Malaria-Associated Respiratory Pathophysiology

Severe malaria frequently involves life-threatening pulmonary complications, notably acute lung injury and acute respiratory distress syndrome. These syndromes arise from a complex interplay between parasite and host, characterised by sequestration of infected erythrocytes in the pulmonary microvasculature, endothelial activation and dysfunction, heightened vascular permeability and diffuse alveolar damage. Innate and adaptive immune responses contribute to this pathology: excessive neutrophil activation may lead to the release of extracellular traps that compromise the alveolar–capillary barrier, while CD8+ T cell recognition of parasite antigens cross-presented by lung endothelium drives cytokine-mediated vascular leakage. The resultant pulmonary oedema and hypoxaemia underlie respiratory distress. Emerging research has illuminated pathways of tissue injury and resolution, revealed potential biomarkers of progression to severe malaria, and pointed to adjunctive therapeutic strategies aimed at modulating inflammatory responses and enhancing endothelial repair. Given the burden of malaria in endemic regions and the high mortality of respiratory complications, a deeper mechanistic understanding promises to inform clinical management and the development of targeted interventions.

Research from Nature Portfolio

Recent studies have identified molecular regulators of neutrophil-mediated lung injury in experimental malaria. Loss of a specific phosphatase in innate immune cells amplifies neutrophil recruitment, reactive-oxygen-species production and extracellular trap deposition in the lung, exacerbating alveolar damage. Pharmacological stabilisation of this phosphatase has been shown to attenuate tissue injury, suggesting a novel adjunctive treatment avenue. In parallel, investigations into endothelial immunobiology have demonstrated that lung endothelial cells capture and process parasite antigens for presentation to CD8+ T cells in an interferon-γ-dependent manner. This cross-presentation precipitates cytotoxic targeting of the vascular barrier, leading to pulmonary leakage. Blockade of CD8+ T cell engagement markedly reduces protein extravasation and improves respiratory function, underscoring the central role of adaptive immunity in malaria-associated respiratory pathology.

Malaria-Associated Respiratory Pathophysiology publication trend

The graph below shows the total number of articles in malaria-associated respiratory pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Acute lung injury (ALI): A syndrome of non-cardiogenic pulmonary oedema resulting from increased permeability of the alveolar–capillary barrier.

Acute respiratory distress syndrome (ARDS): A severe form of ALI marked by diffuse alveolar damage, refractory hypoxaemia and reduced lung compliance.

Neutrophil extracellular traps (NETs): Fibrous networks of decondensed chromatin and granule proteins released by activated neutrophils, implicated in tissue injury.

Endothelial cross-presentation: The process by which vascular endothelial cells present exogenous antigen via MHC class I to CD8+ T cells.

Pulmonary vascular leakage: Abnormal translocation of plasma proteins and fluid across the lung microvascular endothelium, leading to oedema.

Single-cell RNA sequencing: A technique that profiles gene expression in individual cells, enabling identification of cell-type–specific responses.

Parasite sequestration: The adherence and accumulation of Plasmodium-infected red blood cells within organ microvasculature, contributing to local pathology.

References

1. PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury. Nature Communications (2024).
2. Single cell RNA sequencing reveals endothelial cell killing and resolution pathways in experimental malaria-associated acute respiratory distress syndrome.. PLOS Pathogens (2024).
3. Lung Damage Induced by Plasmodium berghei ANKA in Murine Model of Malarial Infection is Mitigated by Dietary Supplementation with DHA-Rich Omega‑3. ACS Infectious Diseases (2024).
4. Lung endothelial cell antigen cross-presentation to CD8+T cells drives malaria-associated lung injury. Nature Communications (2019).