NK cell immunity in Mycobacterium tuberculosis and HIV infection Pubblico
Harris, Levelle (Summer 2020)
Abstract
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB) disease and is one of the most lethal infectious diseases known throughout human history. Most individuals that become infected establish latent infection and have a low risk of reactivation. Currently, it is estimated that one fourth of the global population has latent Mtb infection (LTBI). Each year, 10 million people develop active TB disease, resulting in 1.5 million deaths annually. Although the correlates of protective immunity to Mtb remain undefined, co-infection with human immunodeficiency virus (HIV) is one of the greatest risk factors for reactivation of LTBI and progression to TB disease. The increased risk of TB disease in people living with HIV has highlighted an important role for CD4 T cells in controlling Mtb infection, although many other immune cell populations also contribute to a successful immune response to Mtb. Natural killer (NK) cells have the capacity to rapidly respond to pathogens and kill infected cells, and increasing evidence indicates that NK cells also mediate a wide range of immunomodulatory effects that contribute to shaping the immune response generated after infection or vaccination.
NK cells are classically associated with cancer immunity but more recently have been shown to be involved in immune response to many infectious diseases. In the context of Mtb, NK cells secrete cytokines and cytotoxic molecules that have antimicrobial functions and have also been shown to suppress Mtb growth in macrophages. NK cell activity is regulated through expression of various activating and inhibitory receptors, the expression of which changes in the setting of inflammation, infection, and cancer, and can give rise to differentiation of NK cell populations with specialized functions. We hypothesized that phenotypic and functional profiles of NK cells are modified in the setting of persistent Mtb infection and that co-infection with HIV may further dysregulate NK cell profiles, thus potentially contributing to the increased risk of active TB disease in people living with HIV.
To address these hypotheses, we analyzed NK cell responses in peripheral blood samples collected from cohorts of healthy, TB-unexposed adults in the United States and from cohorts of adults in western Kenya across a spectrum of Mtb and HIV infection states. We used multi-parameter flow cytometry to conduct detailed NK cell phenotyping studies and functional responses to both tumor cell lines and to Mtb antigens. We found that the expression of certain receptors by NK cells in Kenyan adults is markedly different from US adults and that expression of these receptors correlates with dampened effector functions to Mtb antigens in Kenyan adults. By analysis of HIV-infected and HIV-uninfected Kenyan adults with LTBI, we found that HIV infection is associated with perturbations in NK cell phenotype and reduced NK cell reactivity to antibody-coated target cells; however, NK cell cytokine production and degranulation following stimulation with Mtb antigens is similar between HIV-infected and HIV-uninfected Kenyan adults. Overall, our data provide novel insights into the effect of Mtb and HIV infection on the phenotypic and functional profiles of NK cells. These findings will help inform future studies designed to define NK cell correlates of protection against acquisition of Mtb infection and progression to TB disease.
Table of Contents
Table of Contents
Chapter 1. Introduction.. 9
1.1 History and Discovery of Mycobacterium tuberculosis. 10
1.2 Global burden of tuberculosis. 11
1.3 Symptoms of Mtb Infection. 13
1.4 Diagnostic Tests in Mtb. 14
1.5 TB Treatment. 15
1.6 Transmission of Mtb. 17
1.7 Cytokines Associated with Containment of Mtb. 18
1.8 Recognition of Mtb by the Innate Immune Response. 19
1.8.1 Formation of the Granuloma. 21
1.8.2 Macrophages. 22
1.8.3 Neutrophils. 24
1.8.4 Natural Killer Cells. 25
1.8.5 Dendritic Cells. 26
1.9 The Adaptive Immune Response to Mtb. 27
1.10 The Role of NK Cells in the Host Immune Response. 28
1.10.1 NK Cell Function. 29
1.10.2 NK Cells in HIV Infection. 30
1.10.3 NK Cells in Bacterial Infection. 30
1.10.4 Adaptive NK Cells. 31
Thesis Overview.. 33
Chapter 2. Distinct human NK cell phenotypes and functional responses to Mycobacterium tuberculosis in adults from TB endemic and non-endemic regions. 35
2.1 Abstract. 36
2.2 Introduction. 38
2.3 Materials and Methods. 42
2.4 Results. 47
2.5 Discussion. 55
2.6 Tables and Figures. 64
Chapter 3. The effect of HIV co-infection on NK cell phenotypic and functional profiles in Kenyan adults with LTBI 73
3.1 Abstract. 74
3.2 Introduction. 76
3.3 Materials and Methods. 80
3.4 Results. 85
3.4 Discussion. 91
3.5 Tables and Figures. 96
Chapter 4. CMV infection in healthy US adults is associated with dampened NK cell degranulation capacity to Mycobacterium tuberculosis. 104
4.1 Abstract. 105
4.2 Introduction. 106
4.3 Material Methods. 108
4.4 Results. 112
4.5 Discussion. 115
4.6 Tables and Figures. 118
Chapter 5. Discussion.. 124
5.1 Overview of findings. 125
5.2 Conclusion. 126
5.3 Future Implications. 127
References. 135
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