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Intravenous inoculation of a bat-associated rabies virus causes lethal encephalopathy in mice through invasion of the brain via neurosecretory hypothalamic fibers.

Preuss MA, Faber ML, Tan GS, Bette M, Dietzschold B, Weihe E, Schnell MJ - PLoS Pathog. (2009)

Bottom Line: To determine whether certain RV variants might have the capacity to invade the CNS from the periphery via hematogenous spread, we infected mice either intramuscularly (i.m.) or intravenously (i.v.) with the dog-associated RV DOG4 or the silver-haired bat-associated RV SB.The earliest affected regions were those hypothalamic nuclei, which are connected by neurosecretory fibers to the circumventricular organs neurohypophysis and median eminence.Our data suggest that hematogenous spread of SB can lead to a fatal encephalopathy through direct retrograde invasion of the CNS at the neurovascular interface of the hypothalamus-hypophysis system.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University Marburg, Marburg, Germany.

ABSTRACT
The majority of rabies virus (RV) infections are caused by bites or scratches from rabid carnivores or bats. Usually, RV utilizes the retrograde transport within the neuronal network to spread from the infection site to the central nervous system (CNS) where it replicates in neuronal somata and infects other neurons via trans-synaptic spread. We speculate that in addition to the neuronal transport of the virus, hematogenous spread from the site of infection directly to the brain after accidental spill over into the vascular system might represent an alternative way for RV to invade the CNS. So far, it is unknown whether hematogenous spread has any relevance in RV pathogenesis. To determine whether certain RV variants might have the capacity to invade the CNS from the periphery via hematogenous spread, we infected mice either intramuscularly (i.m.) or intravenously (i.v.) with the dog-associated RV DOG4 or the silver-haired bat-associated RV SB. In addition to monitoring the progression of clinical signs of rabies we used immunohistochemistry and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to follow the spread of the virus from the infection site to the brain. In contrast to i.m. infection where both variants caused a lethal encephalopathy, only i.v. infection with SB resulted in the development of a lethal infection. While qRT-PCR did not reveal major differences in virus loads in spinal cord or brain at different times after i.m. or i.v. infection of SB, immunohistochemical analysis showed that only i.v. administered SB directly infected the forebrain. The earliest affected regions were those hypothalamic nuclei, which are connected by neurosecretory fibers to the circumventricular organs neurohypophysis and median eminence. Our data suggest that hematogenous spread of SB can lead to a fatal encephalopathy through direct retrograde invasion of the CNS at the neurovascular interface of the hypothalamus-hypophysis system. This alternative mode of virus spread has implications for the post exposure prophylaxis of rabies, particularly with silver-haired bat-associated RV.

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Related in: MedlinePlus

Strain and Inoculation Route Dependent Distribution of Viral Antigen in the Brain.Brains of mice inoculated i.m. or i.v. with 106 ffu of SB or DOG4 were analyzed when the animals were moribund or at the end of the 20-day observation period as indicated in the panels A to D. Sagittal sections were stained immunohistochemically against RV, subsequently visualized by an enzymatic reaction and documented with bright field microscopy. Abbreviations: Cb, cerebellum; cc, corpus callosum; CGMB, central gray substance of midbrain; Cx, cerebral cortex; Hy, hypothalamus; MO, medulla oblongata; RF, reticular formation; SptN, septal nuclei; Tg, midbrain tegmentum; Tec, tectum; Th, thalamus.
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ppat-1000485-g002: Strain and Inoculation Route Dependent Distribution of Viral Antigen in the Brain.Brains of mice inoculated i.m. or i.v. with 106 ffu of SB or DOG4 were analyzed when the animals were moribund or at the end of the 20-day observation period as indicated in the panels A to D. Sagittal sections were stained immunohistochemically against RV, subsequently visualized by an enzymatic reaction and documented with bright field microscopy. Abbreviations: Cb, cerebellum; cc, corpus callosum; CGMB, central gray substance of midbrain; Cx, cerebral cortex; Hy, hypothalamus; MO, medulla oblongata; RF, reticular formation; SptN, septal nuclei; Tg, midbrain tegmentum; Tec, tectum; Th, thalamus.

Mentions: Independent from the inoculation route, SB was present in the CNS of the two moribund animals in brainstem, cerebellum, thalamus and neocortex (Figure 2A and 2B). However, the virus load was more prominent in the central gray of midbrain and in neocortical areas after i.v. inoculation as compared to i.m. infection.


Intravenous inoculation of a bat-associated rabies virus causes lethal encephalopathy in mice through invasion of the brain via neurosecretory hypothalamic fibers.

Preuss MA, Faber ML, Tan GS, Bette M, Dietzschold B, Weihe E, Schnell MJ - PLoS Pathog. (2009)

Strain and Inoculation Route Dependent Distribution of Viral Antigen in the Brain.Brains of mice inoculated i.m. or i.v. with 106 ffu of SB or DOG4 were analyzed when the animals were moribund or at the end of the 20-day observation period as indicated in the panels A to D. Sagittal sections were stained immunohistochemically against RV, subsequently visualized by an enzymatic reaction and documented with bright field microscopy. Abbreviations: Cb, cerebellum; cc, corpus callosum; CGMB, central gray substance of midbrain; Cx, cerebral cortex; Hy, hypothalamus; MO, medulla oblongata; RF, reticular formation; SptN, septal nuclei; Tg, midbrain tegmentum; Tec, tectum; Th, thalamus.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2691950&req=5

ppat-1000485-g002: Strain and Inoculation Route Dependent Distribution of Viral Antigen in the Brain.Brains of mice inoculated i.m. or i.v. with 106 ffu of SB or DOG4 were analyzed when the animals were moribund or at the end of the 20-day observation period as indicated in the panels A to D. Sagittal sections were stained immunohistochemically against RV, subsequently visualized by an enzymatic reaction and documented with bright field microscopy. Abbreviations: Cb, cerebellum; cc, corpus callosum; CGMB, central gray substance of midbrain; Cx, cerebral cortex; Hy, hypothalamus; MO, medulla oblongata; RF, reticular formation; SptN, septal nuclei; Tg, midbrain tegmentum; Tec, tectum; Th, thalamus.
Mentions: Independent from the inoculation route, SB was present in the CNS of the two moribund animals in brainstem, cerebellum, thalamus and neocortex (Figure 2A and 2B). However, the virus load was more prominent in the central gray of midbrain and in neocortical areas after i.v. inoculation as compared to i.m. infection.

Bottom Line: To determine whether certain RV variants might have the capacity to invade the CNS from the periphery via hematogenous spread, we infected mice either intramuscularly (i.m.) or intravenously (i.v.) with the dog-associated RV DOG4 or the silver-haired bat-associated RV SB.The earliest affected regions were those hypothalamic nuclei, which are connected by neurosecretory fibers to the circumventricular organs neurohypophysis and median eminence.Our data suggest that hematogenous spread of SB can lead to a fatal encephalopathy through direct retrograde invasion of the CNS at the neurovascular interface of the hypothalamus-hypophysis system.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University Marburg, Marburg, Germany.

ABSTRACT
The majority of rabies virus (RV) infections are caused by bites or scratches from rabid carnivores or bats. Usually, RV utilizes the retrograde transport within the neuronal network to spread from the infection site to the central nervous system (CNS) where it replicates in neuronal somata and infects other neurons via trans-synaptic spread. We speculate that in addition to the neuronal transport of the virus, hematogenous spread from the site of infection directly to the brain after accidental spill over into the vascular system might represent an alternative way for RV to invade the CNS. So far, it is unknown whether hematogenous spread has any relevance in RV pathogenesis. To determine whether certain RV variants might have the capacity to invade the CNS from the periphery via hematogenous spread, we infected mice either intramuscularly (i.m.) or intravenously (i.v.) with the dog-associated RV DOG4 or the silver-haired bat-associated RV SB. In addition to monitoring the progression of clinical signs of rabies we used immunohistochemistry and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to follow the spread of the virus from the infection site to the brain. In contrast to i.m. infection where both variants caused a lethal encephalopathy, only i.v. infection with SB resulted in the development of a lethal infection. While qRT-PCR did not reveal major differences in virus loads in spinal cord or brain at different times after i.m. or i.v. infection of SB, immunohistochemical analysis showed that only i.v. administered SB directly infected the forebrain. The earliest affected regions were those hypothalamic nuclei, which are connected by neurosecretory fibers to the circumventricular organs neurohypophysis and median eminence. Our data suggest that hematogenous spread of SB can lead to a fatal encephalopathy through direct retrograde invasion of the CNS at the neurovascular interface of the hypothalamus-hypophysis system. This alternative mode of virus spread has implications for the post exposure prophylaxis of rabies, particularly with silver-haired bat-associated RV.

Show MeSH
Related in: MedlinePlus