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Purpose: PI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells., Methods: Clinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells., Results: Clinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization., Conclusion: By altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related disorder causes a syndromic inborn error of immunity presenting with B-cell deficiency and hypogammaglobulinemia., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Coronavirus disease (COVID-19) is an infectious disease caused by the newly discovered coronavirus, Sars-Cov-2. This infection can cause mild to very severe respiratory and systemic illness mainly related with a cytokine storm. The epidemiology of COVID-19 is under continuous evolution, and studies are ongoing aiming at identifying the possible factors facilitating the diffusion of this infection. It is documented that air pollution and smoking are a leading cause of human morbidity and mortality globally, and can increase the risk of many diseases, including respiratory diseases. Overall, a linear relationship between exposure to atmospheric pollutants and diffusion of the Sars-Cov2 virus seems to exist. However, this correlation, cannot be regarded as a cause-effect relationship.  The available data show that air pollution is responsible for inflammation and hyper-activation of innate immunity that are associated with the worst outcomes of covid-19 but do not allow to conclude that atmospheric particulate is responsible for increased contagion. As to smoking, nicotine activation of nicotinic receptors leads to enhanced protease activation, apoptosis and inflammatory signaling through the same pathways (Renin-angiotensin system (RAS) and angiotensin-converting enzyme 2 (ACE2)) used by the virus increasing the inflammatory/destructive action of the virus itself. The increase in non-communicable diseases and of chronic inflammatory diseases is in line with environmental pollution, related climate changes, and with an augmented susceptibility to infectious diseases with increased contagiousness and morbidity. Restrictive measures to limit environmental pollution are needed worldwide as this represents a threat for human health.

Background: Most clinical isolates of Vibrio parahaemolyticus produce a major virulence factor known as the thermostable direct hemolysin (TDH). TDH is encoded by the tdh gene which is located in a genomic pathogenicity island (PAI). Most environmental isolates are described as tdh negative., Aim: To assess if environmental strains lack the full pathogenicity island or if only the tdh gene is deleted., Material and Methods: Thirty eight clinical and 66 environmental strains of Vibrio parahaemolyticus were studied. PAI was characterized by polymerase chain reaction (PCR). The presence of tdhA and tdhS genes, was determined by Southern blot., Results: Fifty three environmental strains (80%) lacked a full PAI when compared with clinical strains. In environmental strains, Southern blot and sequence analysis showed that a genetic region of 80 kilobase pairs including genes from VPA1310 to VPA1396 was missing., Conclusions: These results highlight the genetic dynamism of Vibrio parahaemolyticus pathogenecity island region and suggest that new pathogenic strains could appear by horizontal transfer of the island between toxigenic and non-toxigenic strains.