The differential effect of Interferon-gamma on acute kidney injury and parasitemia in experimental malaria.

Summary

In two murine malaria models, IFN-gamma deficiency had opposing effects: it protected PbNK65-infected mice from MAKI and MA-ARDS with lower parasitemia and injury markers, but worsened PcAS-induced kidney injury with higher parasitemia. IFN-gamma consistently induced renal CXCL10 without altering TNF-alpha, underscoring a strain-dependent, cytokine-mediated pathophysiology.

Key Findings

• IFN-gamma deficiency protected PbNK65-infected mice from MAKI and MA-ARDS, with low parasitemia, minimal renal histopathology, and reduced NGAL.
• In PcAS infection, IFN-gamma deficiency increased parasitemia and aggravated kidney injury, with proteinuria, hyaline casts, and elevated renal HO-1 and NGAL mRNA.
• IFN-gamma induced renal CXCL10 in both models without affecting TNF-alpha expression.

Clinical Implications

Cytokine-modulating therapies in infectious ARDS should account for pathogen- and context-specific effects; IFN-gamma blockade may benefit some malaria phenotypes but harm others.

Limitations

• Mouse models may not fully recapitulate human malaria pathophysiology.
• Cellular sources/targets of IFN-gamma and CXCL10 were not delineated.

Future Directions

Validate findings in human malaria cohorts with ARDS/AKI phenotyping; dissect cellular pathways of IFN-gamma/CXCL10; test host-directed interventions stratified by parasite species.