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TNF and Plasmodium berghei ANKA-induced cerebral malaria
I A Clark1, S Ilschner, J D MacMicking
1Zoology Department, John Curtin School of Medical Research, Australian National University, Canberra.
Abstract:
The cerebral pathology observed in Plasmodium berghei ANKA-infected CBA mice has been attributed to overproduction of TNF, the mice in which this syndrome is seen being those with the highest serum TNF levels. To investigate this further, we injected recombinant human TNF into malaria-primed mice to see if we could reproduce the cerebral changes observed in P. berghei ANKA infections. A range of doses, administered as a single or repeated injections, or via osmotic pumps, failed to reproduce these changes, but did induce hypoglycaemia, midzonal liver necrosis and neutrophil adhesion in pulmonary vessels. This pathology is seen in terminal Plasmodium vinckei infections, but absent in terminal P. berghei ANKA. In addition, the permeability of the blood-brain barrier to Evan's blue, which is present in P. berghei ANKA but not in normal or P. vinckei-infected mice, was not induced by exogenous TNF. Serum levels of TNF were measured in an ELISA assay, and found to be consistently higher in P. vinckei rather than P. berghei ANKA terminal infections. This is consistent with the pathological changes we could reproduce by injecting TNF. For these reasons we suggest that the cerebral pathology seen in mice infected with P. berghei ANKA may be governed by TNF produced locally by monocytes sequestered within the cerebral blood vessels, not simply by systemic levels of this cytokine.
Insights
Systemic tumor necrosis factor (TNF) does not cause cerebral malaria in mice. Local TNF production within the brain may be responsible for cerebral pathology in Plasmodium berghei ANKA infections.
Area of Science:
- Immunology
- Pathology
- Infectious Diseases
Background:
- Cerebral pathology in Plasmodium berghei ANKA-infected mice is linked to high serum tumor necrosis factor (TNF) levels.
- Investigating the role of systemic TNF in malaria-induced cerebral pathology is crucial.
Purpose of the Study:
- To determine if exogenous tumor necrosis factor (TNF) can replicate cerebral pathology observed in Plasmodium berghei ANKA infections.
- To investigate the relationship between systemic TNF levels and specific pathological outcomes in malaria-infected mice.
Main Methods:
- Administration of recombinant human TNF to malaria-primed mice via various routes (single/repeated injections, osmotic pumps).
- Monitoring for cerebral changes, hypoglycemia, liver necrosis, and neutrophil adhesion.
- Assessing blood-brain barrier permeability using Evan's blue.
- Quantifying serum TNF levels using ELISA in Plasmodium berghei ANKA and Plasmodium vinckei infected mice.
Main Results:
- Exogenous TNF administration did not induce cerebral pathology but caused hypoglycemia, liver necrosis, and pulmonary neutrophil adhesion.
- Blood-brain barrier permeability to Evan's blue was not induced by exogenous TNF.
- Serum TNF levels were higher in Plasmodium vinckei infections compared to Plasmodium berghei ANKA infections.
Conclusions:
- Systemic tumor necrosis factor (TNF) is unlikely to be the sole driver of cerebral pathology in Plasmodium berghei ANKA infections.
- Local TNF production by sequestered monocytes within cerebral blood vessels may contribute to cerebral malaria.
- Pathological differences between Plasmodium berghei ANKA and Plasmodium vinckei infections correlate with systemic TNF levels.