Spatially resolved modelling of immune responses following a multiscale approach: from computational implementation to quantitative predictions

2019 ◽  
Vol 34 (5) ◽  
pp. 253-260 ◽  
Author(s):  
Dmitry S. Grebennikov ◽  
Gennady A. Bocharov
Keyword(s):  
Cell Migration ◽  
Hiv Infection ◽  
Initial Boundary ◽  
Multiscale Model ◽  
Euler Method ◽  
Reaction Diffusion Equations ◽  
Target Cells ◽  
Multiscale Approach ◽  
Type I ◽  
Computational Implementation

Abstract In this work we formulate a hybrid multiscale model for describing the fundamental immune processes in human immunodeficiency type 1 (HIV) infection. These include (i) the T cell migration in the lymphoid tissue, (ii) the replication cycle of HIV within an infected cell, (iii) the type I interferon (IFN) response of the target cells, and (iv) the spatiotemporal dynamics of the HIV and type I IFN fields. Computational implementation of the hybrid multiscale model is presented. It is based on the use of semi-implicit first-order symplectic Euler method for solving the equations of the second Newton’s law for cell migration and the alternating direction method for the initial-boundary value problem for reaction–diffusion equations governing the spatial evolution of the virus and IFN fields in 2D domain representing the lymph node (LN) tissue. Both, the stochastic and deterministic descriptions of the intracellular HIV infection and the IFN reaction are developed. The potential of the calibrated multiscale hybrid model is illustrated by predicting the dynamics of the local HIV infection bursts in LN tissue.

A MULTISCALE APPROACH TO CELL MIGRATION IN TISSUE NETWORKS

2012 ◽  
Vol 22 (03) ◽  
pp. 1150017 ◽  
Author(s):  
JAN KELKEL ◽  
CHRISTINA SURULESCU
Keyword(s):  
Cell Migration ◽  
Existence And Uniqueness ◽  
Local Existence ◽  
Multiscale Model ◽  
Multiscale Approach ◽  
Biologically Relevant ◽  
Tumor Cell Migration ◽  
Local Existence And Uniqueness ◽  
Soluble Ligand ◽  
Uniqueness Of A Solution

We derive a multiscale model for tumor cell migration allowing to account for the receptor-mediated movement of the cells, the degradation of tissue fibers and the subsequent production of a soluble ligand whose concentration gradient then acts together with the distribution of tissue fibers as a directional cue for the cells. For this model we present a result on the local existence and uniqueness of a solution in all biologically relevant space dimensions.

scholarly journals HIV infection does not alter Interferon α/β receptor expression on mucosal immune cells

2019 ◽  
Author(s):  
Julia Ickler ◽  
Sandra Francois ◽  
Marek Widera ◽  
Mario L. Santiago ◽  
Ulf Dittmer ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Immune Cells ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Critical Role ◽  
Receptor Expression ◽  
Interferon Α ◽  
Target Cells ◽  
Type I

AbstractThe innate immune response induced by type I interferons (IFNs) play a critical role in the establishment of HIV infection. IFNs are induced early in HIV infection and trigger an antiviral defense program by signaling through the IFNa/b receptor (IFNAR), which consists of two subunits, IFNAR1 and IFNAR2. Changes in IFNAR expression in HIV target cells, as well as other immune cells, could therefore have important consequences for initial HIV spread. It was previously reported that IFNAR2 expression is increased in peripheral blood CD4+CXCR4+T cells of HIV+patients compared to HIV uninfected controls, suggesting that HIV infection may alter the IFN responsiveness of target cells. However, the earliest immune cells affected by HIVin vivoreside in the gut-associated lymphoid tissue (GALT). To date, it remains unknown if IFNAR expression is altered in GALT immune cells in the context of HIV infection and exposure to IFNs, including the 12 IFNa subtypes. Here, we analyzed the expression of surface bound and soluble IFNAR2 on Lamina propria mononuclear cells (LPMCs) isolated from the GALT of HIV−individuals and in plasma samples of HIV+patients. IFNAR2 expression varied between different T cells, B cells and natural killer cells, but was not altered following HIV infection. Furthermore, expression of the soluble IFNAR2a isoform was not changed in HIV+patients compared to healthy donors, nor in LPMCs after HIV-1 infectionex vivo. Even though the 12 human IFNα subtypes trigger different biological responses and vary in their affinity to both receptor subunits, stimulation of LPMCs with different recombinant IFNα subtypes did not result in any significant changes in IFNAR2 surface expression. Our data suggests that potential changes in the IFN responsiveness of mucosal immune cells during HIV infection is unlikely dictated by changes in IFNAR2 expression.

PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

2008 ◽  
Vol 31 (4) ◽  
pp. 13
Author(s):  
Martin Hyrcza ◽  
Mario Ostrowski ◽  
Sandy Der
Keyword(s):  
Dendritic Cells ◽  
Influenza Virus ◽  
Hiv Infection ◽  
Gene Transcription ◽  
Sendai Virus ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

scholarly journals TRIM22. A Multitasking Antiviral Factor

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1864
Author(s):  
Isabel Pagani ◽  
Guido Poli ◽  
Elisa Vicenzi
Keyword(s):  
Protein Interactions ◽  
Influenza A ◽  
Direct Interaction ◽  
Type I Interferons ◽  
Viral Gene ◽  
Target Cells ◽  
Type I ◽  
Protein Protein Interactions ◽  
Viral Genomes ◽  
Dna And Rna

Viral invasion of target cells triggers an immediate intracellular host defense system aimed at preventing further propagation of the virus. Viral genomes or early products of viral replication are sensed by a number of pattern recognition receptors, leading to the synthesis and production of type I interferons (IFNs) that, in turn, activate a cascade of IFN-stimulated genes (ISGs) with antiviral functions. Among these, several members of the tripartite motif (TRIM) family are antiviral executors. This article will focus, in particular, on TRIM22 as an example of a multitarget antiviral member of the TRIM family. The antiviral activities of TRIM22 against different DNA and RNA viruses, particularly human immunodeficiency virus type 1 (HIV-1) and influenza A virus (IAV), will be discussed. TRIM22 restriction of virus replication can involve either direct interaction of TRIM22 E3 ubiquitin ligase activity with viral proteins, or indirect protein–protein interactions resulting in control of viral gene transcription, but also epigenetic effects exerted at the chromatin level.

A Multiscale Approach to Modeling the Passive Mechanical Contribution of Cells in Tissues

2013 ◽  
Author(s):  
Victor K. Lai ◽  
Mohammad F. Hadi ◽  
Robert T. Tranquillo ◽  
Victor H. Barocas
Keyword(s):  
Extracellular Matrix ◽  
Soft Tissues ◽  
Multiscale Model ◽  
Tissue Mechanics ◽  
Multiscale Approach ◽  
Cellular Solids ◽  
Comprehensive Model ◽  
Modeling Framework ◽  
Tissue Biomechanics ◽  
Tensegrity Model

In addition to their obvious biological roles in tissue function, cells often play a significant mechanical role through a combination of passive and active behaviors. Phenomenological and continuum modeling approaches to understand tissue biomechanics have included improved constitutive laws that incorporate anisotropy in the extracellular matrix (ECM) and/or cellular phenomenon, e.g, [1]. The lack of microstructural detail in these models, however, limits their ability to explore the respective contributions and interactions between different components within a tissue. In contrast, structural approaches attempt to understand tissue biomechanics by incorporating microstructural details directly into the model, e.g., the tensegrity model [2], cellular solids models [3], or biopolymer models [4]. Research in our group focuses on developing a comprehensive model to predict the mechanical behavior of soft tissues via a multiscale approach, a technique that allows integration of the microstructural details of different components into the modeling framework. A significant gap in our previous models, however, is the absence of cells. The current work represents an improvement of the multiscale model via the addition of cells, and investigates the passive mechanical contribution of cells to overall tissue mechanics.

scholarly journals Specific Activation of Mitogen-activated Protein Kinase by Transforming Growth Factor-β Receptors in Lipid Rafts Is Required for Epithelial Cell Plasticity

2009 ◽  
Vol 20 (3) ◽  
pp. 1020-1029 ◽  
Author(s):  
Wei Zuo ◽  
Ye-Guang Chen
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Protein Kinase ◽  
Lipid Rafts ◽  
Transforming Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Coated Pits ◽  
Mapk Activation ◽  
Mitogen Activated Protein

Transforming growth factor (TGF)-β regulates a spectrum of cellular events, including cell proliferation, differentiation, and migration. In addition to the canonical Smad pathway, TGF-β can also activate mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt, and small GTPases in a cell-specific manner. Here, we report that cholesterol depletion interfered with TGF-β–induced epithelial-mesenchymal transition (EMT) and cell migration. This interference is due to impaired activation of MAPK mediated by cholesterol-rich lipid rafts. Cholesterol-depleting agents specifically inhibited TGF-β–induced activation of extracellular signal-regulated kinase (ERK) and p38, but not Smad2/3 or Akt. Activation of ERK or p38 is required for both TGF-β–induced EMT and cell migration, whereas PI3K/Akt is necessary only for TGF-β–promoted cell migration but not for EMT. Although receptor heterocomplexes could be formed in both lipid raft and nonraft membrane compartments in response to TGF-β, receptor localization in lipid rafts, but not in clathrin-coated pits, is important for TGF-β–induced MAPK activation. Requirement of lipid rafts for MAPK activation was further confirmed by specific targeting of the intracellular domain of TGF-β type I receptor to different membrane locations. Together, our findings establish a novel link between cholesterol and EMT and cell migration, that is, cholesterol-rich lipid rafts are required for TGF-β–mediated MAPK activation, an event necessary for TGF-β–directed epithelial plasticity.

scholarly journals Viral Dynamics of Acute HIV-1 Infection

1999 ◽  
Vol 190 (6) ◽  
pp. 841-850 ◽  
Author(s):  
Susan J. Little ◽  
Angela R. McLean ◽  
Celsa A. Spina ◽  
Douglas D. Richman ◽  
Diane V. Havlir
Keyword(s):  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Doubling Time ◽  
Basic Reproductive Number ◽  
Reproductive Number ◽  
Target Cells ◽  
Viral Dynamics ◽  
Acute Hiv Infection ◽  
Acute Hiv ◽  
The Mean

Viral dynamics were intensively investigated in eight patients with acute HIV infection to define the earliest rates of change in plasma HIV RNA before and after the start of antiretroviral therapy. We report the first estimates of the basic reproductive number (R0), the number of cells infected by the progeny of an infected cell during its lifetime when target cells are not depleted. The mean initial viral doubling time was 10 h, and the peak of viremia occurred 21 d after reported HIV exposure. The spontaneous rate of decline (α) was highly variable among individuals. The phase 1 viral decay rate (δI = 0.3/day) in subjects initiating potent antiretroviral therapy during acute HIV infection was similar to estimates from treated subjects with chronic HIV infection. The doubling time in two subjects who discontinued antiretroviral therapy was almost five times slower than during acute infection. The mean basic reproductive number (R0) of 19.3 during the logarithmic growth phase of primary HIV infection suggested that a vaccine or postexposure prophylaxis of at least 95% efficacy would be needed to extinguish productive viral infection in the absence of drug resistance or viral latency. These measurements provide a basis for comparison of vaccine and other strategies and support the validity of the simian immunodeficiency virus macaque model of acute HIV infection.

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