Peptidoglycan Recognition Protein 4 Limits Bacterial Clearance and Inflammation in Lungs by Control of the Gut Microbiota

Abstract

Streptococcus pneumoniae is the most frequent cause of community-acquired pneumonia. Endogenous host defense molecules such as peptidoglycan recognition protein 4 (PGLYRP4) might influence the course of this disease. To the best of our knowledge, there are no reports on the relevance of PGLYRP4 in pneumonia. Therefore, wild type (WT) and PGLYRP4-deficient (PGLYRP4KO) mice were analyzed in an in vivo and in vitro experimental setting to examine the influence of PGLYRP4 on the course of pneumococcal pneumonia. Furthermore, caecal 16S rRNA microbiome analysis was performed, and microbiota were transferred to germfree WT mice to assess the influence of microbiotal communities on the bacterial burden. Mice lacking PGLYRP4 displayed an enhanced bacterial clearance in the lungs, and fewer mice developed bacteremia. In addition, an increased recruitment of immune cells to the site of infection, and an enhanced bacterial killing by stronger activation of phagocytes could be shown. This may depend partly on the detected higher expression of complement factors, interferon-associated genes, and the higher pro-inflammatory cytokine response in isolated primary PGLYRP4KO vs. WT cells. This phenotype is underlined by changes in the complexity and composition of the caecal microbiota of PGLYRP4KO compared to WT mice. Strikingly, we provided evidence, by cohousing and stable transfer of the respective WT or PGLYRP4KO mice microbiota into germfree WT mice, that the changes of the microbiota are responsible for the improved clearance of S. pneumoniae lung infection. In conclusion, the deficiency of PGLYRP4, a known antibacterial protein, leads to changes in the gut microbiota. Thus, alterations in the microbiota can change the susceptibility to S. pneumoniae lung infection independently of the host genotype.

Gene variations in Autism Spectrum Disorder are associated with alternation of gut microbiota, metabolites and cytokines

“…The deficiency of PGLYRP4 leads to changes in the gut microbiota. 37 Other associations involved by the immunity-related genes include CD180 variation (chr5:66479217, c.C1454A, p.T485N) associated with Bacteroides dorei and Clostridium sp. CAG:7, RAET1G variation (rs4870111, c.G668A, p.R223K) associated with two Bacteroides species and Catenibacterium mitsuokai , and RTN4 variation associated with Hungatella hathewayi.…”

Weighted Gene Co-Expression Network Analysis Combined with Machine Learning Validation to Identify Key Modules and Hub Genes Associated with SARS-CoV-2 Infection

“…Whereas a large number of the identified hub genes had a remarkable enrichment in type I interferon (IFN) pathway genes, PGLYRP4 is known to play a vital IFN-independent role in the regulation of immune responses [80]. PGLYRP4 is a member of the highly conserved human peptidoglycan recognition proteins (PGLYRPs) family, which recognizes not only bacterial peptidoglycan but also shows direct bactericidal activities against a range of Gram-positive and Gram-negative bacteria [81]. In contrast to this well-known canonical function, PGLYRP4 has been conclusively demonstrated to display significant inhibitory effects on the expression of pro-inflammatory mediators and tight junction genes, which attenuates host inflammatory defense, and phagocyte recruitment and activation in the lung result in impaired clearance of bacteria and subsequent bacteremia during pneumococcal pneumonia [82].…”

“…However, the anti-inflammatory effects of PGLYRP4 demonstrated significant benefits to reduce early inflammatory processes leading to pulmonary damage and hyper inflammation [81]. Strikingly, PGLYRP4 has been shown to contribute to sphingosine-1-phosphate receptor (S1PR) agonist-mediated disease attenuation during Bordetella pertussis infection, and its beneficial preventive and therapeutic effects on suppressing SARS-CoV-2-related lung damage have been revealed by several studies [90][91][92].…”

RNA Sequencing and Pathways Analyses of Middle Ear Epithelia From Patients With Otitis Media

“…Peptidoglycan recognition protein 4 (PGLYRP4) is a receptor that detects Gram‐positive bacteria. PGLYRP4 knockout mice demonstrate reduced pulmonary S. pneumoniae burden potentially due to its intrinsic anti‐inflammatory properties 12 . Polymeric immunoglobulin receptor (PIGR) binds polymeric IgA and IgM on the basolateral surface of epithelial cells to facilitate secretion.…”