Fungal pathogen genome stability and adaptive potential depend on host immune status and pathogen ploidy Open Access

Smith, Amanda (Summer 2021)

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Candida albicans is the predominate opportunistic fungal pathogen of humans and can cause a broad range of infection, depending on host immune function. The interaction between the host and C. albicans facilitates the generation of natural variation and includes changes in ploidy. This natural variation is due to the high-level of genetic plasticity, where large-scale genome perturbations, including recombination, chromosomal aneuploidy, and whole-shifts in ploidy, are frequent. While research has demonstrated that genomic perturbations in C. albicans are frequent and lead to phenotypic heterogeneity, less is known about how host and pathogen genetic background impacts C. albicans genome dynamics and evolvability. To investigate how pathogen genetic background and ploidy impacts C. albicans genome dynamics in vivo, I evaluated the genome stability of three diploid and three tetraploid C. albicans strains representing different backgrounds within the host environment. I found that tetraploids rapidly undergo chromosome loss within the host environment regardless of genetic background, but diploids remain approximately diploid. However, clinical diploids had a higher frequency of loss-of-heterozygosity (LOH) compared to the laboratory diploid. Together, these findings suggest that C. albicans ploidy and genetic background impact the rate at which genotypic heterogeneity is generated within a host environment. Next, I evaluated how host genotype, specifically immune status, impacts C. albicans genome stability. Host-produced reactive oxygen species (ROS) elevated genome instability regardless of pathogen genetic background, but host-produced antimicrobial peptides (AMPs) only elevated C. albicans genome instability in one of the strains tested. These results suggest that a specific pathogen genotype and host genotype/environment (immunity) interaction is responsible for generating C. albicans genome instability. Finally, I investigated how host immunity and pathogen ploidy impact C. albicans virulence evolution. I predicted that more genetic variation would be generated in C. albicans evolved in immunocompetent hosts compared to immunocompromised hosts, enabling evolution to occur faster. Both diploid and tetraploid C. albicans evolved virulence rapidly in immunocompetent but not immunocompromised hosts, supporting my hypothesis that host immunity generates genetic heterogeneity in C. albicans that allows for evolution to occur. Additionally, I observed that tetraploids evolved faster than diploids likely due to their elevated instability and ability to generate genotypic diversity quicker. Together, this dissertation emphasizes the role both host and pathogen genotype have in generating pathogen genetic variation which enables adaptation.

Table of Contents

Chapter I: Introduction  1

1.1 Fungi are an important, but often overlooked component of the microbiome  1         

1.1.2 Defining Candida albicans as a pathogen according to the damage response

Framework  1

1.2.1 C. albicans interactions with the host immune system  2

1.2.2 Antimicrobial peptides mode of action against C. albicans  3

1.2.3 Reactive oxygen species mode of action against C. albicans   4

1.2.4 C. albicans evasion of immune detection and elimination  4

1.3 Generating genetic variation for adaptation  5

1.4 Consequences of genetic variation across different species  6

1.4.2 Genetic variation and adaptation to the host environment 7

1.5 Caenorhabditis elegans is a robust model system for investigating C. albicans 

 genome stability and virulence evolution 9

1.6 Summary 13

1.7 References 13

Chapter II: Host-induced Genome Instability Rapidly Generates Phenotypic

Variation across Candida albicans Strains and Ploidy States  21

2.1 Abstract 21

2.2 Importance  22

2.3 Introduction  22

2.4 Materials and Methods 25       

2.5 Results 32

2.6 Discussion 43

2.7 Acknowledgments 46

2.8 Tables & Supplemental Material 47

2.9 References 55

Chapter III: Host defense mechanisms induce genome instability in an

opportunistic fungal pathogen 60

3.1 Abstract 60

3.2 Introduction  61

3.3 Materials and Methods 63

3.4 Results  67

3.5 Discussion 77       

3.6 Acknowledgments  79       

3.7 Supplementary Material  80

3.8 References 85

Chapter IV: Host immunity and pathogen ploidy determine virulence evolution

 trajectories  90

4.1 Abstract  90

4.2 Introduction 91

4.3 Materials and Methods 94

4.4 Results 96

4.5 Discussion 105

4.6 References 107     

Chapter V: Discussion 111

5.1 Summary of results & contributions to the current literature  111

5.2 Outstanding Questions & Limitations 114

5.3 Future directions 117

5.4 Final Thoughts & Implications 118

5.5: References 119

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