Showing papers by "Simeone Marino published in 2011"

Multiscale Computational Modeling Reveals a Critical Role for TNF-α Receptor 1 Dynamics in Tuberculosis Granuloma Formation

Abstract: Multiple immune factors control host responses to Mycobacterium tuberculosis infection, including the formation of granulomas, which are aggregates of immune cells whose function may reflect success or failure of the host to contain infection. One such factor is TNF-α. TNF-α has been experimentally characterized to have the following activities in M. tuberculosis infection: macrophage activation, apoptosis, and chemokine and cytokine production. Availability of TNF-α within a granuloma has been proposed to play a critical role in immunity to M. tuberculosis. However, in vivo measurement of a TNF-α concentration gradient and activities within a granuloma are not experimentally feasible. Further, processes that control TNF-α concentration and activities in a granuloma remain unknown. We developed a multiscale computational model that includes molecular, cellular, and tissue scale events that occur during granuloma formation and maintenance in lung. We use our model to identify processes that regulate TNF-α concentration and cellular behaviors and thus influence the outcome of infection within a granuloma. Our model predicts that TNF-αR1 internalization kinetics play a critical role in infection control within a granuloma, controlling whether there is clearance of bacteria, excessive inflammation, containment of bacteria within a stable granuloma, or uncontrolled growth of bacteria. Our results suggest that there is an interplay between TNF-α and bacterial levels in a granuloma that is controlled by the combined effects of both molecular and cellular scale processes. Finally, our model elucidates processes involved in immunity to M. tuberculosis that may be new targets for therapy.

A multifaceted approach to modeling the immune response in tuberculosis.

Abstract: Tuberculosis (TB) is a deadly infectious disease caused by Mycobacterium tuberculosis (Mtb). No available vaccine is reliable and, although treatment exists, approximately 2 million people still die each year. The hallmark of TB infection is the granuloma, a self-organizing structure of immune cells forming in the lung and lymph nodes in response to bacterial invasion. Protective immune mechanisms play a role in granuloma formation and maintenance; these act over different time/length scales (e.g., molecular, cellular, and tissue scales). The significance of specific immune factors in determining disease outcome is still poorly understood, despite incredible efforts to establish several animal systems to track infection progression and granuloma formation. Mathematical and computational modeling approaches have recently been applied to address open questions regarding host-pathogen interaction dynamics, including the immune response to Mtb infection and TB granuloma formation. This provides a unique opportunity to identify factors that are crucial to a successful outcome of infection in humans. These modeling tools not only offer an additional avenue for exploring immune dynamics at multiple biological scales but also complement and extend knowledge gained via experimental tools. We review recent modeling efforts in capturing the immune response to Mtb, emphasizing the importance of a multiorgan and multiscale approach that has tuneable resolution. Together with experimentation, systems biology has begun to unravel key factors driving granuloma formation and protective immune response in TB. WIREs Syst Biol Med 2011 3 479-489 DOI: 10.1002/wsbm.131