Cerebral tissue oxygenation impairment during experimental cerebral malaria

Abstract

Ischemia and hypoxia have been implicated in cerebral malaria (CM) pathogenesis, although direct measurements of hypoxia have not been conducted. C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) develop a neurological syndrome known as experimental cerebral malaria (ECM), whereas BALB/c mice are resistant to ECM. In this study, intravital microscopy methods were used to quantify hemodynamic changes, vascular/tissue oxygen (O₂) tension (PO₂), and perivascular pH in vivo in ECM and non-ECM models, employing a closed cranial window model. ECM mice on day 6 of infection showed marked decreases in pial blood flow, vascular (arteriolar, venular), and perivascular PO₂, perivascular pH, and systemic hemoglobin levels. Changes were more dramatic in mice with late-stage ECM compared with mice with early-stage ECM. These changes led to drastic decreases in O₂ delivery to the brain tissue. In addition, ECM animals required a greater PO₂ gradient to extract the same amount of O₂ compared with non-infected animals, as the pial tissues extract O₂ from the steepest portion of the blood O₂ equilibrium curve. ECM animals also showed increased leukocyte adherence in postcapillary venules, and the intensity of adhesion was inversely correlated with blood flow and O₂ extraction. PbA-infected BALB/c mice displayed no neurological signs on day 6 and while they did show changes similar to those observed in C57BL/6 mice (decreased pial blood flow, vascular/tissue PO₂, perivascular pH, hemoglobin levels), non-ECM animals preserved superior perfusion and oxygenation compared with ECM animals at similar anemia and parasitemia levels, resulting in better O₂ delivery and O₂ extraction by the brain tissue. In conclusion, direct quantitative assessment of pial hemodynamics and oxygenation in vivo revealed that ECM is associated with severe progressive brain tissue hypoxia and acidosis.

Keywords: :

• cerebral malaria
• pial microcirculation
• oxygen tension
• oxygen delivery
• anemia

This article is referred to by:

Looking through a cranial window

10.4161/viru.26348

Disclosure of Potential Conflicts of Interest

The authors declare that there are no conflicts of interest.

Financial Disclosure

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Acknowledgments

This work was supported by grants R01-AI82610, R01-HL52684, and MERIT R37-HL040696.