The role of delays in innate and adaptive immunity to intracellular bacterial infection

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2007, 4(2): 261-286. doi: 10.3934/mbe.2007.4.261

The role of delays in innate and adaptive immunity to intracellular bacterial infection

Simeone Marino ^1, , Edoardo Beretta ^2, and Denise E. Kirschner ^3,

1.	Dept. of Microbiology and Immunology, University of Michigan Medical School, 6730 Med. Sci. Bldg. II, Ann Arbor, MI 48109-0620, United States
2.	Institute of Biomathematics, University of Urbino, Italy
3.	Dept. of Microbiology and Immunology, University of Michigan Medical School, 6730 Med. Sci. Bldg. II, Ann Arbor, MI 48109-062, United States

Received September 2006 Revised November 2006 Published February 2007

Abstract
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The immune response in humans is complex and multi-fold. Initially an innate response attempts to clear any invasion by microbes. If it fails to clear or contain the pathogen, an adaptive response follows that is specific for the microbe and in most cases is successful at eliminating the pathogen. In previous work we developed a delay differential equations (DDEs) model of the innate and adaptive immune response to intracellular bacteria infection. We addressed the relevance of known delays in each of these responses by exploring different kernel and delay functions and tested how each affected infection outcome. Our results indicated how local stability properties for the two infection outcomes, namely a boundary equilibrium and an interior positive equilibrium, were completely dependent on the delays for innate immunity and independent of the delays for adaptive immunity. In the present work we have three goals. The first is to extend the previous model to account for direct bacterial killing by adaptive immunity. This reflects, for example, active killing by a class of cells known as macrophages, and will allow us to determine the relevance of delays for adaptive immunity. We present analytical results in this setting. Second, we implement a heuristic argument to investigate the existence of stability switches for the positive equilibrium in the manifold defined by the two delays. Third, we apply a novel analysis in the setting of DDEs known as uncertainty and sensitivity analysis. This allows us to evaluate completely the role of all parameters in the model. This includes identifying effects of stability switch parameters on infection outcome.

Keywords: Delay differential equations model, uncertainty and sensitivity analysis., bacterial infections, innate and adaptive immunity.

Mathematics Subject Classification: 92B9.

Citation: Simeone Marino, Edoardo Beretta, Denise E. Kirschner. The role of delays in innate and adaptive immunity to intracellular bacterial infection. Mathematical Biosciences & Engineering, 2007, 4 (2) : 261-286. doi: 10.3934/mbe.2007.4.261

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