Neuroprotective interventions targeting detrimental host immune responses protect mice from fatal alphavirus encephalitis.
Systemic treatment with the tetracycline derivative, minocycline, attenuates neurologic deficits in animal models of amyotrophic lateral sclerosis, hypoxic-ischemic brain injury, and multiple sclerosis. Inhibition of microglial activation within the CNS is 1 mechanism proposed to underlie the beneficial effects of the drug in these systems. Given the widening scope of acute viral encephalitis caused by mosquito-borne pathogens, we investigated the therapeutic effects of minocycline in a murine model of fatal alphavirus encephalomyelitis in which widespread microglial activation is known to occur. We found that minocycline conferred significant protection against both paralysis and death, even when started after viral challenge and despite having no effect on CNS virus replication or spread. Further studies demonstrated that minocycline inhibited early virus-induced microglial activation and that diminished CNS production of the inflammatory mediator, interleukin (IL)-1beta, contributed to its protective effect. Therapeutic blockade of IL-1 receptors also conferred significant protection in our model, validating the importance of the IL-1 pathway in disease pathogenesis. We propose that interventions targeting detrimental host immune responses arising from activated microglia may be of benefit in humans with acute viral encephalitis caused by related mosquito-borne pathogens. Such treatments could conceivably act through neuroprotective rather than antiviral mechanisms to generate these clinical effects.
Irani
David N
DN
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. dirani@jhmi.edu
Prow
Natalie A
NA
D000281:Administration, Intranasal; D018354:Alphavirus Infections; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002490:Central Nervous System / Q000821:virology; D004198:Disease Susceptibility; D004660:Encephalitis / Q000401:mortality / Q000517:prevention & control* / Q000821:virology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects; D008911:Minocycline / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D010243:Paralysis / Q000517:prevention & control; D012845:Sindbis Virus / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053583:Interleukin-1beta; D018696:Neuroprotective Agents; D008911:Minocycline