Table 1.
Non-gas exchanging functions of RBCs and hypothesized role in critical illness
| Hypothesized or Proven Adaptation | RBC Feature | Function | Adaptation to Malaria | Consequence to Critical Illness |
|---|---|---|---|---|
| Proven | Heme | Generates reactive oxygen species: activates TLR4 Amplifies cytokine production in the presence of LPS (7) | Hemoglobinopathies/thalassemia (8) | Increased susceptibility to nonmalarial infection (9, 10), anemia/transfusion dependence (11) |
| Duffy Antigen Receptor for Chemokines | Binds chemokines: maintains chemokine gradient (12) | Downregulation: decreased parasite entry (13, 14) | Increased susceptibility to ARDS (15, 16) | |
| Binds pathogens: entry point for P. vivax (13) | ||||
| Glucose-6-Phosphotase | Involved in pathway to consume reactive oxygen species (17) | Deficiency: increased intracellular oxidative stress decreases parasite survival (18) | COVID-19 severity (19) | |
| Pyruvate kinase | Catalyzes rate-limiting step in glycolysis to produce intracellular energy in nonmitochondrial cells (mature RBCs) (20) | Deficiency: decreased invasion by P. falciparum and increased phagocytosis of ring- and mature-stage-infected RBCs (20, 21) | Hemolytic anemia/transfusion dependency, functional asplenia (20) | |
| Hypothesized | Glycophorins | Binds pathogens: entry point for P. falciparum (22) | Dantu variant: structural variant in chromosome 4 region, which increases RBC surface tension and decreases merozoite invasion (23) | Potential predisposition to lysis/thrombosis |
| Complement Receptor 1 | Binds P. falciparum-induced ligand (24, 25) | Deficiency: increased cerebral malaria (26) | Increased RBC-bound complement fragments in COVID-19 and non-COVID-19 sepsis (27) | |
| Proinflammatory regulator abundant on RBCs (27) | Deficiency: reduced rosetting conferring protection (25) | |||
| Toll-like Receptor 9 | Binds nucleic acids (28, 29) | Deficiency/gene polymorphisms | Decreased capacity to bind mtDNA to ameliorate lung injury (28) | |
| Involved in P. yoeli infection (30, 31) | ||||
| ABO Glycoproteins | Surface proteins on RBCs responsible for determining ABO blood group (32) | Blood group O demonstrates different propensity to bind to Duffy binding-like regions of infected erythrocytes (33–36) | Blood group A may confer increased risk for ARDS in critically ill patients and associated with increased risk of AKI (37) |
AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; COVID-19, coronavirus disease 2019; LPS, lipopolysaccharide; RBCs, red blood cells.