Lung endothelial cell antigen cross-presentation to CD8+T cells drives malaria-associated lung injury

Nat Commun. 2019 Sep 18;10(1):4241. doi: 10.1038/s41467-019-12017-8.

Abstract

Malaria-associated acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are life-threatening manifestations of severe malaria infections. The pathogenic mechanisms that lead to respiratory complications, such as vascular leakage, remain unclear. Here, we confirm that depleting CD8+T cells with anti-CD8β antibodies in C57BL/6 mice infected with P. berghei ANKA (PbA) prevent pulmonary vascular leakage. When we transfer activated parasite-specific CD8+T cells into PbA-infected TCRβ-/- mice (devoid of all T-cell populations), pulmonary vascular leakage recapitulates. Additionally, we demonstrate that PbA-infected erythrocyte accumulation leads to lung endothelial cell cross-presentation of parasite antigen to CD8+T cells in an IFNγ-dependent manner. In conclusion, pulmonary vascular damage in ALI is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8+T cells induced during infection. The mechanistic understanding of the immunopathogenesis in malaria-associated ARDS and ALI provide the basis for development of adjunct treatments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / immunology
  • Acute Lung Injury / parasitology
  • Acute Lung Injury / pathology*
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • Cross-Priming / immunology*
  • Disease Models, Animal
  • Endothelial Cells / immunology
  • Female
  • Interferon-gamma / immunology*
  • Lung / parasitology
  • Lung / pathology
  • Malaria / drug therapy
  • Malaria / immunology*
  • Malaria / parasitology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Plasmodium berghei / immunology
  • Pulmonary Edema / parasitology
  • Pulmonary Edema / pathology
  • Respiratory Distress Syndrome / immunology
  • Respiratory Distress Syndrome / parasitology
  • Respiratory Distress Syndrome / pathology*

Substances

  • IFNG protein, mouse
  • Interferon-gamma