Type-1 angiotensin receptor signaling in central nervous system myeloid cells is pathogenic during fatal alphavirus encephalitis in mice.

Pennelope K Blakely,Amanda K Huber,David N Irani

doi:10.1186/s12974-016-0683-7

Pennelope K Blakely, Amanda K Huber + Show 1 more

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https://doi.org/10.1186/s12974-016-0683-7

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Abstract

BackgroundAlphaviruses can cause fatal encephalitis in humans. Natural infections occur via the bite of infected mosquitos, but aerosol transmissibility makes some of these viruses potential bioterrorism agents. Central nervous system (CNS) host responses contribute to alphavirus pathogenesis in experimental models and are logical therapeutic targets. We investigated whether reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) activity within the CNS contributes to fatal alphavirus encephalitis in mice.MethodsInfected animals were treated systemically with the angiotensin receptor-blocking drug, telmisartan, given its ability to cross the blood-brain barrier, selectively block type-1 angiotensin receptors (AT1R), and inhibit Nox-derived ROS production in vascular smooth muscle and other extraneural tissues. Clinical, virological, biochemical, and histopathological outcomes were followed over time.ResultsThe importance of the angiotensin II (Ang II)/AT1R axis in disease pathogenesis was confirmed by demonstrating increased Ang II levels in the CNS following infection, enhanced disease survival when CNS Ang II production was suppressed, increased AT1R expression on microglia and tissue-infiltrating myeloid cells, and enhanced disease survival in AT1R-deficient mice compared to wild-type (WT) controls. Systemic administration of telmisartan protected WT mice from lethal encephalitis caused by two different alphaviruses in a dose-dependent manner without altering virus replication or exerting any anti-inflammatory effects in the CNS. Infection triggered up-regulation of multiple Nox subunits in the CNS, while drug treatment inhibited local Nox activity, ROS production, and oxidative neuronal damage. Telmisartan proved ineffective in Nox-deficient mice, demonstrating that this enzyme is its main target in this experimental setting.ConclusionsNox-derived ROS, likely arising from CNS myeloid cells triggered by AT1R signaling, are pathogenic during fatal alphavirus encephalitis in mice. Systemically administered telmisartan at non-hypotensive doses targets Nox activity in the CNS to exert a neuroprotective effect. Disruption of this pathway may have broader implications for the treatment of related infections as well as for other CNS diseases driven by oxidative injury.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0683-7) contains supplementary material, which is available to authorized users.

Highlights

Alphaviruses can cause fatal encephalitis in humans
Animals Inbred C57BL/6 mice, mice heterozygous for deficiencies of the individual Nox subunits, p47phox or gp91phox, both bred on a C57BL/6 background, mice expressing green fluorescent protein (GFP) in one allele of the CX3C chemokine receptor-1 (CX3CR1 or fractalkine receptor) bred on a C57BL/6 background and mice deficient in AT1R bred on a C57BL/6 background (hereafter referred to as AT1R knockout (KO) mice) were all obtained from Jackson Laboratories (Bar Harbor, ME)
Local angiotensin II (Ang II) production was suppressed via systemic administration of captopril (Fig. 1c), an angiotensin converting enzyme (ACE) inhibitor that prevents Ang II cleavage from its precursor, angiotensinogen (AGT)

Summary

Introduction

Alphaviruses can cause fatal encephalitis in humans. Natural infections occur via the bite of infected mosquitos, but aerosol transmissibility makes some of these viruses potential bioterrorism agents. Does NSV cause direct virus-induced neuronal cell death [5], but substantial bystander injury to uninfected neurons occurs [6, 7]. This bystander injury suggests that host responses contribute to alphavirus pathogenesis [8, 9], and recent investigations show that therapies targeting innate immune responses in the central nervous system (CNS) can protect infected hosts without altering virus tropism, replication, or clearance [7, 10, 11]. Microglia and astrocytes are both implicated in this bystander injury [11,12,13,14], but the molecular pathways through which innate host responses lead to neuronal injury during CNS alphavirus infections remain incompletely understood

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