Abstract
The discrete modeling formalism of René Thomas is a well known approach for the modeling and analysis of Biological Regulatory Networks (BRNs). This formalism uses a set of parameters which reflect the dynamics of the BRN under study. These parameters are initially unknown but may be deduced from the appropriately chosen observed dynamics of a BRN. The discrete model can be further enriched by using the model checking tool HyTech along with delay parameters. This paves the way to accurately analyse a BRN and to make predictions about critical trajectories which lead to a normal or diseased response. In this paper, we apply the formal discrete and hybrid (discrete and continuous) modeling approaches to characterize behavior of the BRN associated with MyD88-adapter-like (MAL) – a key protein involved with innate immune response to infections. In order to demonstrate the practical effectiveness of our current work, different trajectories and corresponding conditions that may lead to the development of cerebral malaria (CM) are identified. Our results suggest that the system converges towards hyperinflammation if Bruton's tyrosine kinase (BTK) remains constitutively active along with pre-existing high cytokine levels which may play an important role in CM pathogenesis.
Highlights
Severe forms of malaria claim a huge number of lives worldwide, contributing to over a million deaths annually, mostly that of children [1]
GENOTECH generates the state graph of the MAL associated Biological Regulatory Networks (BRNs) (Figure 2) representing all possible transitions from one state to the other (Figure 3), where each state indicates the concentrations of every entity at a particular time
A state is represented by Bruton’s tyrosine kinase (BTK), MAL, NF-kB, inflammatory cytokines (INCY) and SOCS-1, in the respective order
Summary
Severe forms of malaria claim a huge number of lives worldwide, contributing to over a million deaths annually, mostly that of children [1]. In a few cases a severe pathogenesis occurs due to hyperinflammation, usually following Plasmodium falciparum infection, that may turn fatal. The blood flow through small blood vessels to the brain is severely hampered as the infected erythrocytes are sequestered by parasites causing ischaemic hypoxia and increased nitric oxide production in brain tissues, leading to coma, a condition known as diffuse encephalopathy or CM [3,4,5]. In cases where pathogenesis becomes severe, chronic over production of cytokines contributes to elevated levels of a cellular messenger, induced nitric oxide synthase (iNOS). These elevated levels of iNOS plus the hypoxia caused by the parasites work in sync to create a condition of chronic hyperinflammation causing an augmentation of CM pathogenesis [3,10]
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