An investigation into vaccine-mediated immune responses against invasive Salmonella Typhimurium infection

Persaud, Ruby Rene ORCID: 0000-0002-8626-5311 (2024). An investigation into vaccine-mediated immune responses against invasive Salmonella Typhimurium infection. University of Birmingham. Ph.D.

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Abstract

Salmonella enterica serovar Typhimurium is one of the main causative agents of invasive non-typhoidal Salmonella (iNTS) disease. Resistance to antimicrobial agents is a rising concern, complicating treatment, and prognosis. The need for effective preventative strategies against iNTS is crucial for controlling spread of infection and preventing severe disease. Outer membrane vesicles (OMVs) are naturally shed outer membrane blebs that mimic the bacterial surface and are being explored as a cost-effective vaccine against many infections. Understanding the immunological mechanisms that constitute successful vaccine responses is key for vaccine design. In this thesis, I explored specific innate immune components that are crucial for generating productive immune responses to vaccination with OMVs, resulting in improved ability to control iNTS infections in mice. I showed that complement component 3 (C3) was essential for protection in OMV-vaccinated and challenged mice. Further, I discovered a novel antigen persistence phenotype in OMV-vaccinated and challenged mice. Further investigation of this phenotype revealed that it is specific to OMVs with intact LPSO-Ag chains, and not induced by immunisation with subunit vaccines such as sFliC, or Salmonella Typhi-derived Vi polysaccharide or conjugated vaccines. This phenotype was not influenced by an absence of lymphoid cells, and depletion of macrophages altered the distribution of persistent antigen, however this phenotype was not associated with protection. The results presented in this thesis identify key immune components required for successful protection against iNTS infections in mice, but also potentially pathogenic phenotypes resulting from OMV-vaccination, which bare importance on vaccine design.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):