cell responses saturated. Recent advances in CD8 T-cell–based vaccines have focused on replication-incompetent or single-cycle vectors. However, these approaches deliver relatively limited amounts of antigen after immunization. Our results highlight the requirement that T-cell–based vaccines should deliver sufficient antigen during the initial period of the immune response to elicit a large number of CD8 T cells that may be needed for protection.

scholarly journals The Cytomegalovirus-Specific CD4+ T-Cell Response Expands with Age and Markedly Alters the CD4+ T-Cell Repertoire

2007 ◽  
Vol 81 (14) ◽  
pp. 7759-7765 ◽  
Author(s):  
Batoul Pourgheysari ◽  
Naeem Khan ◽  
Donna Best ◽  
Rachel Bruton ◽  
Laxman Nayak ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Immune Response ◽  
T Cell Repertoire ◽  
Immune Senescence ◽  
Cell Repertoire

ABSTRACT Immune function in the elderly is associated with a number of phenotypic and functional abnormalities, and this phenomenon of immune senescence is associated with increased susceptibility to infection. The immune response to pathogens frequently declines with age, but the CD8+ T-cell response to cytomegalovirus (CMV) is unusual, as it demonstrates a significant expansion over time. Here we have documented the CD4+ T-cell immune response to CMV in healthy donors of different ages. The magnitude of the CMV-specific CD4+ T-cell immune response increases from a mean of 2.2% of the CD4+ T-cell pool in donors below 50 years of age to 4.7% in donors aged over 65 years. In addition, CMV-specific CD4+ T cells in elderly donors demonstrate decreased production of interleukin-2 and less dependence on costimulation. CMV seropositivity is associated with marked changes in the phenotype of the overall CD4+ T-cell repertoire in healthy aged donors, including an increase in CD57+ expression and a decrease in CD28 and CD27 expression, a phenotypic profile characteristic of immune senescence. This memory inflation of CMV-specific CD4+ T cells contributes to evidence that CMV infection may be damaging to immune function in elderly individuals.

Cytomegalovirus Specific Immunity Protects From Cytomegalovirus Replication After Hematopoietic Stem Cell Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1281-1281
Author(s):  
Fátima de la Cruz Vicente ◽  
Omar BenMarzouk-Hidalgo ◽  
Irene Gracia-Ahufinger ◽  
Raul García-Lozano ◽  
Manuela Aguilar-Guisado ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Immune Reconstitution ◽  
T Cell Response ◽  
Cmv Infection ◽  
Post Transplant

Abstract Abstract 1281 Background: Cytomegalovirus (CMV) end-organ disease is a serious complication after allogeneic stem cell transplantation (Allo-SCT). The quality of the post-transplant immune reconstitution plays a crucial role in the development of both, post-transplant infections and relapse of the underlying disease, two of the main factors conditioning post-transplant mortality and hence final survival. The relationship between viral replication and CMV specific immune reconstitution has not been completely unveiled. This knowledge would allow identifying patients at risk for developing CMV disease and eventually improving their clinical management. Objectives: to analyze the relationship between CMV replication and specific CMV immune reconstitution and the potential influence of this relationship in main clinical outcomes. Patients and Methods: A prospective study of consecutive recipients of Allo-SCT was performed from June 2008 through December 2009 at a single institution. Blood samples were collected from one week before transplant, weekly during the first three months after transplant, every other week from month three to six and monthly from month seven to complete one year of follow up. CMV viral load was determined by real time PCR and CMV-specific T cell response was determined by flow cytometry with surface markers and intracellular cytokine staining. The percentage of activated CD4+, CD8+ and CD3+ T cells expressing CD69 were considered positive when IFN-’Y cytokine secretion was over 0.25%. Chimerism of the isolated CD8+ T cell subpopulation was determined by PCR. CD69 expression and cytokine secretion were compared in both CD4+ and CD8+ T cells between the different time points and both subsets of patients by the Wilcoxon test. CMV viral load reduction without treatment administration was compared by Wilcoxon test. Differences were considered statistically significant for p-values < 0.05. All statistical analyses were performed using SPSS 16.0 software (Chicago, IL). Results: Twenty-six patients were enrolled in the study with a median age of 33 years (range:15-61). We identified two groups of patients. A first group of 18 (69.2%) patients developed CMV infection and acquired CMV-specific T cell response by median week 8 (range:1-22; Figure 1A). The decline in the incidence of CMV replication episodes correlated with the acquisition of CMV-specific T cell response (Linear regresion r2=0.781, Pearson correlation p=0.01). A second group of 8 patients (30.8%) never developed CMV infection after the transplant, with a median value of 2 weeks (range:1-7; Figure 1B). The time of the acquisition of CMV-specific T cell response for the group with viremia and for the non-viremic group (week 2 vs. week 8) was statistically different (p= 0.01). Fifteen per cent of the patients (n=4) developed end-organ disease. Three out of five patients with end-organ disease developed replication CMV episodes over 10,000 copies/ml, while only 1 out of 13 patients with no end-organ disease developed viral loads under 10,000 copies/ml (p=0.04). The percentage of positive CD8+ T cells expressing IFN-γ in the patients that developed disease tended to be lower than in the patients that did not develop disease (median percentage of IFN-g positive CD8 T cells 0.3 vs. 0.5, respectively). The chimerism of the CD8+ T cells subpopulation after acquiring the specific immune response was of complete donor origin for all the patients. Conclusions: Developing donor-derived T-cell mediated CMV-specific immune response within the following two weeks after the transplant is inversely associated with the development CMV infection. The level of CMV viral load may predict end-organ disease. The use of a tool to determine T-cell mediated CMV-specific immune response in the clinical practice may help to improve the management of these patients, avoiding unnecessary treatments, and predicting clinical outcomes. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CD8+ T-Cell Mediated Control of HIV-1 in a Unique Cohort With Low Viral Loads

2021 ◽  
Vol 12 ◽  
Author(s):  
Amber D. Jones ◽  
Svetlana Khakhina ◽  
Tara Jaison ◽  
Erin Santos ◽  
Stephen Smith ◽  
...  
Keyword(s):  
Viral Load ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Undetectable Viral Load ◽  
Underlying Mechanism ◽  
T Cell Response ◽  
Dependent Manner ◽  
Viral Loads ◽  
Hiv 1

A unique population of HIV-1 infected individuals can control infection without antiretroviral therapy. These individuals fall into a myriad of categories based on the degree of control (low or undetectable viral load), the durability of control over time and the underlying mechanism (i.e., possession of protective HLA alleles or the absence of critical cell surface receptors). In this study, we examine a cohort of HIV-1 infected individuals with a documented history of sustained low viral loads in the absence of therapy. Through in vitro analyses of cells from these individuals, we have determined that infected individuals with naturally low viral loads are capable of controlling spreading infection in vitro in a CD8+ T-cell dependent manner. This control is lost when viral load is suppressed by antiretroviral therapy and correlates with a clinical CD4:CD8 ratio of &lt;1. Our results support the conclusion that HIV-1 controllers with low, but detectable viral loads may be controlling the virus due to an effective CD8+ T-cell response. Understanding the mechanisms of control in these subjects may provide valuable understanding that could be applied to induce a functional cure in standard progressors.

scholarly journals Immunosequencing and epitope mapping reveal substantial preservation of the T cell immune response to Omicron generated by SARS-CoV-2 vaccines

2021 ◽  
Author(s):  
Damon H. May ◽  
Benjamin E. R. Rubin ◽  
Sudeb C. Dalai ◽  
Krishna Patel ◽  
Shahin Shafiani ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cellular Immune Response ◽  
Epitope Mapping ◽  
Protective Efficacy ◽  
T Cell Response ◽  
Cell Immune Response ◽  
Cell Immunity ◽  
Cellular Immune

The Omicron SARS-CoV-2 variant contains 34 mutations in the spike gene likely impacting protective efficacy from vaccines. We evaluated the potential impact of these mutations on the cellular immune response. Combining epitope mapping to SARS-CoV-2 vaccines that we have determined from past experiments along with T cell receptor (TCR) repertoire sequencing from thousands of vaccinated or naturally infected individuals, we estimate the abrogation of the cellular immune response in Omicron. Although 20% of CD4+ T cell epitopes are potentially affected, the loss of immunity mediated by CD4+ T cells is estimated to be slightly above 30% as some of the affected epitopes are relatively more immunogenic. For CD8+ T cells, we estimate a loss of approximately 20%. These reductions in T cell immunity are substantially larger than observed in other widely distributed variants. Combined with the expected substantial loss of neutralization from antibodies, the overall protection provided by SARS-CoV-2 vaccines could be impacted adversely. From analysis of prior variants, the efficacy of vaccines against symptomatic infection has been largely maintained and is strongly correlated with the T cell response but not as strongly with the neutralizing antibody response. We expect the remaining 70% to 80% of on-target T cells induced by SARS-CoV-2 vaccination to reduce morbidity and mortality from infection with Omicron.

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