The immunostimulatory roles of synthetic bacterial-derived peptidoglycan fragments from pathogenic and commensal bacteria

Abstract

The host-pathogen interactions between the human body and microbial pathogens have been the subject of numerous studies for more than a century. Exploration of different aspects of such interactions has led to the emergence of several models such as ‘Self/Non-self’ and ‘Danger’ models, attempting to describe the underlying principles of these encounters. In recent decades and with the advancement of available chemical tools, we have been able to tackle the molecular details of such interactions. In this regard, the human innate immunity has been shown to play a major role, using different classes of pattern recognition receptors (PRRs) to identify pathogens-associated molecular patterns (PAMPs). One of the main sources of these molecular motifs is the bacterial cell wall. Fragments that are shed from the bacterial cell wall are sensed by different classes of innate immune proteins. The human nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs) are among these receptors that recognize small synthetic bacterial fragments such as muramyl dipeptide (MDP) and -D-glutamyl-meso-diaminopimelic acid (iE-DAP) and trigger the immune responses. However, as our understanding of potential receptors for these fragments has evolved, our knowledge of chemical intricacies of the bacterial cell wall construct has also been growing. Despite the commonality of the bacterial peptidoglycan (PG) structure, a host of chemical modifications is observed in different bacterial species suggesting that general PG fragments such as MDP does not necessarily represent the full scope of the PAMPs, and consequently, the corresponding receptors. ☐ Currently, researchers are limited to small sets of PG probes to study the cellular responses, despite the large pool of potential fragments. In this thesis, the importance of such chemical diversities in the PG structure is explored. Different synthetic methodologies have been used to expand the scope of the PG probes, while examining the significance of subtle chemical changes in the outcome of their immune recognition. In particular, the synthesis of a diverse set of larger cross-linked PG fragments is followed by testing the ability of these distinct PG fragments to elicit immune responses. The results here show that not only different PG-derived molecules can have a differential effect in activation of immune signaling pathways, some of the subtle chemical changes of the PG structure can alter the immunogenicity of resulting fragments and contribute to the pathogenicity of the microorganism. Moreover, since microbial colonization in the human body comprises other players such as fungi and viruses, this work also focuses on the regulatory effects of PG fragments in cellular settings beyond human cells. Particularly, the role of PG fragments in the virulence of Candida albicans, one of the common fungal species in the human microbiota, is shown here. ☐ This work indicates the immunological importance of chemical properties of PG fragments at molecular levels. The results here are essential for improving our knowledge of molecular mechanisms involved in the human innate immunity, which is crucial for a better understanding of the host-pathogen interactions. Furthermore, these results can open new ways for designing new antibiotic and preventive therapeutics, as aberrant responses to the PG fragments are linked to several pathological conditions including inflammatory bowel disease, cardiovascular disease, and cancer.