The roles of the anaphylatoxin receptors during invasive disease as well as mucosal colonization caused by Neisseria meningitidis

• Applicant: Dr. Kay Ole Johswich
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens ; Immunology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 278593213

Neisseria meningitidis (meningococcus, Nme) is the causative agent of fulminant sepsis and meningitis which can lead to death within 24 hours. Usually, however, Nme colonizes the nasopharynx without causing disease and is found in approximately 10% of the general population. The complement system represents the most important branch of the innate immune system to control invasive meningococcal disease (IMD). Especially the contribution of the terminal membrane attack complex in defence against Nme is well characterized. Yet, complement activation also liberates the small pro-inflammatory split products C3a and C5a, the so-called anaphylatoxins (AT). These highly potent mediators of inflammation activate a set of three cognate receptors, the anaphylatoxin receptors (ATR) C3aR, C5aR and C5L2, which can exacerbate systemic inflammation. There is a surprising lack of data regarding the contribution of the AT and ATR to IMD pathophysiology or their role during asymptomatic Nme colonization of the respiratory mucosa. In the first part of the project, the influence of the individual ATR will be delineated in an intraperitoneal infection model of meningococcal sepsis by comparing the course of disease in wild-type versus knockout mice lacking ATR. The obtained results will be corroborated by targeting the AT as well as ATR by specific antibodies or peptide antagonists, which will also determine their potential as therapeutic targets in IMD. Specific in vivo depletion protocols as well as in vitro experiments will identify the cells which mediate the ATR-dependent IMD immunopathology. In the second part of the project, the overall role of complement in the mucosal defence against Nme will be characterized. Especially the role of the ATR in the local inflammatory response will be elaborated in this context with respect the recruitment of phagocytes, which clear Nme mucosal colonization. Furthermore, the impact of ATR on the adaptive immune response towards Nme will be elucidated with focus on the generation of protective Nme-specific IgG subclasses, which target complement activation (IgG2a, IgG2b). In order to consider the human-restricted tropism of Nme, these studies will be conducted using a novel transgenic mouse expressing human CEACAM1, which allows for Nme colonization in mice, in conjunction with knockout mice lacking ATR or other complement components. Taken together, this project will, for the first time, define the role of complement-mediated inflammation during infection with Nme. To do so, this project will embrace the dichotomy of both, the Nme lifestyle (commensal during mucosal colonization versus pathogenic during sepsis) as well as the ATR-mediated inflammation (physiologic during mucosal colonization versus deregulated during sepsis). Therefore, this project will bear novel insights for the fields of research on pathogenic Neisseriae as well as on the complement system.

• DFG Programme: Research Grants