Even, G. | Search bioRxiv

bioRxiv2022

Involvement of an IgE/Mast cell/B cell amplification loop in abdominal aortic aneurysm progression

AimsIgE type immunoglobulins and their specific effector cells, mast cells (MCs), are associated with abdominal aortic aneurysm (AAA) progression. In parallel, immunoglobulin-producing B cells, organised in tertiary lymphoid organs (TLOs) within the aortic wall, have also been linked to aneurysmal progression. We aimed at investigating the potential role and mechanism linking local MCs, TLO B cells, and IgE production in aneurysmal progression. Methods and ResultsThrough histological assays conducted on human surgical samples from AAA patients, we uncovered that activated MCs were enriched at sites of unhealed haematomas, due to subclinical aortic wall fissuring, in close proximity to adventitial IgE+ TLO B cells. Remarkably, in vitro the IgEs deriving from these samples enhanced MC production of IL-4, a cytokine which favors IgE class-switching and production by B cells. Finally, the role of MCs in aneurysmal progression was further analysed in vivo in ApoE-/- mice subjected to angiotensin II infusion aneurysm model, through MC-specific depletion after the establishment of dissecting aneurysms. MC-specific depletion improved intramural haematoma healing and reduced aneurysmal progression. ConclusionsOur data suggest that MC located close to aortic wall fissures are activated by adventitial TLO B cell-produced IgEs and participate to their own activation by providing support for further IgE synthesis through IL-4 production. By preventing prompt repair of aortic subclinical fissures, such a runaway MC activation loop could precipitate aneurysmal progression, suggesting that MC-targeting treatments may represent an interesting adjunctive therapy for reducing AAA progression.

pathology↗

bioRxiv2022

Putative SET-domain methyltransferases in Cryptosporidium parvum and histone methylation during infection

Cryptosporidium parvum is a major cause of an intestinal pathology called cryptosporidiosis which affects humans and other vertebrates. Despite being declared as a public health problem by World Health Organization (WHO) since 2006, pathogenesis caused by this parasite remains poorly understood. More recently, C. parvum has been linked with oncogenesis. In particular, the mechanisms involved in the processes of gene expression regulation are completely unexplored in Cryptosporidium. In the current study, we took the opportunity to investigate a dynamic epigenetic modification called histone lysine methylation during the life cycle of the parasite. We successfully identified putative SET-domain containing proteins, lysine methyltransferases (KMTs), which catalyze the methylation of different lysine residues. Phylogenetic analysis classified them into distinct subfamilies namely CpSET1, CpSET2, CpSET8, CpKMTox and CpAKMT. Structural analysis further characterized CpSET1, CpSET2 and CpSET8 to be histone lysine methyltransferases (HKMTs). Their functional significance was predicted by using site-specific methyl-lysine antibodies during development of the parasite (CpSET1:H3K4; CpSET2:H3K36; CpSET8:H4K20). In particular, the SET domain of CpSET8 showcased methyltransferase activity confirming the existence of functional HKMTs in Cryptosporidium. Moreover, the consequence of C. parvum infection on the host lysine methylation events highlights the inherit potential of the parasite to exploit the host epigenetic regulation to its advantage. Thus, this study is the first one to provide insights on epigenetics mechanisms occurring throughout the parasites life cycle and during the interaction with its host. As Cryptosporidium is a protozoan that significantly affects the health of both humans and animals, a better understanding of its developmental processes within the definitive host may highlight novel infection control strategies. Author SummaryCryptosporidium species have a very compact genome (~9.2 Mb) unlike its apicomplexan homologs such as Toxoplasma (~63 Mb). Moreover, the lack of large families of transcriptional factors requires them to heavily rely on chromatin remodeling components for its gene regulation. Thus, study and identification of novel elements which contribute to chromatin dynamics could assist a better understanding of the biology of this parasite. In the current study we investigated histone lysine methylation, a dynamic epigenetic modification which regulates gene activation as well as repression. More importantly, characterizing the enzymes which bring about this regulation, provides potential new druggable targets to attack the parasite.

microbiology↗