Comparison of the immune response to typhoid fever and invasive nontyphoidal salmonella disease

Hart, Peter (2015). Comparison of the immune response to typhoid fever and invasive nontyphoidal salmonella disease. University of Birmingham. Ph.D.

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Nontyphoidal \(Salmonella\) is strongly associated with HIV infection, whereas there is a negative association between HIV and typhoid fever. To investigate this phenomenon, we explored humoral and cytokine responses in HIV-infected and uninfected blood and sera against \(S.\) Typhimurium and \(S.\) Typhi, finding that HIV-infected sera had significantly impaired bactericidal and opsonic activity against \(S.\) Typhi compared with HIV-uninfected sera. We observed dysregulated cytokine responses in blood from HIV-infected individuals after Salmonella stimulation, with RANTES levels being modulated by HIV status and \(Salmonella\) serovar. Most \(S.\) Typhi isolates express Vi capsule and O:9 O-antigen. The roles played by the Vi capsule and by anti- \(S.\) Typhi antibody in infection are unclear. Effective vaccines against typhoid exist, but the mechanisms of protection afforded by the antibody they elicit is poorly characterised. We investigated the role of Vi capsule and anti-S. Typhi antibody in the killing of \(Salmonella\). Using isogenic Vi+/- \(Salmonella\) we show that Vi-expression is associated with reduced antibody and complement deposition on \(Salmonella\) and increased resistance to serum and phagocyte killing. We characterised the bactericidal and opsonic activity of purified human anti-Vi and anti-O:9 antibodies against \(S.\) Typhi, finding that both antibodies kill \(Salmonella\) but anti-O:9 antibody has poor opsonic activity.

Collectively our data suggest cytokine, but not antibody, dysregulation may underlie the dichotomy of \(Salmonella\) infection in the context of HIV. We demonstrate that both anti-capsular and anti-O-antigen antibodies elicit bactericidal activity against \(S.\) Typhi but anti-O:9 antibody is a poor opsonin. This has implications in the development of O:9 vaccines against O:9 –expressing \(Salmonellae\).

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: School of Immunity and Infection
Funders: None/not applicable
Subjects: R Medicine > RC Internal medicine


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