The immune response in tuberculous meningitis using mathematical models

Background

Tuberculosis (TB) is the second most common cause of mortality due to an infectious disease in children and adults worldwide. The worldwide incidence of TB is still increasing, but prevalence and death rates are beginning to fall. Two billion people, equal to one-third of the world’s population, are infected with Mycobacterium (M.) tuberculosis. Each year, 9 million people develop TB, 11% of them younger than 15 years old . About 2 million people die each year as a consequence of this disease especially in  the poor population. The most frequent manifestation of TB in children is pulmonary, but extra-pulmonary complications may occur in lymph nodes, intestinal organs, bones and meninges. Miliary TB is a disseminated infection in multiple organs. Tuberculous meningitis (TBM) is considered the most severe extra-pulmonary complication and occurs frequently during early childhood. Of the patients who contract TB, over 10% develop meningitis. These are mainly young children under 5 years of age. TBM is an extremely serious syndrome that causes the death of 10% of the children, while 50% suffer sequelae such as spasticity, other handicaps or serious mental problems.

Previous studies

We recently developed an experimental mouse model for TBM (see J. Infect Dis 2007;195:694-7). In the near future we are planning to perform more experiments in knock-out mice for certain proteins and receptors (cytokines, Toll-like receptors), to further examine the role of these components in the pathophysiology of TBM. However, in a mouse it is only possible to knock-out one or two of these proteins in one experiment at a time, and each experiment takes many months. Therefore it is of great importance to develop a mathematical model for TBM. Then we will able to knock-out many components at the same time. Moreover, with the knowledge obtained from this mathematical model  we will know better which knock-out experiments to perform in mice.

Research question

Which immunological determinants (such as T cells, macrophages, cytokines) are of influence on the outcome (mortality, granuloma formation, cytokine levels) of TBM.

Model

Prof. Denise Kirschner, Dept. of Microbiology and Immunology, University of Michigan Medical School, Michigan, USA. (see http://malthus.micro.med.umich.edu for literature) has developed mathematical models to understand the immune response in tuberculosis.

What are you going to do during this project?

• Literature search concerning the immunological determinants of importance during TB
• Learning of basic mathematical models for TB by Prof. Dr. D. Kirschner
• Exploring the possibility of a mathematical model for TBM
  

Project team

-Dr. A.M. van Furth, Dept. of Pediatrics and Infectious Diseases, W: www.kids-info.nl E: am.vfurth@vumc.nl
-Dr. M. van der Kuip, , Dept. of Pediatrics and Infectious Diseases, E:   m.vanderkuip@vumc.nl
-Prof. dr. W.J. Fokkink, Dept. of Computer Science, E: wanf@cs.vu.nl
-Prof. dr. J. Heringa, Centre for Integrative Bioinformatics VU, E: heringa@cs.vu.nl