The type IV secretion (T4S) systems of gram-negative bacteria are versatile nano-machines involved in processes relevant to bacterial infection, such as horizontal transfer of virulence and antibiotic resistance genes between bacteria, and the translocation of bacterial effector proteins into eukaryotic target cells. Effector-translocating T4S systems are widely distributed among human pathogenic bacteria that are mostly causing chronic infections, including Helicobacter pylori (causing gastritis and gastric cancer), Legionella pneumophila (causing Legionnaires disease), Bartonella spp. (causing bartonellosis) and Brucella spp. (causing brucellosis).

In recent years we have – with support from the SNF (grants 3100-061777 and 31003A-109925) - established Bartonella as a powerful model for studying the cellular, molecular and evolutionary basis of T4S in bacterial pathogenesis. In the frame of the proposed project we will continue to explore this paradigmatic model of T4S. Moreover, we will expand the successful approach for studying T4S as established for Bartonella to the closely related pathogen Brucella – the etiological agent of the most important bacterial zoonosis worldwide that causes chronic infections in various mammals.

We will apply a multidisciplinary experimental approach including bacterial genetics, cell biology, molecular biology, biochemistry, structural biology, genomics, and animal experimentation. In subproject A targeting T4S in Bartonella, we will perform a structure/function analysis of the T4S system-translocated effector proteins and their cellular targets, and study molecular evolutionary mechanisms of host adaptation mediated by these effectors. In subproject B targeting T4S in Brucella, we will focus on the characterization of the T4S-dependent intracellular trafficking route of Brucella resulting in the establishment of an endoplasmic reticulum-associated replication niche, the systematic identification of the involved host factors and the structure/function analysis of the T4S effectors interacting with the identified host factors.

By studying the molecular mechanism of T4S in the closely related pathogens Bartonella and Brucella, we anticipate to provide fundamental contributions to our understanding how this wide-spread virulence mechanism facilitates chronic bacterial infection, which may also help to design novel strategies to combat bacterial virulence. Based on the specific subversion of multiple cellular functions by the T4S effectors of these pathogens we also expect to contribute new basic knowledge and novel tools to different fields of cell biology.