Modeling Innate Immune Response to EarlyMycobacteriumInfection

Abstract

In the study of complex patterns in biology, mathematical and computational models are emerging as important tools. In addition to experimental approaches, these modeling tools have recently been applied to address open questions regarding host-pathogen interaction dynamics, including the immune response to mycobacterial infection and tuberculous granuloma formation. We present an approach in which a computational model represents the interaction of the Mycobacterium infection with the innate immune system in zebrafish at a high level of abstraction. We use the Petri Net formalism to model the interaction between the key host elements involved in granuloma formation and infection dissemination. We define a qualitative model for the understanding and description of causal relations in this dynamic process. Complex processes involving cell-cell or cell-bacteria communication can be modeled at smaller scales and incorporated hierarchically into this main model; these are to be included in later elaborations. With the infection mechanism being defined on a higher level, lower-level processes influencing the host-pathogen interaction can be identified, modeled, and tested both quantitatively and qualitatively. This systems biology framework incorporates modeling to generate and test hypotheses, to perform virtual experiments, and to make experimentally verifiable predictions. Thereby it supports the unraveling of the mechanisms of tuberculosis infection.

Mycobacterium avium MAV2054 protein induces macrophage apoptosis by targeting mitochondria and reduces intracellular bacterial growth

“…Mycobacteria are intracellular facultative pathogens that grow within macrophages, which constitute the first line of innate immunity against most mycobacteria78. Therefore, mycobacterial virulence depends on the ability of these bacteria to invade, persist, and replicate within the hostile environment of macrophages.…”

Coupling of Petri Net Models of the Mycobacterial Infection Process and Innate Immune Response

“…In previous work [22], we have developed a qualitative Petri net model of the mycobacterial infection process and the subsequent innate immune response. We organized our model at the level of cell dynamics, and it is characterized by steps involved in the Mycobacterium marinum infection and granuloma formation in zebrafish.…”

“…At the outset of our modeling work [22] we have used colored qualitative Petri nets (QPN C ) to model the early stages of the mycobacterial infection process and granuloma formation. In all of our modeling work we have used an infection model of M. marinum in zebrafish embryos as this allows us to connect with empirical work.…”

“…In the research described in this paper, we now combine our former models [22,23] into one hierarchical structure in order to capture the infection process from the level of molecular interactions to the level of granuloma formation. In order to accomplish this, we have converted the QPN model and its hierarchical sub-models into a colored Petri net.…”

“…The set of color-sets from [22] is extended with a new color-set, Dot. This is a color-set with only one element as a color.…”