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Natural Immunity to Salmonella in Humans

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Natural Immunity to Salmonella in Humans NATURAL IMMUNITY TO SALMONELLA IN HUMANS Thesis submitted in accordance with the requirements of the University of Malawi and University of Liverpool for the degree of Doctor in Philosophy by Tonney Stophen Nyirenda February 2015 University of Malawi and University of Liverpool DECLARATION DECLARATION THIS WORK HAS NOT PREVIOUSLY BEEN ACCEPTED IN SUBSTANCE FOR ANY DEGREE AND IS NOT BEING CURRENTLY SUBMITTED IN CANDIDATURE FOR ANY DEGREE Signed: ……………………………………………………………..... Tonney S. Nyirenda 10th February 2015 THIS THESIS IS THE RESULT OF MY OWN INVESTIGATION, EXCEPT WHERE OTHER WISE STATED. OTHER SOURCES ARE ACKNOWLEDGED AND BIBLIOGRAPHY IS APPENDED. Signed: ……………………………………………………………….. Tonney S. Nyirenda 10th February 2015 I HEREBY GIVE CONSENT FOR MY THESIS. IF ACCEPTED, TO BE AVAILABLE FOR PHOTOCOPYING AND FOR INTER-LIBRARY LOAN AND FOR THE TITLE AND ABSTRACT TO BE MADE AVAILABLE TO OUTSIDE ORGANISATIONS. Signed: ………………………………………………………………… Tonney S. Nyirenda 10th February 2015 i DECLARATION DECLARATION OF WORK DONE This work was part of four studies titled “Development of adaptive immunity to nontyphoidal Salmonella in Malawian children”, “Salmonella exposure and development of specific immunity in Malawian children”, “Development of T cell and antibody mediated immunity in response to invasive Salmonella infection” and “Ty21a oral typhoid vaccine induced immunity in the peripheral blood and gut mucosa of healthy adults”. All studies were under the supervision of Dr Melita Gordon, Dr Wilson Mandala, Prof Robert Heyderman and Prof Stephen Gordon. Some of the work in my study was shared among a number of individuals. My contributions for the reported work were as follows: Activity Responsibility Study designs and protocols shared Ethical applications shared Study community and health care workers sensitizations shared Participant’s recruitment and consent others Study participants follow up others Clinical assessment others Sample collection (stool, oropharynx swabs, blood, milk, biopsy) others HIV testing others Malaria testing others ii DECLARATION Blood stream infection surveillance others Immuno-phenotyping (IPT) sole Intracellular cytokine staining (ICS) sole Enzyme-linked immunosorbent assay (ELISA) s ole Serum Bactericidal Assay (SBA) sole Preparation of S. Typhimurium homogenate sole Development of real time PCR primers shared DNA extraction sole Real time PCR testing sole Development of Milk Bactericidal Assay sole Isolation of Salmonella in stool and oropharynx sole ELISpot shared iii ABSTRACT ABSTRACT Background: Salmonella bacteraemia is an important public health problem in children from sub Saharan Africa (SSA). Understanding what constitutes natural acquired immunity to Salmonella is crucial for the development of Salmonella vaccine. It was hypothesized that natural Salmonella exposure within the GIT and peripheral blood induces the generation of specific-antibodies and T cells and these might provide protection to subsequent Salmonella infection. Methods: Natural acquisition of antibody and T cell immunity to Salmonella was investigated in healthy and Salmonella infected Malawian children. Acquisition of typhoid vaccine induced T cell immunity in healthy adults from the United Kingdom (UK) was investigated to model natural immunizing events occurring within the gut associated lymphoid tissues (GALTs) following Salmonella infection. Acquisition of immunity was examined using immunological tools including the intra-cellular cytokine staining assay (ICS), serum bactericidal activity (SBA) assay, ELISA and ELISpot. Exposure to Salmonella was examined using microbiological tools including standard culture and real-time PCR. Principal findings: CD4+ T cells and IgG antibodies to Salmonella develops sequentially in under-five children. Acquisition of Salmonella-specific CD4+ T cells and antibodies coincides with the decline in S. Typhimurium bacteraemia cases in older children. As much as 47% of Malawian children (aged 6-18 months) are exposed to Salmonella at least once within the gastrointestinal tract (GIT). Natural Salmonella iv ABSTRACT exposure within the GIT is associated with development of potentially protective SBA in children. Invasive Salmonella infection elicits an increase in generation of Salmonella- specific CD4+T cells, IgG and IgA antibody secreting cells (ASC). Oral Ty21a vaccination (model of natural Salmonella infection) did not elicit an increase in generation of both CD4+Cytokine+ and CD8+Cytokine+ T cells in the peripheral blood and gut mucosa compartments at day 11, and day 18 post vaccination. Conclusion: Young children (<2 years of age) are more vulnerable to invasive Salmonella infection. Salmonella exposure within the GIT and peripheral blood compartments tissues facilitates acquisition of robust immunity (mediated by antibodies and T cells) in children and these might provide protection to subsequent Salmonella infection. Public health interventions are urgently required in SSA including vaccination with cross-protective Salmonella vaccine, improvements in sanitation, access to clean and safe water and food hygiene. v ACKNOWEDGEMENTS ACKNOWLEDGEMENTS Many thanks to my supervisors; Dr Melita Gordon, Dr Wilson Mandala, Prof Robert Heyderman and Prof Stephen Gordon for continuous support and guidance, without your input, I would not have a delivered a good quality PhD. I would also like to thank the following people for their contributions in various ways; my dear wife Deborah Nyirenda and sons Tamandani and Thanthwe for continuous support, understanding and encouragement, my research team; Hellen Mangochi, Rose Nkhata and Fiskani Chilongo for diligently collecting study specific data in the field, fellow researchers; Dr James Gilchrist, Shaun Pennington and Ndaru Kaluwa for the help you provided in performing some laboratory experiments, to fellow researchers; Dr Henry Mwandumba, Dr Kondwani Jambo and Dr Sarah Glennie for refining study ideas during laboratory meetings, Malawi Liverpool Wellcome Trust Clinical Research Programme (MLW) and Liverpool School of Tropical Medicine (LSTM), Blantyre Malaria Project (BMP), and Blantyre District Health Office for providing space and infrastructure for my studies and my collaborators Prof Calman MacLennan, Dr James Gilchrist, Prof Adam Cunningham, Dr Chisomo Msefula, Dr Nicholas Feasey, Dr Dean Everret, Dr Maaike Alerts and Dr Robert Kingsley for their support in providing Salmonella antigens, development of PCR test and also refining study ideas. I would like to thank the Wellcome Trust, Malawi Liverpool Wellcome Trust Clinical Research Programme (MLW), Commonwealth Scholarship Commission (CSC), and Consortium for Advanced Research Training in Africa (CARTA), Health Research Capacity Strengthening Initiative (HRCSI) and Knowledge Exchange Scheme (KE) for providing financial support for this PhD study. vi ACKNOWEDGEMENTS CARTA also tremendously contributed to refining research study ideas and analysis of the data through joint advanced seminars (JAS). Above all, I thank God Almighty for good health and ability to deliver a good quality PhD. vii TABLE OF CONTENTS TABLE OF CONTENTS DECLARATION…………………………………………………………………………. i DECLARATION OF WORK DONE …………………………………………………... ii ABSTRACT………………………………………………………………………………. iv ACKNOWLEDGEMENTS……………………………………………………………… vi TABLE OF CONTENTS………………………………………………………………… viii LIST OF FIGURES………………………………………………………………………. xvi LIST OF TABLES………………………………………………………………………... xix ABBREVIATIONS ………………………………………………………………………. xx CHAPTER 1: INTRODUCTION……………………………………………………….. 1 1. THEME AND OVERVIEW……………………………………………………………. 1 1.1 THE SALMONELLA BACTERIUM ……………………………………………….. 1 1.2 NOMENCLATURE ………………………………………………………………... 2 1.3 BURDEN OF SALMONELLA INFECTIONS IN HUMANS ……………………… 5 1.3.1 Geographical distribution and epidemiology of S. Typhi …………………….. 5 1.3.2 Geographical distribution and epidemiology of nontyphoidal Salmonella……. 8 1.3.3 Invasive NTS molecular genetics ……………………………………………… 9 1.3.4 Environmental risk factors …………………………………………………….. 11 1.3.4.1 Food and water ……………………………………………………………. 11 1.3.4.2 Transmission of Salmonella ……………………………………………… 11 1.4 CLINICAL FEATURES AND MANAGEMENT OF INVASIVE SALMONELLA DISEASE …………………………………………………………………………… 12 1.4.1 Clinical features of typhoid fever ……………………………………………… 12 1.4.2 Clinical presentation of invasive NTS disease (NTS bacteraemia) …………… 13 1.4.3 Treatment of typhoid fever …………………………………………………….. 13 1.4.4 Treatment of NTS bacteraemia ……………………………………………….. 15 1.5 S. TYPHIMURIUM AND S. TYPHI AS A PATHOGENS AND HOST ADAPTIVE DIFFERENCES ……………………………………………………….. 15 1.5.1 Flagella ………………………………………………………………………… 15 viii TABLE OF CONTENTS 1.5.2 Vi capsule ……………………………………………………………………… 16 1.5.3 Lipopolysaccharide ……………………………………………………………. 17 1.5.4 Salmonella Pathogenicity Island and Type Three Secretion System …………. 19 1.5.5 PhoP/PhoQ regulator …………………………………………………………... 20 1.6 IMMUNITY TO SALMONELLA INFECTION …………………………………… 21 1.6.1 Spread of ingested Salmonella to distant tissues via the GIT ……………….. 21 1.6.2 Innate immunity in response to Salmonella infection ………………………… 23 1.6.2.1 Activation of innate immune responses to Salmonella infection …………… 24 1.6.2.2 Phagocytosis and intracellular killing by phagocytes ……………………. 24 1.6.2.3 Phagocytes killing and the role of cytokines ……………………………… 26 1.6.2.4 Complement mediated immunity to Salmonella ………………………….. 27 1.6.3 Adaptive immunity to Salmonella …………………………………………... 28 1.6.3.1 Salmonella antigen processing and presentation by the APC ………….. 28
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