The ultimate tradeoff: how red cell adaptations to malaria alter the host response during critical illness

The human immune system evolved in response to pathogens. Among these pathogens, malaria has proven to be one of the deadliest and has exerted the most potent selective pressures on its target cell, the red blood cell. Red blood cells have recently gained recognition for their immunomodulatory properties, yet how red cell adaptations contribute to the host response during critical illness remains understudied. This review will discuss how adaptations that may have been advantageous for host survival might influence immune responses in modern critical illness. We will highlight the current evidence for divergent host resilience arising from the adaptations to malaria and summarize how understanding evolutionary red cell adaptations to malaria may provide insight into the heterogeneity of the host response to critical illness, perhaps driving future precision medicine approaches to syndromes affecting the critically ill such as sepsis and acute respiratory distress syndrome (ARDS).