ABSTRACT
Epidemiological and immunological evidence suggests that some vaccines can reduce all-cause mortality through nonspecific changes made to innate immune cells. Here, we present the first data to describe the nonspecific immunological impact of oral vaccination with live-attenuated Salmonella Typhi strain Ty21a. We vaccinated healthy adults with Ty21a and assessed aspects of innate and adaptive immunity over the course of 6 months. Changes to monocyte phenotype/function were observed for at least 3 months. Changes to innate and adaptive immune cell cytokine production in response to stimulation with vaccine and unrelated nonvaccine antigens were observed over the 6-month study period. The changes that we have observed could influence susceptibility to infection through altered immune responses mounted to subsequently encountered pathogens. These changes could influence all-cause mortality.
Subject(s)
Polysaccharides, Bacterial/immunology , Salmonella typhi/immunology , Typhoid Fever/prevention & control , Typhoid-Paratyphoid Vaccines/immunology , Vaccination , Vaccines, Attenuated/immunology , Administration, Oral , Adult , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cytokines/metabolism , Female , Healthy Volunteers , Humans , Male , Middle Aged , Monocytes/immunology , Monocytes/metabolism , Polysaccharides, Bacterial/administration & dosage , Typhoid Fever/immunology , Typhoid Fever/metabolism , Typhoid-Paratyphoid Vaccines/administration & dosage , Vaccines, Attenuated/administration & dosage , Young AdultABSTRACT
INTRODUCTION: The pathogenicity at differing points along the aggregation pathway of many fibril-forming proteins associated with neurodegenerative diseases is unclear. Understanding the effect of different aggregation states of these proteins on cellular processes is essential to enhance understanding of diseases and provide future options for diagnosis and therapeutic intervention. OBJECTIVES: To establish a robust method to probe the metabolic changes of neuronal cells and use it to monitor cellular response to challenge with three amyloidogenic proteins associated with neurodegenerative diseases in different aggregation states. METHOD: Neuroblastoma SH-SY5Y cells were employed to design a robust routine system to perform a statistically rigorous NMR metabolomics study into cellular effects of sub-toxic levels of alpha-synuclein, amyloid-beta 40 and amyloid-beta 42 in monomeric, oligomeric and fibrillar conformations. RESULTS: This investigation developed a rigorous model to monitor intracellular metabolic profiles of neuronal cells through combination of existing methods. This model revealed eight key metabolites that are altered when neuroblastoma cells are challenged with proteins in different aggregation states. Metabolic pathways associated with lipid metabolism, neurotransmission and adaptation to oxidative stress and inflammation are the predominant contributors to the cellular variance and intracellular metabolite levels. The observed metabolite changes for monomer and oligomer challenge may represent cellular effort to counteract the pathogenicity of the challenge, whereas fibrillar challenge is indicative of system shutdown. This implies that although markers of stress are more prevalent under oligomeric challenge the fibrillar response suggests a more toxic environment. CONCLUSION: This approach is applicable to any cell type that can be cultured in a laboratory (primary or cell line) as a method of investigating how protein challenge affects signalling pathways, providing additional understanding as to the role of protein aggregation in neurodegenerative disease initiation and progression.
