Experimental Models to Study the Pathogenesis of Malaria-Associated Acute Respiratory Distress Syndrome.

Malaria-associated acute respiratory distress syndrome (MA-ARDS) is increasingly gaining recognition as a severe malaria complication because of poor prognostic outcomes, high lethality rate, and limited therapeutic interventions. Unfortunately, invasive clinical studies are challenging to conduct and yields insufficient mechanistic insights. These limitations have led to the development of suitable MA-ARDS experimental mouse models. In patients and mice, MA-ARDS is characterized by edematous lung, along with marked infiltration of inflammatory cells and damage of the alveolar-capillary barriers. Although, the pathogenic pathways have yet to be fully understood, the use of different experimental mouse models is fundamental in the identification of mediators of pulmonary vascular damage. In this review, we discuss the current knowledge on endothelial activation, leukocyte recruitment, leukocyte induced-endothelial dysfunction, and other important findings, to better understand the pathogenesis pathways leading to endothelial pulmonary barrier lesions and increased vascular permeability. We also discuss how the advances in imaging techniques can contribute to a better understanding of the lung lesions induced during MA-ARDS, and how it could aid to monitor MA-ARDS severity.

Malaria abrogates O'nyong-nyong virus pathologies by restricting virus infection in nonimmune cells.

O'nyongnyong virus (ONNV) is a re-emerging alphavirus previously known to be transmitted by main malaria vectors, thus suggesting the possibility of coinfections with arboviruses in co-endemic areas. However, the pathological outcomes of such infections remain unknown. Using murine coinfection models, we demonstrated that a preexisting blood-stage Plasmodium infection suppresses ONNV-induced pathologies. We further showed that suppression of viremia and virus dissemination are dependent on Plasmodium-induced IFNγ and are associated with reduced infection of CD45- cells at the site of virus inoculation. We further proved that treatment with IFNγ or plasma samples from Plasmodium vivax-infected patients containing IFNγ are able to restrict ONNV infection in human fibroblast, synoviocyte, skeletal muscle, and endothelial cell lines. Mechanistically, the role of IFNγ in restricting ONNV infection was confirmed in in vitro infection assays through the generation of an IFNγ receptor 1 α chain (IFNγR1)-deficient cell line.

PET Imaging of Translocator Protein as a Marker of Malaria-Associated Lung Inflammation.

Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a severe complication of malaria that occurs despite effective antimalarial treatment. Currently, noninvasive imaging procedures such as chest X-rays are used to assess edema in established MA-ARDS, but earlier detection methods are needed to reduce morbidity and mortality. The early stages of MA-ARDS are characterized by the infiltration of leukocytes, in particular monocytes/macrophages; thus, monitoring of immune infiltrates may provide a useful indicator of early pathology. In this study, Plasmodium berghei ANKA-infected C57BL/6 mice, a rodent model of MA-ARDS, were longitudinally imaged using the 18-kDa translocator protein (TSPO) imaging agent [18F]FEPPA as a marker of macrophage accumulation during the development of pathology and in response to combined artesunate and chloroquine diphosphate (ART+CQ) therapy. [18F]FEPPA uptake was compared to blood parasitemia levels and to levels of pulmonary immune cell infiltrates by using flow cytometry. Infected animals showed rapid increases in lung retention of [18F]FEPPA, correlating well with increases in blood parasitemia and pulmonary accumulation of interstitial inflammatory macrophages and major histocompatibility complex class II (MHC-II)-positive alveolar macrophages. Treatment with ART+CQ abrogated this increase in parasitemia and significantly reduced both lung uptake of [18F]FEPPA and levels of macrophage infiltrates. We conclude that retention of [18F]FEPPA in the lungs is well correlated with changes in blood parasitemia and levels of lung-associated macrophages during disease progression and in response to ART+CQ therapy. With further development, TSPO biomarkers may have the potential to accurately assess the early onset of MA-ARDS.

Cytoadherence Properties of Plasmodium knowlesi-Infected Erythrocytes.

Plasmodium knowlesi is responsible for zoonotic malaria infections that are potentially fatal. While the severe pathology of falciparum malaria is associated with cytoadherence phenomena by Plasmodium falciparum-infected erythrocytes (IRBC), information regarding cytoadherence properties of P. knowlesi-IRBC remained scarce. Here, we characterized the cytoadherence properties of RBC infected with the laboratory-adapted P. knowlesi A1-H.1 strain. We found that late-stage IRBC formed rosettes in a human serum-dependent manner, and rosettes hampered IRBC phagocytosis. IRBC did not adhere much to unexposed (unstimulated) human endothelial cell lines derived from the brain (hCMEC/D3), lungs (HPMEC), and kidneys (HRGEC). However, after being "primed" with P. knowlesi culture supernatant, the IRBC-endothelial cytoadherence rate increased in HPMEC and HRGEC, but not in hCMEC/D3 cells. Both endothelial cytoadherence and rosetting phenomena were abrogated by treatment of P. knowlesi-IRBC with trypsin. We also found that different receptors were involved in IRBC cytoadherence to different types of endothelial cells. Although some of the host receptors were shared by both P. falciparum- and P. knowlesi-IRBC, the availability of glycoconjugates on the receptors might influence the capacity of P. knowlesi-IRBC to cytoadhere to these receptors.

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

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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

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-CD8ß 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 TCRß-/- 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.