Transregional Collaborative Research Center SFB-TR 84 - “Innate Immunity of the Lung: Mechanisms of Pathogen Attack and Host Defence in Pneumonia“

A A A

Forgot password?

B1-Subproject

Peptidoglycan recognition proteins (PGLYRPs) as regulators of innate immunity in the lung (Zahlten / Suttorp / Hain)

 

Antimicrobial peptides (AMPs) are known to play a vital role in innate immunity of the lung. Human peptidoglycan recognition proteins (PGLYRPs) represent an AMP-group with four members. Three of them (PGLYRP1, 3 and 4) have been long believed to be bactericidal against gram-negative and gram-positive bacteria, while PGLYRP2 has an amidase activity. PGLYRPs are expressed in many tissues including pulmonary epithelial cells and contribute to defence against some invading pathogens and possibly to the maintenance of a healthy commensal composition.

Own work performed during the first funding period demonstrates that PGLYRP1, 3, and 4 do not act antimicrobially against Streptococcus pneumoniae. Surprisingly, treatment of infected mice with recombinant PGLYRP1 resulted in a higher bacterial load in lung tissue. Moreover, we discovered in a mouse model of pneumococcal pneumonia, that infected PGLYRP4-KO mice had a 100-fold lower bacterial load than wild-type mice, suggesting that PGLYRP4 is not bactericidal and that it appears to have anti-inflammatory activities. Another set of experiments addressed the induction of the different PGLYRPs in lung epithelial cells during pneumonia and interestingly only PGLYRP2 and 4 were up-regulated while PGLYRP1 and 3 remained unchanged.

We propose that a shift in balance between the pro-inflammatory PGLYRP2 and the anti-inflammatory PGLYRP4 causes disease. In the second funding period we will address this balance by characterising the actions of PGLYRP2 and 4 on several immune responses and by a rigorous analysis of the mechanism how PGLYRP4 impedes microbial killing. Second, on the level of the microbiome we will explore the possibility that PGLYRPs may change the composition or the predominance of bacteria in the lung, which in turn may act on the alertness level of the local innate immune system. These concepts can now be elaborated easily, because important tools (PGLYRP2-KO mice, large scale production of recombinant PGLYRPs) were prepared.