Moleculare basis of Mycoplasma pneumoniae pathogenicity: The role of variable adhesins and adhesion-related proteins in host interactions

Mycoplasma pneumoniae is one of the most frequent causes of all non-nosocomial cases of atypical pneumonia in children and young adults. In addition to respiratory tract disease, this organism is also responsible for post- infectious arthritis and chronic pathological manifestations in heart, lung, skin and the central nervous system. The sometimes observed long persistence of this wall-less bacterium in patients even after treatment with antibiotics as well as the lack of immunity against re-infections represent two major problems of infections caused by this agent. The only strategy to completely understand the pathogenesis of diseases caused by M. pneumoniae is the identification of biochemical, genetic and immunological features of virulent organisms by which they differ from avirulent organisms. The susceptibility to phagocytosis is one factor which determines the virulence of a bacterial pathogen. Different species of bacteria or even variants of one strain of a species vary widely regarding their susceptibility towards phagocytosis and intracellular killing by macrophages. Since about 0.7% of all individuals of a population of M. pneumoniae exhibit loss or alteration of highly immunogenic surface proteins which are involved in cytadherence, this pathogen represents an appropriate model to study the effect of. surface variability on its interaction with macrophages as well as on its survival and distribution in the host. The aim of the proposed project is to solve the following questions: (i) Are cytadherence-negative mutants of M. pneumoniae - either isolated as spontaneous mutants or obtained by transposon mutagenesis - able to: interact with macrophages in the same manner as the wild type or do they lack binding capacity to macrophages? (ii) Are mutants which have lost their ability to cytadhere because of rearrangements, alterations or loss of surface antigens more resistant against phagocytosis and therefore able to escape the immune response? (iii) Which are the consequences of this surface antigenic variability on the persistence and dissemination of M. pneumoniae in the host and the development of chronic disease? Taken together, the results obtained from these studies will enhance our knowledge about the variability of immunogenic surface proteins of M. pneumoniae involved in cytadherence and the molecular basis of interaction occurring between this organism and the human cellular immune system. This information is a prerequisite for understanding the molecular mechanisms of pathogenesis underlying the various diseases caused by M. pneumonia which may ultimately lead to new concepts of therapy design.