Immunology and Pathogenesis of Acute and Relapsing Malaria Open Access
Joyner, Chester (Fall 2017)
Abstract
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
References
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