Limited brain metabolism changes differentiate between the progression and clearance of rabies virus.
Central nervous system (CNS) metabolic profiles were examined from rabies virus (RABV)-infected mice that were either mock-treated or received post-exposure treatment (PET) with a single dose of the live recombinant RABV vaccine TriGAS. CNS tissue harvested from mock-treated mice at middle and late stage infection revealed numerous changes in energy metabolites, neurotransmitters and stress hormones that correlated with replication levels of viral RNA. Although the large majority of these metabolic changes were completely absent in the brains of TriGAS-treated mice most likely due to the strong reduction in virus spread, TriGAS treatment resulted in the up-regulation of the expression of carnitine and several acylcarnitines, suggesting that these compounds are neuroprotective. The most striking change seen in mock-treated RABV-infected mice was a dramatic increase in brain and serum corticosterone levels, with the later becoming elevated before clinical signs or loss of body weight occurred. We speculate that the rise in corticosterone is part of a strategy of RABV to block the induction of immune responses that would otherwise interfere with its spread. In support of this concept, we show that pharmacological intervention to inhibit corticosterone biosynthesis, in the absence of vaccine treatment, significantly reduces the pathogenicity of RABV. Our results suggest that widespread metabolic changes, including hypothalamic-pituitary-adrenal axis activation, contribute to the pathogenesis of RABV and that preventing these alterations early in infection with PET or pharmacological blockade helps protect brain homeostasis, thereby reducing disease mortality.
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
Keith
K
Schutsky
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
Carla
C
Portocarrero
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
D Craig
DC
Hooper
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
Bernhard
B
Dietzschold
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
Milosz
M
Faber
D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D056704:Adaptive Immunity; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism* / Q000821:virology; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D018450:Disease Progression; D004734:Energy Metabolism; D005260:Female; D015870:Gene Expression; D054884:Host-Pathogen Interactions; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000821:virology; D051379:Mice; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000821:virology; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011818:Rabies / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D011820:Rabies virus / Q000276:immunology*; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014765:Viral Vaccines / Q000627:therapeutic use
D000998:Antiviral Agents; D011725:Pyridines; D014764:Viral Proteins; D014765:Viral Vaccines; C116917:acylcarnitine; C013109:metapyrone; D002331:Carnitine; D020155:3-Hydroxybutyric Acid; D003345:Corticosterone