Competition and cooperation of respiratory pathogens in spatially structured environments Open Access

Jacobs, Nathan (Summer 2019)

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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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