Iron Deficiency and Iron Supplementation Conspire to Mediate Susceptibility to Erythrocytic Stage Plasmodium falciparum Infection

Malaria and iron deficiency are interconnected public health concerns, which disproportionally affect children and pregnant women. Malaria causes an estimated 250 million infections and 1 million deaths per year. Plasmodium falciparum is the most virulent species of the malaria parasite that infects humans. Anemia, predominantly iron deficiency anemia, is the most common nutritional deficiency worldwide, and affects up to 50% of populations in the developing world. The World Health Organization recommends universal iron supplementation in regions where malnutrition is common. This recommendation has been complicated by clinical evidence that iron deficiency protects against malaria infection, and that iron supplementation increases susceptibility to malaria infection. The mechanisms underlying the interaction between malaria, host iron, and iron supplementation remain unclear. Here, I've employed the in vitro system for cultivating erythrocytic stage P. falciparum to assess first, the impact of extracellular iron on parasite growth as well as the bioavailable iron content of parasitized erythrocytes. I have found that extracellular iron is incorporated into parasitized erythrocytes but does not have affect parasite growth. Second, I assessed the capacity of erythrocytes from iron deficient and iron supplemented donors to support erythrocytic stage P. falciparum growth. In these studies I observed that P. falciparum propagation is reduced in iron deficient erythrocytes and that reduced parasite propagation is a result of decreased parasite invasion into iron deficient erythrocytes as well as decreased production of infectious daughter merozoites within iron deficient erythrocytes. I additionally observe that P. falciparum propagation is recovered in erythrocytes donated by iron supplemented iron deficient donors. Furthermore, I attribute the recovery of P. falciparum erythrocyte propagation to the replacement of iron deficient erythrocytes with young iron-replete erythrocytes that are produced in response to iron supplementation. These results are consistent with clinical observations that iron deficiency is protective against malaria infection and iron supplementation increases the risk of malaria infection. Moreover, my results suggest that iron mediated alterations to erythrocyte physiology and intra-host erythrocyte population dynamics as well as potentially altered serum iron levels contribute to the underlying mechanisms governing the relationship between the malaria parasite, iron deficiency, and iron supplementation.Doctor of Philosoph

Judicial Panel: Tennessee Legal Reform from a Judicial Standpoint

A transcript of the judicial panel discussion held at the Belmont University College of Law Symposium, Tennessee Legal Reform

RBC barcoding allows for the study of erythrocyte population dynamics and P. falciparum merozoite invasion.

Plasmodium falciparum invasion of host erythrocytes is essential for the propagation of the blood stage of malaria infection. Additionally, the brief extracellular merozoite stage of P. falciparum represents one of the rare windows during which the parasite is directly exposed to the host immune response. Therefore, efficient invasion of the host erythrocyte is necessary not only for productive host erythrocyte infection, but also for evasion of the immune response. Host traits, such as hemoglobinopathies and differential expression of erythrocyte invasion ligands, can protect individuals from malaria by impeding parasite erythrocyte invasion. Here we combine RBC barcoding with flow cytometry to study P. falciparum invasion. This novel high-throughput method allows for the (i) direct comparison of P. falciparum invasion into different erythrocyte populations and (ii) assessment of the impact of changing erythrocyte population dynamics on P. falciparum invasion

Influence of host iron status on Plasmodium falciparum infection

Iron deficiency affects one quarter of the world's population and causes significant morbidity, including detrimental effects on immune function and cognitive development. Accordingly, the World Health Organization (WHO) recommends routine iron supplementation in children and adults in areas with a high prevalence of iron deficiency. However, a large body of clinical and epidemiological evidence has accumulated which clearly demonstrates that host iron deficiency is protective against falciparum malaria and that host iron supplementation may increase the risk of malaria. Although many effective antimalarial treatments and preventive measures are available, malaria remains a significant public health problem, in part because the mechanisms of malaria pathogenesis remain obscured by the complexity of the relationships that exist between parasite virulence factors, host susceptibility traits, and the immune responses that modulate disease. Here we review (i) the clinical and epidemiological data that describes the relationship between host iron status and malaria infection and (ii) the current understanding of the biological basis for these clinical and epidemiological observations

Tropical river suspended sediment and solute dynamics in storms during an extreme drought

Droughts, which can strongly affect both hydrologic and biogeochemical systems, are projected to become more prevalent in the tropics in the future. We assessed the effects of an extreme drought during 2015 on stream water composition in the Luquillo Mountains of Puerto Rico. We demonstrated that drought base flow in the months leading up to the study was sourced from trade-wind orographic rainfall, suggesting a resistance to the effects of an otherwise extreme drought. In two catchments (Mameyes and Icacos), we sampled a series of four rewetting events that partially alleviated the drought. We collected and analyzed dissolved constituents (major cations and anions, organic carbon, and nitrogen) and suspended sediment (inorganic and organic matter (particulate organic carbon and particulate nitrogen)). The rivers appeared to be resistant to extreme drought, recovering quickly upon rewetting, as (1) the concentration-discharge (C-Q) relationships deviated little from the long-term patterns; (2) “new water” dominated streamflow during the latter events; (3) suspended sediment sources had accumulated in the channel during the drought flushed out during the initial events; and (4) the severity of the drought, as measured by the US drought monitor, was reduced dramatically after the rewetting events. Through this interdisciplinary study, we were able to investigate the impact of extreme drought through rewetting events on the river biogeochemistry

Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum.

Iron deficiency and malaria have similar global distributions, and frequently co-exist in pregnant women and young children. Where both conditions are prevalent, iron supplementation is complicated by observations that iron deficiency anaemia protects against falciparum malaria, and that iron supplements increase susceptibility to clinically significant malaria, but the mechanisms remain obscure. Here, using an in vitro parasite culture system with erythrocytes from iron-deficient and replete human donors, we demonstrate that Plasmodium falciparum infects iron-deficient erythrocytes less efficiently. In addition, owing to merozoite preference for young erythrocytes, iron supplementation of iron-deficient individuals reverses the protective effects of iron deficiency. Our results provide experimental validation of field observations reporting protective effects of iron deficiency and harmful effects of iron administration on human malaria susceptibility. Because recovery from anaemia requires transient reticulocytosis, our findings imply that in malarious regions iron supplementation should be accompanied by effective measures to prevent falciparum malaria

Rapid 5 lb Weight Gain Is Not Associated with Readmission in Patients with Heart Failure

Aims Heart failure (HF) patients are taught to identify a rapid 5 lb body‐weight gain for early detection of cardiac decompensation. Few data support this common advice. The study aim was to determine whether a 5 lb weight gain in 1 week and signs and symptoms of HF increased risk for unplanned physician or emergency department (ED) visits or hospital admission in rural HF patients. Methods and results This was a secondary analysis of a randomized trial. Patients tracked body weight and HF symptoms using diaries. We included patients adherent to daily diaries \u3e 50% over 24 months (N = 119). Mean age was 69 ± 11 years; 77% (65) were male, and 67% completed diaries. A weight gain of 5 lb over 7 days was associated with a greater risk for ED visits but not hospital admission [hazard ratio (HR) 1.06, 95% confidence interval (CI) 1.04, 1.08; P \u3c 0.0001 vs. HR 1.01, 95% CI 0.88, 1.16; P = 0.79]. Increased dyspnoea over 7 days was associated with a greater risk of ED visits and hospital admissions (HR 9.64, 95% CI 3.68, 25.22; P \u3c 0.0001 vs. HR 5.89, 95% CI 1.73, 20.04; P = 0.01). Higher diary adherence was associated with older age, non‐sedentary behaviour, lower depression, and HF knowledge. Conclusions Heart failure patients are counselled to observe for body‐weight gain. Our data do not support that a 5 lb weight gain was associated with hospital admission. Dyspnoea was a better predictor of ED visits and hospital admissions. Daily tracking of dyspnoea symptoms may be an important adjunct to daily weight to prevent hospitalization