Cerebral malaria (CM) and severe malarial anemia (SMA) are associated with long-term cognitive impairment in children, but little is known about cognitive impairment in children with other forms of severe malaria. In this prospective cohort study of 600 Ugandan children 6 months to 4 years of age with 1 or more of the 5 most common forms of severe malaria (CM, respiratory distress, malaria with multiple seizures, SMA, or prostration), overall cognitive ability, attention, and associative memory were evaluated 12 months after hospital discharge. Age-adjusted z-scores for each domain were calculated from the scores of community children (CC) with no acute illness. Groups were compared using linear regression adjusted for potential confounding factors. Children with CM or SMA had significantly lower overall cognition scores than CC (mean difference [95% CI]: CM -0.66 [-1.12, -0.21], P = .001, SMA -0.71 [-1.05, -0.37], P < .001), and a greater proportion of children with CM (5/47, 10.6%) or SMA (17/140, 12.1%) had cognitive impairment (z-score < -2) than CC (2/104, 1.9%, P = .003 and 0.018, respectively). Cognition scores did not differ significantly between children with respiratory distress, multiple seizures or prostration and CC. Attention and associative memory scores did not differ significantly between children with any form of severe malaria and CC. CM and SMA, but not other forms of severe malaria, are associated with long-term cognitive impairment in children <5 years of age.

Background: Hemolysis, inflammatory activation, and poor iron control all contribute to anaemia, a frequent complication of malaria. Hepcidin is the main hormone that regulates iron in the body, and its extreme importance to the body is underscored by its response to cytokine signals and its regulation of the amount of available iron for red blood cell formation. This understanding can help explain why anemia worsens in some patients. Hypotheses: To investigate hepcidin's function in malaria-induced anaemia and its correlation with pro-inflammatory cytokines in circulation, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), as well as markers of vital iron metabolism. Material and Methods: This was a cross-sectional study wherein 160 cases of laboratory-confirmed malaria were identified. Haemoglobin and erythrocyte indices were measured with the help of an automated analyser. Measures of hepcidin serum, IL-6, TNF-alpha, and IL-10 were measured using ELISA. Biochemical parameters to be examined included an analysis of iron in the bloodstream, using standard biochemical techniques, including monthly serum iron, ferritin, ferritin saturation, and total iron-binding capacity. We also observed the C-reactive protein and erythrocyte sedimentation rate. Correlation and group-comparison methods were used in the statistical analysis. Results: The mean Hb among participants was 8.9 g/dL ± 1.5, and a quarter of the cases met the criteria for severe anaemia. The hepcidin levels were also high, with a mean of 79.22 ± 20.6, compared with 92.52 ± 17.8 in severe anaemia (p &lt; 0.001). Good positive correlations between IL-6 (69.4 ± 18.7 pg/mL) and TNF-69.447 pg/mL and hepcidin (r = 0.73 and 0.67, respectively; p &lt; 0.001). There were significant reductions in serum iron (36.1 pmol/dl) and transferrin saturation (11.2 pmol/dmol/per cent), and no decrease in ferritin (548 pmol/dl). The increase in parasitemia is associated with decreased haemoglobin (r = -0.55, p &lt; 0.001) and increased IL-6 (r = 0.60, p &lt; 0.001). Conclusion: The findings reveal that hepcidin plays a role in the pathogenesis of malarial anaemia by reducing iron supply due to cytokine-mediated effects. The addition of hepcidin and inflammatory markers to routine analysis could improve the early diagnosis of individuals at risk of severe anaemia and guide clinical care. Keywords: Hepcidin, Malarial anaemia, Iron metabolism, inflammatory cytokines, TNF- alpha Functional iron deficiency.

Plasmodium falciparum gene expression signatures and antibody profiling implicate the fikk, phist, and surf multigene families in severe malaria syndromes.

BackgroundSevere malarial anaemia and cerebral malaria can result in long-term cognitive, behavioral, and mental health impairments that may influence future household wealth. However, the magnitude and mechanisms of this impact on wealth remain unclear. We assessed the association between different forms of severe malaria and household wealth, 4 to 20 years after the episode.MethodsData were obtained from children previously enrolled in three prospective cohort studies with one of five forms of severe malaria: cerebral malaria (CM; cohorts 1, 2, and 3), severe malarial anaemia (SMA; cohorts 2 and 3), and malaria with respiratory distress, complicated seizures, or prostration (cohort 3). Community children (CC) from the prior studies served as the reference group. Regression analyses assessed the association between forms of severe malaria types and current household socioeconomic index (SEI).Results996 participants and their households were included in the analyses: CM (n = 237), SMA (n = 257), other severe malaria (n = 238), and CC (n = 264). In a regression model including children from cohorts 1, 2 and 3 with CM or SMA, compared to CC, we found that households of children with SMA but not CM had lower SEI than CC (mean difference [95% CI]): SMA, -0.15 (-0.30, -0.01), p = 0.046, at an average of 10.1 years (SD 3.4) following the childhood severe malaria episode. In a regression model for cohort 3, comparing children in this cohort with CM, SMA, or other forms of severe malaria to CC, SMA was the only form of severe malaria associated with lower household SEI compared to CC in unadjusted analysis, and no severe malaria groups was associated with lower household SEI compared to CC after adjustment for household characteristics.ConclusionsOur findings indicate that severe malarial anaemia in childhood, but not other forms of severe malaria, may be associated with decreased household wealth 4 to 20 years later. Controlling malaria in low-resource settings could protect poor households from worse socioeconomic index over time.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12889-025-25057-1.

BackgroundThe magnitude and specificity of naturally acquired antibody responses to Plasmodium falciparum merozoite surface proteins could influence the clinical presentation of malaria in young children. As many putative targets of immunity are structurally diverse, lack of antibodies to the infective parasite genotype could lead to immune evasion, higher parasitaemia and more severe clinical manifestation of the disease.MethodsThe degree of concordance between IgG responses to polymorphic and dimorphic antigenic regions of vaccine candidates MSP-1 and MSP-2 and the infective parasites detected by PCR was investigated in 269 paediatric patients presenting with cerebral malaria (CM), severe malarial anaemia (SMA) or uncomplicated malaria (UM) in Blantyre, Malawi.ResultsOverall, the specificities of antibodies matched the infecting P. falciparum genotypes, more so at convalescence, although levels generally decreased after parasite clearance. At presentation, no evidence that children with severe malaria (SM) had lower concentrations of antibodies matching parasite genotypes, defined by polymorphic MSP-1 block 2 alleles, than children with UM, was found. However, a lower IgG response to MSP-2 type B (FC27) correlated with CM while a lower response to MSP-2 type A (IC1/3D7) parasites correlated with SMA. In addition, discordant antibody-genotype responses were associated with neurological sequelae after CM compared to full recovery.ConclusionsAlthough antibody specificities were generally concordant with the genotyped parasites, UM patients tended to have a higher proportion of antibody responses matching the dimorphic MSP-2 parasite genotypes than SM patients, and thus antigenic diversity of blood stage antigens could contribute to immune escape and malaria severity.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12936-025-05660-8.

Factors governing the clinical trajectory of Plasmodium falciparum infection remain an important area of investigation. Here we present transcriptomic, proteomic and metabolomic analyses comparing clinical subtypes of severe Plasmodium falciparum malaria to matched controls with uncomplicated disease in 79 children from Mali. MMP8, IL1R2, and ARG1 transcription is higher across cerebral malaria, severe malarial anemia, and concurrent cerebral malaria and severe malarial anemia, indicating a shared inflammatory signature. Tissue inhibitor of metalloproteinases 1 is the most upregulated protein in cerebral malaria, which along with elevated MMP8 and MMP9 transcription, underscores the importance of the metalloproteinase pathway in central nervous system pathophysiology. L-arginine metabolites are decreased in cerebral malaria, which coupled with increased ARG1 transcription suggests a putative mechanism impairing cerebral vasodilation. Using multi-omics approaches, we thus describe the inflammatory cascade in severe malaria syndromes, and identify potential therapeutic targets and biological markers.

ABSTRACTBackgroundSoluble forms of progenitor cell receptors may be implicated in the delayed erythropoietic response during severe anemia. In this study, plasma levels of soluble erythropoietin receptor (sEPO‐R) and soluble granulocyte, macrophage‐colony stimulating factor receptor (sGM‐CSFR) were assessed in Plasmodium falciparum‐infected children in Ghana.MethodsThis case‐control study was conducted at Tamale Teaching Hospital, Ghana. One hundred and twenty P. falciparum‐infected, and 60 uninfected children aged 12–144 months were recruited from April to July, 2023. About 4 mL of blood was collected for malaria microscopy, full blood count using a haematology analyser, and sEPO‐R, sGM‐CSFR and erythropoietin (EPO) estimation using enzyme‐linked immunosorbent assays. Data were analyzed using SPSS version 26.0.ResultsPlasma levels of sEPO‐R were higher among participants with severe malarial anemia (SMA) than those in the non‐SMA and control groups (p < 0.001). Plasma sGM‐CSFR levels were higher in P. falciparum‐infected children than in controls, but the levels were similar between the SMA and non‐SMA groups. Hemoglobin (r = −0.823, p < 0.001), RBC (r = −0.852, p < 0.001), HCT (r = −0.790, p < 0.001) and platelets (r = −0.810, p < 0.001) negatively correlated with sEPO‐R. There was a strong positive correlation between sEPO‐R and EPO in P. falciparum‐infected children (r = 0.901, p < 0.001). Plasma sEPO‐R better predicted severe anemia among malaria‐infected children (cut‐off point: 161.5 pg/mL, sensitivity: 96.0%, specificity: 82.9%, AUC: 0.964, p < 0.001).ConclusionP. falciparum‐infected children had higher plasma levels of sGM‐CSFR, sEPO‐R and EPO. Plasma sEPO‐R correlated negatively with erythrocyte parameters, suggesting a possible contribution of the endogenous receptor to the development of severe anemia in children with malaria. Further studies to investigate the neutralizing effects of sEPO‐R on erythropoietic response during malaria are recommended.

BackgroundMalaria remains a major public health concern, particularly among children under 5 years in the WHO African Region. Malarial anaemia is a common complication in this population. Factors that are associated with the development of malarial anaemia include haemolysis, dyserythropoiesis, erythrophagocytosis and bone marrow suppression, with studies reporting varying erythropoietin (epo) responses to severe anaemia. Studies on anti‐epo antibodies being linked to malarial anaemia have yielded conflicting results, associated with malarial anaemia in pregnant women but not in children. This study sought to investigate anti‐epo antibody production in children with malaria and explore their association with malarial anaemia.MethodologyThe study recruited 90 children aged 1–10 years in Tano North Municipality, Ghana. Of these, 60 children diagnosed with malaria (30 with anaemia and 30 without anaemia) formed the case group, while 30 healthy children served as the control group. Venous blood samples were collected into K2EDTA (for full blood count, G6PD activity and malaria microscopy) and serum‐separator tubes (SSTs) (sera for measurement of epo concentrations and anti‐epo antibodies using ELISA kits).ResultsIn all, anti‐epo antibodies were detected in 5.6% of participants who had malaria, with none of the controls being positive for the antibodies. However, the difference in anti‐epo antibody positivity between the two groups was not statistically significant. Within the subgroup of 30 malarial anaemia patients, 5.0% had anti‐epo antibodies compared to 3.37% within the subgroup of malaria without anaemia (p = 0.640). Antibody positivity was significantly associated with elevated epo concentrations and younger age when compared to those with malaria who did not produce anti‐epo antibodies.ConclusionAnti‐epo antibody production is not linked to Plasmodium falciparum infection or malarial anaemia but is strongly associated with younger age and elevated epo levels in children.

Few studies have described post-discharge morbidity of children with specific manifestations of severe malaria (SM) beyond severe malarial anemia or cerebral malaria. Children 6 months to 4 years of age admitted at Jinja and Mulago hospitals in Uganda, with one or more of the five most common manifestations of SM, cerebral malaria (n=53), respiratory distress syndrome (n=108), malaria with complicated seizures (n=160), severe malarial anemia (n=155) or prostration (n=75), were followed for 12 months after discharge, along with community children (CC) (n=120) recruited from the household or neighborhood of the children with SM. Incidence and risk of post-discharge readmission, death or outpatient clinic visits were compared between children with SM and CC. 312/551 (56.6%) of children with SM had one or more post-discharge readmission, compared to 37/120 (30.8%, p<0.001) of CC. Frequency of readmission was similar across all forms of SM. Compared to CC, children with SM had significantly higher risk of post-discharge readmission or death (adjusted hazard ratio (aHR) 2.06, 95% confidence interval (CI) 1.51-2.81, p<0.001), but a similar risk of outpatient malaria (aHR 1.30, 95% CI 0.97-1.74, p=0.08). 82% of readmissions in children with SM were due to malaria. In this malaria endemic region, children with the most common forms of SM had higher rates of post-discharge readmission or death than CC, and >80% of readmissions were due to malaria. Studies of post-discharge malaria chemoprevention are urgently needed for children with SM, to determine if this treatment can reduce post-discharge morbidity and mortality.

Children with severe malarial anemia (SMA) typically have low in-hospital mortality but have a high risk of postdischarge readmission or death. We hypothesized that the dysregulation of hematopoiesis, vascular growth factors, and endothelial function that occurs in SMA might affect risk of readmission or death. Plasma was obtained from children 18 months to 12 years old with SMA (n = 145) in Kampala, Uganda on admission, and outcomes were assessed over 12-month follow-up. Admission plasma levels of 10 biomarkers of vascular growth, hematopoiesis, and endothelial function were compared to risk of readmission or death over 12-month follow-up. Over 12-month follow-up, 19 of 145 children with SMA were either readmitted or died: 15 children were readmitted (13 with malaria) and 4 children died. In multivariable analyses adjusted for age and sex, elevated plasma levels of platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor (VEGF) on admission were independently associated with a decreased risk of all-cause readmission or death (adjusted hazard ratios [95% confidence intervals], 0.28 [.16-.51] and 0.19 [.08-.48], respectively) and a decreased risk of readmission due to severe malaria (0.27 [.15-.51] and 0.16 [.05-.47]) but not with risk of uncomplicated malaria (1.01 [.53-1.95] and 2.07 [.93-4.64]). In children with severe malarial anemia, elevated plasma levels of PDGF-BB and VEGF, 2 factors that promote angiogenesis, are associated with a decreased risk of readmission or death in the year following admission, primarily driven by a decrease in the risk of recurrent severe malaria.

Pediatric severe malaria is a significant contributor of morbidity and mortality in Uganda. Most information is derived from tertiary referral centers and urban centers. Little is known about routine care or post-discharge outcomes in rural areas. We conducted a longitudinal cohort study of pediatric severe malaria at St. Paul's Level IV Health Center (SPHC) in Kasese, Uganda. We collected demographic, clinical, and laboratory results, and conducted follow-up 14 days post-discharge to assess patient outcomes in the immediate post-discharge period. The initial cohort included 187 children aged 0 to 17 years enrolled between July 9th, 2023 and January 9th, 2024. Almost all (94.7%) participants had a parasitological confirmed malaria diagnosis by rapid diagnostic tests or blood smear. While at SPHC, 95.7% of patients received 3+ doses of intravenous Artesunate, and 92.0% also received oral antimalarials. 62.0% had at least one symptom of severe malaria, with altered consciousness (40.6%) and convulsions (29.9%) the most frequently reported. 26.1% had evidence of severe malarial anemia (Hb <5 g/dl), of whom 93.5% received a blood transfusion. Most (82.2%) patients received care that we assessed as consistent with key elements of WHO management guidelines. We were able to contact 183 of the 187 patient caregivers post-discharge. Caregivers reported that 25.6% of patients were experiencing symptoms related to their hospitalization, with fever (18.5%) and nausea/ not feeding well (10.3%) reported most frequently. Children who experienced altered consciousness during their acute illness had 1.69 times the adjusted risk of reporting symptoms 14-days post-discharge compared to those who did not have altered consciousness (aRR: 1.69, 95% CI: 1.01-2.82). Six deaths were recorded, including three at SPHC and three post-transfer or discharge. Findings suggest that at private health facilities in rural areas, treatment appears to be consistent with guidelines. Future research should investigate high morbidity in the immediate post-discharge period.

Severe malarial anemia (SMA, Hb < 6.0 g/dL) is a leading cause of childhood morbidity and mortality in holoendemic Plasmodium falciparum transmission zones. This study explored the entire expressed human transcriptome in whole blood from 66 Kenyan children with non-SMA (Hb ≥ 6.0 g/dL, n = 41) and SMA (n = 25), focusing on host immune response networks. RNA-seq analysis revealed 6862 differentially expressed genes, with equally distributed up-and down-regulated genes, indicating a complex host immune response. Deconvolution analyses uncovered leukocytic immune profiles indicative of a diminished antigenic response, reduced immune priming, and polarization toward cellular repair in SMA. Weighted gene co-expression network analysis revealed that immune-regulated processes are central molecular distinctions between non-SMA and SMA. A top dysregulated immune response signaling network in SMA was the HSP60-HSP70-TLR2/4 signaling pathway, indicating altered pathogen recognition, innate immune activation, stress responses, and antigen recognition. Validation with high-throughput gene expression from a separate cohort of Kenyan children (n = 50) with varying severities of malarial anemia (n = 38 non-SMA and n = 12 SMA) confirmed the RNA-seq findings. Proteomic analyses in 35 children with matched transcript and protein abundance (n = 19 non-SMA and n = 16 SMA) confirmed dysregulation in the HSP60-HSP70-TLR2/4 signaling pathway. Additionally, glutamine transporter and glutamine synthetase genes were differentially expressed, indicating altered glutamine metabolism in SMA. This comprehensive analysis underscores complex immune dysregulation and novel pathogenic features in SMA.

Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) is important in malaria pathogenicity as it mediates Pf-infected erythrocytes cytoadherence to host endothelial microvasculature receptors. Naturally acquired antibodies against specific PfEMP-1 antigens may be beneficial in clinical malaria protection. This study determined antibodies to DBLα2, CIDRα1, DBLβ12, and DBLγ6 domains of PfEMP-1 in children with P. falciparum malaria in Tamale, Ghana. Sixty P. falciparum-infected children, and 30 controls, aged 1-12 years were recruited for this case-control study from April to July 2023 in Northern Ghana. Participants with uncomplicated malaria had asexual P. falciparum in peripheral blood and Hb ≥ 5.0 g/dL, and severe malaria was diagnosed when participants had Hb < 5.0 g/dL in addition to asexual P. falciparum in peripheral blood. Blood cell indices were measured using hematology analyzer, and IgG antibodies to DBLα2, CIDRα1, DBLβ12, and DBLγ6 domains of PfEMP-1 and pro-inflammatory cytokines were detected using enzyme-linked immunosorbent assay. Data were analyzed using SPSS version 26.0. The prevalence of PfEMP-1 IgG antibodies among P. falciparum-infected children and the uninfected group was 65.0% and 6.7%, respectively. PfEMP-1 IgG antibodies were present in 83.3% of uncomplicated malaria cases, and 46.7% in severe malaria subjects. Plasma levels of PfEMP-1 IgG antibodies were elevated in participants with uncomplicated malaria compared to those with severe malaria (p < 0.001). Hemoglobin, RBC, HCT, and platelet were significantly lower among P. falciparum-infected children without PfEMP-1 IgG antibodies than among those with the antibodies. Prevalence of anemia among children with PfEMP-1 IgG antibodies and those without the antibodies were 74.4% and 100%, respectively. The high prevalence of PfEMP-1 IgG antibodies to DBLα2, CIDRα1, DBLβ12, and DBLγ6 domains observed in participants with uncomplicated malaria, and the relationship between PfEMP-1 IgG antibodies and blood cell parameters could indicate that the antibodies may be related to effective erythropoietic response in P. falciparum malaria. Immune antibodies against DBLα2, CIDRα1, DBLβ12, and DBLγ6 domains of PfEMP-1 may suppress the deteriorating effects of PfEMP-1 antigens and provide immune protection against severe malarial anemia in children.

Immune Complexes in Blackwater Fever and Severe Malarial Anemia: New Insights From Old Forgotten Friends.

BackgroundPlasmodium falciparum infection is associated with the human ABO blood group. However, there is a paucity of data on the role that ABO and Rhesus blood groups play in malaria clinical presentations. Therefore, the objective of this study was to assess the association of human ABO blood groups and the Rhesus blood (Rh) types with the severity of malaria.MethodsThis cross-sectional study was carried out at the Suhum Government Hospital in the Eastern region of Ghana. Conveniently, study participants with malaria, diagnosed by microscopy, were selected into the study. Subsequently, their ABO and Rh blood groups were determined (Accucare ABO/Rh monoclonal antibodies, Chennai, India). Malaria severity was assessed using the criteria for assessing severe malarial anaemia published by the World Health Organization. According to the criteria, severe malarial anaemia was classified as having haemoglobin (Hb) < 5 g/dL for children < 12 years and in patients ≥ 12 years, Hb level < 7 g/dL, with parasitaemia > 10,000/µL in both cases. Severe malarial anaemia was also classified as having plasma bilirubin > 50 µmol/L with parasitaemia ≥ 100,000/µL, for all ages. Chi square statistical analysis was used to test the association between the blood groups and the clinical or laboratory findings, while multivariate analysis was performed to identify which blood groups were more vulnerable to develop severe malarial anaemia.ResultsOf the total number of the study participants (n = 328), most of the patients had blood group O Rh positive (35.7%) while few of them had blood group AB Rh negative (2.1%). The types of Rhesus did not associate with malaria. However, compared to blood group O, the odds of developing severe malarial anaemia, in children < 12 years and in patients ≥ 12 years, were 16 times and 17.8 times higher among patients with blood group A, respectively. Furthermore, the odds of having bilirubin level > 50 µmol/L with parasitaemia ≥ 100,000 /µL was 10 times higher among patients with blood groups A and 2.6 times higher in patients with blood group B, compared to blood group O. Finally, in patients with blood group A majority (71.6%) of them developed high temperature (> 37.5 °C) while 43.3% of them vomited and had diarrhoea. However, pallor (group B = 46.2% vs group A = 37.3%), fever (group B = 84.6% vs group A = 79.1%) and nausea (group B = 46.2% vs group A = 25.4%) were more frequent in patients with blood group B than A.ConclusionsThis study found that people with blood groups A and B were severely affected by malaria, with group A being the most vulnerable. It is recommended that blood group assessment be performed for all patients with malaria. Patients found to have blood group A or B must be promptly and efficiently managed to avoid the development of severe malaria anaemia.

This study on severe malarial anemia (SMA: Hb < 6.0 g/dL), a leading global cause of childhood morbidity and mortality, compares the entire expressed whole blood host transcriptome between Kenyan children (3-48 mos.) with non-SMA (Hb ≥ 6.0 g/dL, n = 39) and SMA (n = 18). Differential expression analyses reveal 1403 up-regulated and 279 down-regulated transcripts in SMA, signifying impairments in host inflammasome activation, cell death, and innate immune and cellular stress responses. Immune cell profiling shows decreased memory responses, antigen presentation, and immediate pathogen clearance, suggesting an immature/improperly regulated immune response in SMA. Module repertoire analysis of blood-specific gene signatures identifies up-regulation of erythroid genes, enhanced neutrophil activation, and impaired inflammatory responses in SMA. Enrichment analyses converge on disruptions in cellular homeostasis and regulatory pathways for the ubiquitin-proteasome system, autophagy, and heme metabolism. Pathway analyses highlight activation in response to hypoxic conditions [Hypoxia Inducible Factor (HIF)−1 target and Reactive Oxygen Species (ROS) signaling] as a central theme in SMA. These signaling pathways are also top-ranking in protein abundance measures and a Ugandan SMA cohort with available transcriptomic data. Targeted RNA-Seq validation shows strong concordance with our entire expressed transcriptome data. These findings identify key molecular themes in SMA pathogenesis, offering potential targets for new malaria therapies.

Severe malarial anemia (SMA) increases the morbidity and mortality of Plasmodium, the causative agent of malaria. SMA is mainly developed by children and pregnant women in response to the infection. It is characterized by ineffective erythropoiesis caused by impaired erythropoietin (EPO) signaling. To gain new insights into the pathogenesis of SMA, we investigated the relationship between the immune system and erythropoiesis, conducting comparative analyses in a mouse model of malaria. Red blood cell (RBC) production was evaluated in infected and reinfected animals to mimic endemic occurrences. Higher levels of circulating EPO were observed in response to (re)infection. Despite no major differences in bone marrow erythropoiesis, compensatory mechanisms of splenic RBC production were significantly reduced in reinfected mice. Concomitantly, a pronounced immune response activation was observed in erythropoietic organs of reinfected animals in relation to single-infected mice. Aged mice were also used to mimic the occurrence of malaria in the elderly. The increase in symptom severity was correlated with the enhanced activation of the immune system, which significantly impaired erythropoiesis. Immunocompromised mice further support the existence of an immune-shaping regulation of RBC production. Overall, our data reveal the strict correlation between erythropoiesis and immune cells, which ultimately dictates the severity of SMA.

Amino acid supplementation confers protection to red blood cells before Plasmodium falciparum bystander stress

BackgroundDyslipidemia is becoming prevalent in Africa, where malaria is endemic. Observational studies have documented the long‐term protective effect of malaria on dyslipidemia; however, these study designs are prone to confounding. Therefore, we used Mendelian randomization (MR, a method robust to confounders and reverse causation) to determine the causal effect of severe malaria (SM) and the recurrence of non‐severe malaria (RNM) on lipid traits.MethodWe performed two‐sample MR using genome wide association study (GWAS) summary statistics for recurrent non‐severe malaria (RNM) from a Benin cohort (N = 775) and severe malaria from the MalariaGEN dataset (N = 17,000) and lipid traits from summary‐level data of a meta‐analyzed African lipid GWAS (MALG, N = 24,215) from the African Partnership for Chronic Disease Research (APCDR) (N = 13,612) and the Africa Wits‐IN‐DEPTH partnership for genomics studies (AWI‐Gen) dataset (N = 10,603).ResultNo evidence of significant causal association was obtained between RNM and high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol (LDL‐C), total cholesterol and triglycerides. However, a notable association emerged between severe malarial anaemia (SMA) which is a subtype of severe malaria and reduced HDL‐C levels, suggesting a potential subtype‐specific effect. Nonetheless, we strongly believe that the small sample size likely affects our estimates, warranting cautious interpretation of these results.ConclusionOur findings challenge the hypothesis of a broad causal relationship between malaria (both severe and recurrent non‐severe forms) and dyslipidemia. The isolated association with SMA highlights an intriguing area for future research. However, we believe that conducting larger studies to investigate the connection between malaria and dyslipidemia in Africa will enhance our ability to better address the burden posed by both diseases.

We assessed the diagnostic potential of erythroferrone as a biomarker for iron homeostasis comparing iron deficiency cases with anaemia of inflammation and controls. The dysregulation of the hepcidin axis was observed by Latour etal. in a mouse model of malarial anaemia induced by prolonged Plasmodium infection leading to increased erythroferrone concentrations. In line with that, we found significantly higher erythroferrone levels in cases with malaria and anaemia in an African population, compared to asymptomatic controls. Therefore, our findings extend the previous ones of the mouse model, suggesting also a dysregulation of the hepcidin axis in humans, which should be further corroborated in prospective studies and may lay the basis for the development of improved treatment strategies according to ERFE concentrations in such patients.