Host Control of Malaria Infections: Constraints on Immune and Erythropoeitic Response Kinetics

The two main agents of human malaria, Plasmodium vivax and Plasmodium falciparum, can induce severe anemia and provoke strong, complex immune reactions. Which dynamical behaviors of host immune and erythropoietic responses would foster control of infection, and which would lead to runaway parasitemia and/or severe anemia? To answer these questions, we developed differential equation models of interacting parasite and red blood cell (RBC) populations modulated by host immune and erythropoietic responses. The model immune responses incorporate both a rapidly responding innate component and a slower-responding, long-term antibody component, with several parasite developmental stages considered as targets for each type of immune response. We found that simulated infections with the highest parasitemia tended to be those with ineffective innate immunity even if antibodies were present. We also compared infections with dyserythropoiesis (reduced RBC production during infection) to those with compensatory erythropoiesis (boosted RBC production) or a fixed basal RBC production rate. Dyserythropoiesis tended to reduce parasitemia slightly but at a cost to the host of aggravating anemia. On the other hand, compensatory erythropoiesis tended to reduce the severity of anemia but with enhanced parasitemia if the innate response was ineffective. For both parasite species, sharp transitions between the schizont and the merozoite stages of development (i.e., with standard deviation in intra-RBC development time ≤2.4 h) were associated with lower parasitemia and less severe anemia. Thus tight synchronization in asexual parasite development might help control parasitemia. Finally, our simulations suggest that P. vivax can induce severe anemia as readily as P. falciparum for the same type of immune response, though P. vivax attacks a much smaller subset of RBCs. Since most P. vivax infections are nonlethal (if debilitating) clinically, this suggests that P. falciparum adaptations for countering or evading immune responses are more effective than those of P. vivax

Climate Change and Highland Malaria: Fresh Air for a Hot Debate

In recent decades, malaria has become established in zones at the margin of its previous distribution, especially in the highlands of East Africa. Studies in this region have sparked a heated debate over the importance of climate change in the territorial expansion of malaria, where positions range from its neglect to the reification of correlations as causes. Here, we review studies supporting and rebutting the role of climatic change as a driving force for highland invasion by malaria. We assessed the conclusions from both sides of the argument and found that evidence for the role of climate in these dynamics is robust. However, we also argue that over-emphasizing the importance of climate is misleading for setting a research agenda, even one which attempts to understand climate change impacts on emerging malaria patterns. We review alternative drivers for the emergence of this disease and highlight the problems still calling for research if the multidimensional nature of malaria is to be adequately tackled. We also contextualize highland malaria as an ongoing evolutionary process. Finally, we present Schmalhausen's law, which explains the lack of resilience in stressed systems, as a biological principle that unifies the importance of climatic and other environmental factors in driving malaria patterns across different spatio-temporal scales

Human malarial disease: a consequence of inflammatory cytokine release

Malaria causes an acute systemic human disease that bears many similarities, both clinically and mechanistically, to those caused by bacteria, rickettsia, and viruses. Over the past few decades, a literature has emerged that argues for most of the pathology seen in all of these infectious diseases being explained by activation of the inflammatory system, with the balance between the pro and anti-inflammatory cytokines being tipped towards the onset of systemic inflammation. Although not often expressed in energy terms, there is, when reduced to biochemical essentials, wide agreement that infection with falciparum malaria is often fatal because mitochondria are unable to generate enough ATP to maintain normal cellular function. Most, however, would contend that this largely occurs because sequestered parasitized red cells prevent sufficient oxygen getting to where it is needed. This review considers the evidence that an equally or more important way ATP deficency arises in malaria, as well as these other infectious diseases, is an inability of mitochondria, through the effects of inflammatory cytokines on their function, to utilise available oxygen. This activity of these cytokines, plus their capacity to control the pathways through which oxygen supply to mitochondria are restricted (particularly through directing sequestration and driving anaemia), combine to make falciparum malaria primarily an inflammatory cytokine-driven disease

Uncovering the role of IFNAR1 in Experimental Cerebral malaria

Dissertation presented the Ph.D degree in BiologyCerebral malaria is a severe and fatal form of clinical Plasmodium falciparum infection, resulting in brain injury from a damaging cascade of vascular, inflammatory and immunological host responses. However progression to cerebral malaria can be modified by host genetic factors. This thesis work extensively reveals the role of Interferon type I receptor (IFNAR1) in the development of Experimental cerebral malaria, through the use of the mouse model Ifnar1-/-. We found Ifnar1-/- mice protected from Experimental cerebral malaria upon infection with Plasmodium berghei ANKA-GFP, compared with susceptible wild-type C57BL/6 mice. Ifnar1-/- mice showed diminished blood brain barrier breakage, despite parasite accumulation in the periphery and accumulation of immune cells within the brain tissue during infection.(...

Functional antibody responses to the Plasmodium falciparum merozoite

Plasmodium falciparum is a leading cause of death among children under the age of five and pregnant women in sub-Saharan Africa. More than one third of the world’s population is at risk of contracting malaria, and 70 % of the cases are found in sub-Saharan Africa. Emerging drug resistance in parasites and limited effect of vector control calls for an effective vaccine. It is known that individuals living in malaria endemic countries develop naturally acquired immunity after repeated exposure. Antibodies are important components of acquired immunity, and it has been shown that passive transfer of antibodies from immune donors to individuals with P. falciparum infections reduced parasitemia and clinical symptoms. Antibodies against several P. falciparum merozoite antigens have been found to be associated with protective immunity. It is of great importance to understand the underlying functional role of antibodies in the development of protective immunity against severe malaria. In a cross-sectional study in Uganda, the quantitative and qualitative differences in antibody responses to a panel of merozoite antigens in children with uncomplicated or severe malaria were evaluated using a set of assays including ELISA, Invasion Inhibition Assays (IIA), NH4SCN-ELISA and Surface Plasmon Resonance (SPR). Children with uncomplicated malaria had higher antibody levels against PfEBA-181, MSP2-Fc27, MSP2-3D7 and PfAMA1 when compared to children with severe malaria. Acquired antibodies against PfRh2 and PfAMA1 in ELISA correlated with invasion inhibition of two clinical isolates in IIA, and anti-PfAMA1-antibodies in ELISA correlated with increased anti- PfAMA1-antibody affinity in SPR. Importantly, the only assay that correlated with initial parasitemia in the children was the IIA. Both MSP2-Fc27 and MSP2-3D7 allelic variants were present in both children groups, but there was a higher number of genotypes in uncomplicated malaria compared to in children with severe malaria. P. falciparum clinical isolates collected from Ugandan children with uncomplicated malaria or severe malaria were further investigated for rosetting, parasite multiplication and RBC invasion. Optimal in vitro growth conditions were established, which allowed for phenotypic studies of clinical P. falciparum isolates. Presence of serum in growth cultures was found to be essential for optimal surface presentation of PfEMP1 and maintenance of rosettes. Higher peripheral parasitemia, higher rosetting levels and higher multiplication rates were observed in children with severe malaria and these correlated positively with one another. Rosetting might enhance successful merozoite invasion in vivo, hence could be the reason it is found to be associated with severe disease. Furthermore, parasite invasion into trypsinand chymotrypsin-treated RBC differed between the uncomplicated and severe groups, and isolates from children with uncomplicated malaria showed higher sensitivity to enzyme treatment. The majority of clinical isolates used a sialic acid independent invasion pathway. Parasite invasion is central to parasite replication and virulence, and it is essential to know which invasion pathways are used for vaccine studies. Naturally acquired antibody responses to P. falciparum merozoite antigens was further studied in a longitudinal study over almost one year in children and adults from Nigeria. The malaria protective effects of the hemoglobin S (HbAS) allele were also investigated. In both children and adults, the antibody response against PfEBA175 was more prominent than that against PfRh2, and cytophilic IgG1 and IgG3 against PfEBA175 were the predominant antibodies even though we could also see some response for IgG2 and IgG4. Individuals with higher total IgG responses against both PfEBA175 and PfRh2 had lower parasitemia over the course of the study period. Furthermore, children with HbAS had higher antibody responses against merozoite antigens compared to adults, and this might have protective effects against malaria. In conclusion this thesis emphasizes the great importance of using a combination of functional assays, such as SPR and IIA, to study the functional role of acquired antibodies in the development of protective immunological responses against severe malaria. Furthermore, investigations of parasite invasion and rosetting in the context of pathogenesis of severe malaria are crucial as both are important for parasite replication and virulence. Taken together, future vaccine studies should include functional assays that would allow the investigation of differences in immunological responses against severe and uncomplicated malaria. Also, to consider the protective effects of red blood polymorphisms and their role in acquired immunity in the populations, would be of great value for future vaccine studies

Colorado State University, College of Veterinary Medicine and Biomedical Sciences, 8th annual CVMBS research day scientific proceedings

Includes the Pfizer Research Award winner and abstracts only of the oral sessions and posters

Maternal-child health - interdisciplinary aspects within the perspective of global health

Maternal-Child Health is one of the greatest challenges the world has to cope with today. Every year, thousands of women, newborns and children die unnecessarily, particularly in resource-poor settings. There is a great disparity caused by food insecurity and hunger, environmental health risks, sanitation challenges, cultural barriers and non-accessibility to diagnosis and treatment. "Maternal-Child Health: Interdisciplinary Aspects within the Perspective of Global Health" addresses these issues. The contributions of this book are based on the ONE HEALTH concept by focusing on infectious and non-communicable diseases and to present interdisciplinary views from more than 60 authors who come from 14 countries. The aim is to shape our understanding on Maternal-Child Health Solutions by looking at > agricultural and environmental > economic, social and theological > biomedical and nutritional > clinical human and veterinary as well as > epidemiology and > public health expertise. The Göttingen International Health Network is corresponding to a variety of different geographic regions and programs to improve global health perspective and health of the most vulnerable: mothers and their children

Immune response and tissue cytoprotection: two sides of the same coin in immunopathology

Dissertation presented to obtain the Ph.D degree in BiochemistryThe immune system is fundamental to maintaining the host’s viability upon infection. Nonetheless, the mechanisms used to control pathogens may also cause tissue damage, leading to the development of immunopathology. The host’s capacity to survive infections depends on its ability to control the pathogen burden, while avoiding the deleterious effect of immune responses on its own tissues. To achieve this goal, the host may apply the following strategies: increasing tissue resilience to immune-mediated insult and/or controlling exacerbated immune activation. This Thesis sought insight into the mechanisms used by the host to successfully employ both strategies(...)The work presented on this Thesis has been funded by the grant SFHR/BD/33218/2007 from Fundação para a Ciência e Tecnologi

Explorations into host defense against Plasmodium falciparum: mechanistic and structure-function studies of antimalarial chemokines

Antimicrobial peptides (AMPs) are small (2-8kDa) peptides that have remained an important part of innate immunity over evolutionary time. AMPs vary greatly in sequence and structure, but display broad-spectrum activity against bacteria, yeast, and fungi via direct perturbation of the pathogen membrane. AMPs are typically amphipathic, and contain 2-4 positively charged amino acid residues. It has been previously shown that many chemokines also display AMP activity, both via their canonical function recruiting immune cells to the site of an infection and by direct interaction with the pathogen itself. Many antimicrobial chemokines have the same tertiary structure: an N-terminal loop responsible for receptor recognition; a three-stranded antiparallel β-sheet domain that provides a stable scaffold; and a C-terminal α-helix that folds over the β-sheet and helps to stabilize the overall structure. The α-helix of these chemokines tends to be amphipathic and retains AMP activity on its own. The work presented here focuses on two antimicrobial chemokines - platelet factor 4 (CXCL4/PF4) and macrophage inflammatory protein-3α (CCL20/MIP-3α) - and shows that they have activity against the malaria parasite. Chapter 2 details the exploration into the mechanism of action of PF4 against P. falciparum, and the translation of this mechanism to small molecules that mimic antimicrobial peptides. Additionally, this antimalarial activity is also present in a mouse model of malaria. Chapter 3 focuses on finding additional chemokines with antimalarial activity, and explores the structure-function relationship between the conserved domains and how they modulate i) the antimalarial activity, and ii) provide a protective scaffold to prevent harm to host cells. We provide evidence that PF4 and small molecule mimics of AMPs kill parasites by exclusively lysing the digestive vacuole. Furthermore, the C-terminal α-helix of PF4 and CCL20 are the active components of each chemokine, and are necessary for parasite killing. The N-terminal loop is necessary to stabilize the tertiary structure of each chemokine, providing a stable scaffold that aides in the selectivity to protect host cells. Taken together, these data suggest that antimicrobial chemokines and small molecule mimics may provide an interesting scaffold and mechanism for potential therapeutics for the fight against malaria

Increasing Malaria Risk in Eastern Africa. A Multi-Causal Analysis

Global climatic change has been analysed as a key driving force of social-ecological change in the coming decades. The increasing spread of Malaria due to warming is named as a major future problem of East Africa. In contrast to much of northern and southern Africa more humid conditions are expected for countries like Kenya, Uganda and Tanzania. Next to changing precipitation patterns and a profound snow melt on the glaciers of Mt. Kilimandjaro and Mt Kenya, warming and potentially higher rates of precipitation may bring about higher rates of Malaria infection. In fact, the empirically recorded cases of Malaria infections in the region seemingly support this argument. Infection rates have been constantly rising over the past two decades and many areas that had not been affected by Malaria for many decades, now have seasonal Malaria epidemics. It is especially the densely settled zone between 1500m and 2000m – the highly fertile Kenyan highlands – which seem to be affected most. Hence many indicators suggest a strong correlation between climatic change and the increase in Malaria. Barbara Solich shows that underlying social-ecological processes are much more complex than that. In a multi-causal analysis she is able to show that a number of other factors may have even a greater effect on Malaria rates than climatic change. In order to present her argument systematically Solich first of all gives a short out-line of the state of research. Unfortunately most research on increasing Malaria rates in East Africa is concentrating on one explanatory variable only. Also reliable long term data is rare. Solich presents her critique of current research foci and discusses a number of drivers that increase Malaria infections. She roughly differentiates between natural and socio- economic/political drivers – indicating a heuristic basis used in this identification. Among the natural drivers, climate change, land-use and cover changes, and drug resistance have been analysed, while demographic changes, poverty, and inadequate political responses have been identified as socio-economic/political drivers of the spread of Malaria in the region. Based on the analysis, she models the inter-connections between the factors and heir influence on various stages of the malaria infectious cycle. Exemplary analysis of the Kenyan Highlands illustrates this interplay of factors and strengthens Solich’s argument for further studies concerning Malaria-risk multiple causation. Michael J. Casimi