S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria
Abstract
Artesunate remains the mainstay of treatment for cerebral malaria, but it is less effective in later stages of disease when the host inflammatory response and blood-brain barrier integrity dictate clinical outcomes. Nitric oxide (NO) is an important regulator of inflammation and microvascular integrity, and impaired NO bioactivity is associated with fatal outcomes in malaria. Endogenous NO bioactivity in mammals is largely mediated byS-nitrosothiols (SNOs). Based on these observations, we hypothesized that animals deficient in the SNO-metabolizing enzyme,S-nitrosoglutathione reductase (GSNOR), which exhibit enhancedS-nitrosylation, would have improved outcomes in a preclinical model of cerebral malaria. GSNOR knockout (KO) mice infected withPlasmodium bergheiANKA had significantly delayed mortality compared to WT animals (PPP+and CD8+T cells in the brain, improved blood-brain barrier integrity, and improved coma scores, as well as higher levels of gamma interferon. GSNOR KO animals receiving WT bone marrow had significantly reduced survival followingP. bergheiANKA infection compared to those receiving KO bone barrow (P< 0.001). Reciprocal transplants established that survival benefits of GSNOR deletion were attributable primarily to the T cell compartment. These data indicate a role for GSNOR in the host response to malaria infection and suggest that strategies to disrupt its activity will improve clinical outcomes by enhancing microvascular integrity and modulating T cell tissue tropism.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 01, 2017
- Source ID
- 10.1128/iai.00371-17
Entities
People
- Alfred Hausladen
- Clinton S. Robbins
- Eric A. Shikatani
- Jonathan S. Stamler
- Kevin C. Kain
- Mansoor Husain
- Matthew Davies
- Rickvinder Besla
- Robyn E. Elphinstone
- Ziyue Lu
Organizations
- Canada Research Chair
- Canadian Institutes of Health Research
- Case Western Reserve University
- National Institutes of Health
- University of Toronto