Cytoadherence in paediatric malaria: ABO blood group, CD36, and ICAM1 expression and severe Plasmodium falciparum infection

Abstract

As a leading cause of childhood mortality worldwide, selection pressure by Plasmodium falciparum continues to shape the human genome. Severe disturbances within the microcirculation result from the adhesion of infected erythrocytes to host receptors on monocytes, platelets, and endothelium. In this prospective study, we compared expression of all major host cytoadhesion receptors among Ugandan children presenting with uncomplicated malaria (n = 1078) versus children with severe malaria (n = 855), including cerebral malaria (n = 174), severe anaemia (n = 522), and lactic acidosis (n = 154). We report a significant survival advantage attributed to blood group O and increased monocyte expression of CD36 and ICAM1 (CD54). The high case fatality rate syndromes of cerebral malaria and lactic acidosis were associated with high platelet CD36 expression and thrombocytopenia, and severe malaria anaemia was characterized by low ICAM1 expression. In a logistic regression model of disease severity, odds ratios for the mitigating effects of blood group O, CD36, and ICAM1 phenotypes were greater than that of sickle haemoglobin. Host genetic adaptations to Plasmodium falciparum suggest new potential malaria treatment strategies.

Fig. 1

Study design and patient categories. (A) Pre-specified categories of patients enrolled. The analysis of severity of disease compares controls (uncomplicated malaria, UM, n = 1078) with cases (severe malaria, SM, n = 855). (B) Distribution of the three principal severe malaria syndromes among the cases. For analysis, cases are classified into three non-overlapping categories: all cerebral malaria (CM) (grey); severe malaria anaemia (SMA) without CM (white); and isolated lactic acidosis (LA) not attributable to SMA or CM (black).

Fig. 2

ABO blood groups in patients with malaria. (A) ABO groups according to the spectrum of disease severity. Controls have a higher prevalence of group O, and cases have a higher prevalence of non-group O. (B) ABO distributions among the cases (severe or fatal malaria) are significantly different from that observed in healthy adult Ugandan blood donors. (C) Among group A or AB cases, A1 positive cases are more likely to have CM or LA than those negative for A1. UM-o, uncomplicated malaria treated as an outpatient; UM-i, uncomplicated malaria treated as an inpatient. SM-s, severe malaria, survivor; SM-f, severe malaria, fatal; SMA, severe malaria anaemia; LA, lactic acidosis; CM, cerebral malaria.

Fig. 3

Factors associated with uncomplicated or severe malaria. Results of logistic regression model showing the odds ratios (OR, black circles) and 95% confidence intervals (95% CI, horizontal lines) for uncomplicated versus severe or fatal malaria according to input risk factors. Odds ratios for age are scaled per year and for white blood cell count (WBC) and platelet count (Plt) are scaled in increments of 10⁹/l and 10 × 10⁹/l, respectively. Mono, monocyte; Hb S, haemoglobin S.

Fig. 4

Monocyte CD54 and CD36 expression in patients with malaria. (A) The median and inter-quartile range of monocyte counts is shown. (B) The median and inter-quartile range of CD54 (ICAM1) expression on monocytes (measured as median fluorescence intensity using flow cytometry). Low monocyte CD54 expression is seen among cases with SMA. (C) The median and inter-quartile range of CD36 expression on monocytes (measured as median fluorescence intensity using flow cytometry). A progressive decline in monocyte CD36 expression is associated with categories of increasing disease severity. UM-o, uncomplicated malaria treated as an outpatient; UM-i, uncomplicated malaria treated as an inpatient; SM-s, severe malaria; survivor. SM-f, severe malaria, fatal; SMA, severe malaria anaemia; LA, lactic acidosis; CM, cerebral malaria.

Fig. 5

CD36 Expression and platelet count in patients with malaria. (A) The median and inter-quartile range of platelet CD36 expression (measured as median fluorescence intensity through flow cytometry) is shown. (B) A progressive decline in the median and inter-quartile range of the log_e of the ratio of monocyte-to-platelet CD36 expression according to disease severity is shown. (C) Increasing disease severity and cases of CM or LA are associated with progressive thrombocytopenia. (D) A progressive rise in the median and inter-quartile range of the log_e of the ratio of platelet CD36 expression to platelet count with disease severity and with CM and LA is shown. UM-o, uncomplicated malaria treated as an outpatient; UM-i, uncomplicated malaria treated as an inpatient; SM-s, severe malaria, survivor; SM-f, severe malaria, fatal; SMA, severe malaria anaemia; LA, lactic acidosis; CM, cerebral malaria.