Competition and cooperation of respiratory pathogens in spatially structured environments 公开
Jacobs, Nathan (Summer 2019)
Published
Abstract
The focus of this dissertation is the interactions that occur between respiratory pathogens during infection, specifically between members of the same species. The human respiratory tract is home to many microorganisms, both commensal and pathogenic. Two common pathogens are Streptococcus pneumoniae and influenza A viruses. S. pneuomoniae forms biofilms in the upper respiratory tract during colonization, but causes severe disease when it disseminates to the middle ear, lungs, or bloodstream. Disease severity is correlated with capsular serotype, and many colonized individuals carry multiple serotypes, making the dynamics of competition during nasopharyngeal colonization important for predicting an individual’s risk of disease. Co-colonization experiments were conducted, and it was determined that pneumococcal serotypes compete in a contact-dependent manner, but not through previously described mechanisms of fratricide in bacterial biofilms. The genome of influenza A virus comprises eight distinct RNA segments, with all segments being necessary for the production of progeny virions. At low concentrations, many cells infected by a single virus particle contain only a subset of the genome, but complementation through cellular co-infection can allow successful production of progeny. The frequency of incomplete genomes was measured in a model influenza A virus strain and the results were used to parameterize computational models to estimate the fitness costs of genome segment loss. Experimental investigations then revealed that the spatial structure inherent in replication and virus spread provide sufficient complementation, mitigating many of the costs of incomplete genomes. These results highlight the importance of spatial structure and intraspecific interactions in the dynamics of respiratory infections.
Table of Contents
Chapter 1: Introduction1.1 Overview 1
1.2 Competition in the pneumococcus 8
1.3 Cooperation in influenza A virus infections 9
Chapter 2: Competitive Dominance within Biofilm Consortia Regulates the Relative Distribution of Pneumococcal Nasopharyngeal Density
2.1 Abstract 11
2.2 Introduction 12
2.3 Methods 15
2.4 Results 23
2.5 Discussion 40
Chapter 3: Incomplete influenza A Virus Genomes Occur Frequently but are Readily Complemented During Localized Viral Spread
3.1 Abstract 46
3.2 Introduction 47
3.3 Results 50
3.4 Discussion 79
3.5 Computational Methods 84
3.6 Experimental Methods 93
Chapter 4: Discussion4.1 Overview 105
4.2 Discussion of Chapter 2 105
4.3 Discussion of Chapter 3 107
Chapter 5: Appendix5.1 Probabilistic model of cellular infection (Figure 3.2) code 113
5.2 Probabilistic model of population infection (Figure 3.3) code 115
5.3 Individual-based model of replication (Figure 3.4) code 115
5.4 Supplement to Chapter 3 126
5.5 References 133
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