Cross-kingdom effects of live attenuated influenza vaccination on dynamics of and disease due to respiratory bacterial pathogens within divergent ecological domains: Introducing the Generalized Herd Effect Open Access

Abstract

Community interactions between pathogens modulate both health and disease. These interactions might be expected to be most prevalent within gut, respiratory and other mucosal surfaces that harbor complex populations of commensal and, occasionally, pathogenic microbes. In the respiratory tract, multi- species interactions are ubiquitous. A well-known example is the often lethal synergy between influenza virus and Streptococcus pneumoniae - believed to be responsible for much of the mortality during the 1918 influenza pandemic. Though precise mechanisms underlying this interaction remain to be fully elucidated, evidence suggests that influenza virus infection enhances virulence of bacterial pathogens through a combination of virus mediated denudation of the epithelial barriers and by inhibiting proper antibacterial innate immune responses.

Although effects of influenza virus on bacterial colonization of the upper respiratory tract and invasion in the lower respiratory tract have been well established, what has not been considered is the natural extension of this relationship to the live-attenuated influenza vaccine (LAIV).

Here I detail direct within-host effects of a live-attenuated influenza vaccine (LAIV) and it's wild type parent strain on multiple serotypes of important bacterial pathogens (Streptococcus pneumoniae and Staphylococcus aureus) at the mucosal surfaces of the respiratory tract in mice. I find that LAIV, like WT influenza virus significantly enhances density and duration of bacterial carriage and incidence and severity of bacterial acute otitis media (AOM). In a departure from wild-type influenza infection, LAIV vaccination confers significant cross-kingdom protection against lethal pneumonia by the same pathogens that are exacerbated in the upper respiratory tract. Using mathematical modeling approaches, we demonstrate that individual level effects of LAIV on density in the nasopharynx can have profound impacts on bacterial pathogen dynamics across the population. We term these effects of a vaccine "generalized herd-effects" for their ability to confer herd-effects, both detrimental and beneficial, on pathogens outside of the vaccine target species. The results herein are the first to explore the direct effects of an established vaccine on the within- or between-host dynamics of pathogens within divergent ecological domain from the vaccine target species.

Table of Contents

Chapter 1. Influenza and bacterial Coinfections............................................................ 1 1.1 Introduction.............................................................................................. 1 1.2 Evidence from the 19th century - present...................................................... 4 1.3 Influenza and Bacterial Dynamics................................................................. 9 1.4 Windows of susceptibility............................................................................. 16 1.5 Influenza And Non-Specific bacterial adherence.............................................. 19 1.6 Influenza and Specific Bacterial Adherence..................................................... 20 1.7 Influenza and Mucociliary Clearance.............................................................. 26

1.8 Influenza and the innate immune response to Coinfection................................ 27

1.9 Resistance vs. Tolerance To Tissue Damage................................................... 45

1.10 Influenza induced hyperthermia and stress increase bacterial dissemination...... 47

1.11 Influenza Genotype Influences Bacterial Coinfection....................................... 47 1.12 PREVENTION AND TREATMENT STRATEGIES................................................. 50 1.13 Conclusion............................................................................................... 55 1.14 References............................................................................................... 57

Chapter 2. Live-attenuated influenza vaccine enhances colonization of Streptococcus pneumoniae and Staphylococcus aureus in mice 71

2.1 Abstract................................................................................................... 71 2.2 Importance............................................................................................. 72 2.3 Introduction............................................................................................ 72 2.4 Materials and Methods........................................................................... 75

2.5 Results..................................................................................................... 78

2.6 Discussion............................................................................................... 89 2.7 References.............................................................................................. 93

Chapter 3. Live attenuated influenza vaccination predisposes to and increases duration of bacterial acute otitis media in mice 97

3.1 Abstract................................................................................................... 97 3.2 Introduction............................................................................................ 98 3.3 Materials and Methods......................................................................... 100 3.4 Results................................................................................................... 103 3.5 DISCUSSION.......................................................................................... 109 3.6 References............................................................................................ 113

Chapter 4. Cross-kingdom protection against lethal bacterial infection by live attenuated vaccines 117

4.1 Abstract................................................................................................. 117 4.2 Introduction......................................................................................... 118 4.3 Materials and Methods......................................................................... 120 4.4 Results................................................................................................... 122 4.5 DISCUSSION.......................................................................................... 125 4.6 References............................................................................................ 129

Chapter 5. LAIV but not PCV protects against increased density and duration of pneumococcal carriage following influenza infection in pneumococcal colonized mice............................................................................ 133

5.1 Abstract................................................................................................. 133 5.2 Introduction......................................................................................... 134 5.3 Materials and Methods......................................................................... 135 5.4 Results................................................................................................... 137 5.5 Discussion:............................................................................................ 143 5.6 References............................................................................................ 146

Chapter 6. Dynamics of extended IFN-gamma exposure on murine MH-S cell-line alveolar macrophage phagocytosis of Streptococcus pneumoniae 149

6.1 Abstract................................................................................................. 149 6.2 Introduction......................................................................................... 149 6.3 Methods:............................................................................................... 151 6.4 Results:.................................................................................................. 156 6.5 Discussion............................................................................................. 160 6.6 Acknowledgements:............................................................................ 164

Chapter 7. Modelling cross-kingdom effects of vaccination: a live viral vaccine profoundly alters population level bacterial pathogen dynamics 167

7.1 Abstract................................................................................................. 167 7.2 Introduction......................................................................................... 168 7.3 Results................................................................................................... 173 7.4 Discussion............................................................................................. 185 7.5 Model Description................................................................................ 189 7.6 References............................................................................................ 210 Chapter 8. Conclusion............................................................................................. 215 Chapter 9. Supplementary Figures....................................................................... 220

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Population Biology, Ecology & Evolution
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Public Health Biology, Ecology Biology, Microbiology
Keyword	Streptococcus pneumoniae influenza bacterial coinfection Mathematical modeling Herd effect Influenza Staphylococcus aureus Live attenuated influenza vaccine
Committee Chair / Thesis Advisor	Klugman, Keith P, Emory University
Committee Members	Stephens, David S, Emory University Ahmed, Rafi, Emory University Omer, Saad B, Emory University McCullers, Jonathan, St. Jude Children's Research Hospital and University of Tennessee Health Sciences Center Vidal Graniel, Jorge, Emory University

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