T cell immunity during co-infection with Mycobacterium tuberculosis and Schistosoma mansoni 公开

Abstract

Tuberculosis (TB) and schistosomiasis are two of the greatest contributors to global health disparity. Mycobacterium tuberculosis (Mtb), the bacteria that causes TB, infects nearly one quarter of the world. While most infected people do not develop symptoms and are considered latently infected (LTBI), due to the high prevalence of infection, 10 million people developed TB disease in 2018 alone. In fact, TB results in 1.5 million deaths annually, making Mtb the deadliest pathogen in the world. Schistosomiasis affects 200 million people globally, over 90% of whom reside in Sub-Saharan Africa. While schistosomiasis is not often fatal, Schistosoma mansoni (SM), one of five species of schistosome helminths that infects humans, results in an estimated 130,000 deaths annually in Africa.

Classically, the immune response to Mtb and helminths such as SM are characterized by type 1 T cell responses and type 2 T cell responses, respectively. These immune responses have been shown to antagonize one another during mouse models of infection. Furthermore, co-infection with filarial or soil-transmitted helminths has been shown to result in impaired type 1 immunity to Mtb. It is currently unknown whether or not SM also impairs type 1 immunity in TB. Furthermore, the impact of Mtb on immunity to SM has not been evaluated. Due to the geographic overlap of TB and schistosomiasis, it is important to evaluate the immune response during coinfection with Mtb and SM and determine the effect of SM infection on TB disease. We hypothesized that SM infection would impair Mtb-specific type 1 immunity and lead to increased TB disease, but that Mtb would not impact SM immunity.

To address these hypotheses, we used a cohort of SM- and SM+ individuals across a spectrum of Mtb infection states from Kisumu Kenya, to conduct a thorough examination of T cell responses to both organisms. We found that while T cell responses to Mtb are preserved during co-infection with SM, T cell responses to SM are impaired in people with Mtb infection. Our findings also highlight a previously unrecognized response of peripheral γδ T cells to SM worms. In addition, we utilized a novel machine learning approach to measure the probability of TB disease due to co- infection with SM. We found that in HIV+ but not HIV- individuals, SM was associated with a higher probability of TB disease. Overall, our findings provide novel insights into T cell responses during co-infection and highlight the ability of the immune system to concurrently respond to diverse pathogens. 

Table of Contents

Chapter 1 Introduction_____________________________________________ 1

1.1 Tuberculosis _____________________________________________________________ 2

1.1.1 Cause _______________________________________________________________ 2

1.1.2 Global Burden of Disease _______________________________________________ 3

1.1.3 Pathogenesis _________________________________________________________ 4

1.1.4 Diagnosis____________________________________________________________6

1.1.5 Treatment ___________________________________________________________ 8

1.1.6 Coinfections and Comorbidities __________________________________________ 9

1.2 Schistosomiasis _________________________________________________________ 11

1.2.1 Causes _____________________________________________________________ 11

1.2.2 Global Burden of Disease ______________________________________________ 12

1.2.3 Pathogenesis ________________________________________________________ 13

1.2.4 Diagnosis___________________________________________________________14

1.2.5 Treatment __________________________________________________________ 15

1.3 T cell immunity _________________________________________________________ 17

1.3.1 The immune system and infection _______________________________________ 17

1.3.2 CD4 T Cell Subsets ___________________________________________________ 19

1.3.3 Immunity to Tuberculosis ______________________________________________ 20

1.3.4 Immunity to Schistosomiasis ___________________________________________ 21

1.4 Dissertation Overview ____________________________________________________ 23

1.5 Figures ________________________________________________________________ 25

Chapter 2 CD4 T cells in Mycobacterium tuberculosis and Schistosoma mansoni co-infected individuals maintain functional TH1 responses ______ 33

2. 1 Abstract _______________________________________________________________ 34

2.2 Introduction ____________________________________________________________ 36

2.3 Materials and Methods ____________________________________________________ 40

2.4 Results ________________________________________________________________ 46

2.5 Discussion _____________________________________________________________ 55

2.6 Tables and Figures _______________________________________________________ 61

Chapter 3 Adults from Kisumu, Kenya have robust γδ T cell responses to Schistosoma mansoni, which are modulated by tuberculosis _____________ 76

3.1 Abstract _______________________________________________________________77

3.2 Introduction ____________________________________________________________ 78

3.3 Materials and Methods ____________________________________________________ 81

3.4 Results ________________________________________________________________ 87

3.5 Discussion _____________________________________________________________ 92

3.6 Tables and Figures _______________________________________________________ 97

Chapter 4 Schistosoma mansoni Infection is Associated with a Higher Probability of Tuberculosis Disease in HIV+ Adults in Kisumu, Kenya ___ 111

4.1 Abstract ______________________________________________________________112

4.2 Introduction ___________________________________________________________ 113

4.2 Materials and Methods ___________________________________________________ 116

4.3 Results _______________________________________________________________ 119

4.4 Discussion ____________________________________________________________121

4.5 Tables and Figures ______________________________________________________ 125

Chapter 5 Discussion ____________________________________________ 131

5.1 SM Does Not Impair TH1 Immunity ________________________________________ 133

5.1.1 Summary __________________________________________________________ 133

5.1.2 Implications________________________________________________________133

5.1.3 Future Directions____________________________________________________134

5.2 Mtb Impairs SWAP-reactive γδ T cells______________________________________137

5.2.3 Future Studies ______________________________________________________ 139

5.3 SM HIV Co-infection Increase Probability of TB ______________________________ 142

5.3.1 Summary __________________________________________________________ 142

5.3.2 Implications________________________________________________________142

5.4 Overall Conclusions _____________________________________________________ 146

References _________________________________________________________________147 

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Immunology and Molecular Pathogenesis
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Microbiology Health Sciences, Epidemiology Health Sciences, Immunology
关键词	Global Health Epidemiology Machine Learning Neglected Tropical Diseases Parasitology Helminth T cell Schistosomiasis Tuberculosis HIV Immunology
Committee Chair / Thesis Advisor	Cheryl L. Day, Emory University
Committee Members	Lawrence Boise, Emory University Haydn T. Kissick, Emory University William Evan Secor, CDC David S. Weiss, Emory University

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