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, 8 (12), e80918
eCollection

A Model of an Integrated Immune System Pathway in Homo Sapiens and Its Interaction With Superantigen Producing Expression Regulatory Pathway in Staphylococcus Aureus: Comparing Behavior of Pathogen Perturbed and Unperturbed Pathway

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A Model of an Integrated Immune System Pathway in Homo Sapiens and Its Interaction With Superantigen Producing Expression Regulatory Pathway in Staphylococcus Aureus: Comparing Behavior of Pathogen Perturbed and Unperturbed Pathway

Namrata Tomar et al. PLoS One.

Abstract

Response of an immune system to a pathogen attack depends on the balance between the host immune defense and the virulence of the pathogen. Investigation of molecular interactions between the proteins of a host and a pathogen helps in identifying the pathogenic proteins. It is necessary to understand the dynamics of a normally behaved host system to evaluate the capacity of its immune system upon pathogen attack. In this study, we have compared the behavior of an unperturbed and pathogen perturbed host system. Moreover, we have developed a formalism under Flux Balance Analysis (FBA) for the optimization of conflicting objective functions. We have constructed an integrated pathway system, which includes Staphylococcal Superantigen (SAg) expression regulatory pathway and TCR signaling pathway of Homo sapiens. We have implemented the method on this pathway system and observed the behavior of host signaling molecules upon pathogen attack. The entire study has been divided into six different cases, based on the perturbed/unperturbed conditions. In other words, we have investigated unperturbed and pathogen perturbed human TCR signaling pathway, with different combinations of optimization of concentrations of regulatory and signaling molecules. One of these cases has aimed at finding out whether minimization of the toxin production in a pathogen leads to the change in the concentration levels of the proteins coded by TCR signaling pathway genes in the infected host. Based on the computed results, we have hypothesized that the balance between TCR signaling inhibitory and stimulatory molecules can keep TCR signaling system into resting/stimulating state, depending upon the perturbation. The proposed integrated host-pathogen interaction pathway model has accurately reflected the experimental evidences, which we have used for validation purpose. The significance of this kind of investigation lies in revealing the susceptible interaction points that can take back the Staphylococcal Enterotoxin (SE)-challenged system within the range of normal behavior.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. A schematic model of SAg of S. aureus interaction with TCR and MHC class II molecules of an infected H. sapiens.
Here, one can find the difference between antigen and SAg binding site on TCR.
Figure 2
Figure 2. agr and sar loci from S. aureus, adapted from .
Figure 3
Figure 3. Gene regulatory network involving sarA family, agr and rot (transcriptional regulators) in SAg expression regulatory pathway of the S. aureus , .
Sharp arrow head indicates activation and blocked arrow head shows inhibition.
Figure 4
Figure 4. TCR signaling pathway of H. sapiens.
SEB refers to Staphylococcal Enterotoxin B. Sharp arrow head indicates activation and blocked arrow shows inhibition.
Figure 5
Figure 5. Diagram showing the studied biochemical pathways upon perturbed/unperturbed conditions, along with different conflicting objective functions.
Figure 6
Figure 6. Displaying the concept behind the construction of integrated pathway system that includes SAg expression regulatory pathway of S. aureus and TCR signaling pathway of an infected host (H. sapiens).
Figure 7
Figure 7. Graph shows optimization of two conflicting objective functions in an integrated pathway system of SAg expression regulatory pathway of S. aureus and TCR signaling pathway of an infected host (H. sapiens).
Here, formula image is maximized, while formula image is minimized.
Figure 8
Figure 8. Comparing -values [0–1] of the molecules present in TCR signaling pathway of H. sapiens in three cases: (1) in an unperturbed TCR signaling pathway, (2) in a perturbed one and (3) after applying conflicting objective function optimization (case 4) on the perturbed TCR signaling pathway.

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Grant support

Ms. Namrata Tomar, one of the authors, gratefully acknowledges CSIR, India for providing her a Senior Research Fellowship (9/93 (0145)/12, EMR-I). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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