Modulation of the innate immune response during Bartonella infection

Subversion of host cellular functions and modulation of the immune response play essential roles in the virulence of many pathogens. The innate immune response composes an arsenal of humoral and cellular factors constantly threatening the intruders. To deal with these threats, pathogens developed a multitude of virulence factors to evade or downregulate the innate immune response. Many bacteria utilize secretion systems to translocate bacterial effectors into eukaryotic host cells, where they interfere with essential pathways, which trigger inflammation.
Bartonella spp. of lineage 3 and 4 encode the VirB/VirD4 T4SS to translocate Bartonella effector proteins (Beps) into host cells. The scope of this thesis was to identify and describe the function of effector proteins involved in the downregulation of innate immune response. Important questions were: How do Beps downregulate the immune response? Do they play an essential role in host colonization? Are there additional effectors next to the Beps?
Research article I describes the downregulation of the host’s innate immune response facilitated by BepD of B. henselae. BepD recruits the host kinase c-ABL and the transcription factor STAT3 via their SH2 domains. During this process, STAT3 is phosphorylated and triggers expression of anti-inflammatory cytokines. In Research article II, the split NanoLuc luciferase-based translocation assay was established for Bartonella to study effector translocation through the VirB/VirD4 T4SS. Utilizing this translocation assay, an in vitro infection protocol for the mouse-specific strain B. taylorii was generated by step-wise adapting the bacterial culture conditions favoring the translocation of Beps. Moreover, the optimized culture conditions improved the already implemented in vivo mouse infection model. The additional data related to Research article II describe the influence of Beps in host colonization. While translocation-deficient B. taylorii mutants failed to colonize mice, bacteria lacking all Beps still invaded the blood stream. Research article III identifies the Yersinia outer protein J (YopJ) family effector of B. taylorii (YopJBta) as a novel effector translocated by the VirB/VirD4 T4SS. YopJBta blocked signaling via the p38 and JNK MAPK pathways and thereby downregulated secretion of pro-inflammatory cytokines. The chapter also describes the positively charged C-terminal amino acids and an N-proximal helix of YopJBta as crucial parts of the translocation signal. The preliminary data related to Research article III highlight the contribution of Beps and YopJBta in host colonization. The infection rate in mice decreased after inoculation with B. taylorii mutants depleted of Beps and YopJBta compared to wild-type infections. However, the invasion of the blood stream was not completely abolished. The Discussion at the end of this work interconnects the data I obtained during my PhD to form a coherent model of innate immune modulation during Bartonella infection.