Immunology and Pathogenesis of Acute and Relapsing Malaria Open Access

Joyner, Chester (Fall 2017)

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Malaria is a global public health problem that causes significant mortality and morbidity each year. The two predominate malaria parasites that infect humans are Plasmodium falciparum and Plasmodium vivax. Over the past 40 years, malaria research has predominately focused on P. falciparum since this parasite causes the most malaria-related mortality. Although necessary, this focus has stifled progress on understanding the biology, epidemiology, and pathogenesis of P. vivax. These gaps of knowledge are now major obstacles towards malaria eradication.

The studies carried out in this dissertation aimed to improve our understanding of the immunology and pathogenesis of acute and relapsing vivax malaria by capitalizing upon the rhesus macaque – Plasmodium cynomolgi model of P. vivax infection. An initial study performed a detailed characterization of the development of disease, especially during acute infections and relapses, after infecting a cohort of rhesus macaques with P. cynomolgi. The collection of such data for this animal model of malaria was unprecedented and now provides the most comprehensive characterization of pathogenesis to date. Two major results from this initial study were that there was insufficient compensation by the bone marrow for anemia during acute infection and that relapses did not necessarily result in the development of illness.

Insufficient erythropoiesis has been previously reported in individuals infected with P. vivax, but the underlying mechanisms that govern this process have been unclear. Here, these mechanisms were explored using bone marrow aspirates collected throughout the rhesus macaque infections. The results of this study led to the conclusion that monocyte-driven inflammation may disrupt transcriptional networks that are critical for erythropoiesis during acute infections, ultimately resulting in insufficient erythropoiesis. Specifically, GATA1 and GATA2, which are two master regulators of erythroid differentiation in the marrow, were suggested to be dysfunctional. Future studies are now warranted to identify the molecules that may antagonize these proteins during acute malaria.

Relapses have been suggested to be responsible for a significant portion of vivax malaria disease burden, and thus, the lack of illness during relapses caused by P. cynomolgi was unexpected. A follow-up study was designed to address the question whether other infection scenarios (i.e. homologous reinfections or heterologous infections) could be responsible for more clinical cases of vivax malaria than previously realized. Samples from these infections were also used to characterize the immune responses that were important for conferring clinical protection in each of these infections. This study suggested that heterologous infections may be responsible for a greater portion of clinical vivax malaria in endemic areas than previously recognized and also demonstrated that a memory B-cell response was critical for suppressing parasite growth to prevent the development of illness during relapses and homologous reinfections.

Overall, the studies in this dissertation support use of the rhesus macaque – P. cynomolgi infection model of vivax malaria to answer burning questions at the forefront of vivax malaria research. These investigations have advanced the field in understanding clinical aspects of the infections, pathogenesis, and immunity. 

Table of Contents

Chapter I: Introduction to Vivax Malaria: Relapses, Pathogenesis, and Nonhuman Primate Models 1

Introduction 1 Plasmodium vivax Relapses 2

Vivax Malaria Pathogenesis 6

NHP Malaria Model Systems 10

Vivax Malaria – NHP Models 11

Simian Parasite – NHP Models for Vivax Malaria 12

Summary 13

References 15

Chapter II: Plasmodium cynomolgi infections in rhesus macaques display clinical and parasitological features pertinent to modeling vivax malaria pathology and relapse infections 21

Abstract 22

Background 24

Methods 27

Results 34

Primary and relapsing parasitological profiles of P. cynomolgi B strain in M. mulatta during a 100-day experimental infection 34

Different degrees of anemia were observed during the primary blood-stage infections 35

Thromobcytopenia developed during the primary blood-stage infections 36

Relapses did not result in significant changes in clinical parameters 37

Clinical presentations ranged from non-severe to lethal 38

Parasitemia and the lack of an increase in reticulcoytes during the initial phase of the primary infection distinguish the lethal clinical phenotype 39

Discussion 41

Conclusion 46

Chapter III: Severe and complicated cynomolgi malaria in a rhesus macaque resulted in similar histopathological changes as those seen in human malaria 62

Abstract 63

Introduction 64

Methods 65

Results 66

Clinical presentation 66

Physical Examination 66

Gross Pathology 66

Histopathology 67

Discussion 69

Chapter IV: Integrative analysis implicates monocytes in inefficient erythropoiesis during acute Plasmodium cynomolgi malaria in rhesus macaques 83

Abstract 84

Background 85

Methods 87

Results 92

Insufficient compensation for anemia during acute cynomolgi malaria in rhesus macaques 92

Acute malaria, but not relapses, leads to substantial changes in the bone marrow transcriptome 93

Pathways and processes altered in the bone marrow during acute malaria 94

Intermediate and non-classical monocytes may negatively impact the erythroid lineage during acute malaria 96

Intermediate and non-classical monocytes are associated with pathways upregulated during acute malaria in the bone marrow 97

Transcriptional networks related to erythropoiesis are disrupted in the bone marrow during acute malaria 99

Discussion 101

Conclusion 106

Chapter V: Malaria relapses expand B-cell memory that provides strain-specific protection against reinfection 158

Introductory Paragraph 159

Main Text 160

Methods 165

References 165

Chapter VI: Discussion 197

The Plasmodium cynomolgi – rhesus macaque model is an excellent animal model for vivax malaria 197

Inflammation and disruption of GATA1/GATA2 transcriptional programs contribute to inefficient erythropoiesis during acute cynomolgi malaria in macaques 200

Heterologous infections, and not relapses, may be responsible for clinical disease in endemic areas 204

Memory B-cells mediate clinical protection during relapses and homologous reinfections 207

Summary 210


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