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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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Strain and Inoculation Route Dependent Pathogenicity of SB and DOG4 in Mice.Six- to eight-week-old mice were inoculated i.m. or i.v. with 106 ffu of SB or DOG4. (A) The graph depicts the weight curves of ten mice per group as group averages (mean±standard error). Percentages relate to the body weight at the day of inoculation. (B) Kaplan-Meier plots show the survival probability per day for each experimental group. Data are combined from two independent experiments. Survival curves were statistically different (p<0.0001) between SB i.m. (n = 16) and DOG4 i.m. (n = 17), SB i.v. (n = 18) and DOG4 i.v. (n = 17) as well as between DOG4 i.m. and DOG4 i.v.
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ppat-1000485-g001: Strain and Inoculation Route Dependent Pathogenicity of SB and DOG4 in Mice.Six- to eight-week-old mice were inoculated i.m. or i.v. with 106 ffu of SB or DOG4. (A) The graph depicts the weight curves of ten mice per group as group averages (mean±standard error). Percentages relate to the body weight at the day of inoculation. (B) Kaplan-Meier plots show the survival probability per day for each experimental group. Data are combined from two independent experiments. Survival curves were statistically different (p<0.0001) between SB i.m. (n = 16) and DOG4 i.m. (n = 17), SB i.v. (n = 18) and DOG4 i.v. (n = 17) as well as between DOG4 i.m. and DOG4 i.v.

Mentions: As a first step to obtain evidence that certain RV variants might have the capacity to reach the brain from a peripheral site via hematogenous spread, we infected mice i.m. or i.v. with either DOG4 or SB. After i.m. injection of 106 focus forming units (ffu) of SB (group 1) or DOG4 (group 2), all mice developed classical rabies symptoms like fur ruffling, weight loss (Figure 1A), hunchback posture and hind limb paralysis. 94% of the SB-infected and 88% the DOG4-infected mice succumbed to the infection with average survival times of 8.3±1.2 and 10.9±1.2 days, respectively. In contrast to the i.m. inoculation, only mice that were inoculated i.v. with SB (group 3) developed rabies with a mortality rate of 100%, while all mice which were inoculated i.v. with DOG4 (group 4) survived. The mean survival time after SB i.v. infection (10.4±2.4 days) was not significantly different from the survival time after SB i.m. infection (p>0.05, Figure 1B). Although the disease onset as indicated by the loss of body weight was alike in both SB groups (Figure 1A), mice infected i.v. with SB did not develop hind limb paralysis. Of note, i.v. injected SB caused disease symptoms similar to those reported for intracerebral inoculation [11].


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 Pathogenicity of SB and DOG4 in Mice.Six- to eight-week-old mice were inoculated i.m. or i.v. with 106 ffu of SB or DOG4. (A) The graph depicts the weight curves of ten mice per group as group averages (mean±standard error). Percentages relate to the body weight at the day of inoculation. (B) Kaplan-Meier plots show the survival probability per day for each experimental group. Data are combined from two independent experiments. Survival curves were statistically different (p<0.0001) between SB i.m. (n = 16) and DOG4 i.m. (n = 17), SB i.v. (n = 18) and DOG4 i.v. (n = 17) as well as between DOG4 i.m. and DOG4 i.v.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1000485-g001: Strain and Inoculation Route Dependent Pathogenicity of SB and DOG4 in Mice.Six- to eight-week-old mice were inoculated i.m. or i.v. with 106 ffu of SB or DOG4. (A) The graph depicts the weight curves of ten mice per group as group averages (mean±standard error). Percentages relate to the body weight at the day of inoculation. (B) Kaplan-Meier plots show the survival probability per day for each experimental group. Data are combined from two independent experiments. Survival curves were statistically different (p<0.0001) between SB i.m. (n = 16) and DOG4 i.m. (n = 17), SB i.v. (n = 18) and DOG4 i.v. (n = 17) as well as between DOG4 i.m. and DOG4 i.v.
Mentions: As a first step to obtain evidence that certain RV variants might have the capacity to reach the brain from a peripheral site via hematogenous spread, we infected mice i.m. or i.v. with either DOG4 or SB. After i.m. injection of 106 focus forming units (ffu) of SB (group 1) or DOG4 (group 2), all mice developed classical rabies symptoms like fur ruffling, weight loss (Figure 1A), hunchback posture and hind limb paralysis. 94% of the SB-infected and 88% the DOG4-infected mice succumbed to the infection with average survival times of 8.3±1.2 and 10.9±1.2 days, respectively. In contrast to the i.m. inoculation, only mice that were inoculated i.v. with SB (group 3) developed rabies with a mortality rate of 100%, while all mice which were inoculated i.v. with DOG4 (group 4) survived. The mean survival time after SB i.v. infection (10.4±2.4 days) was not significantly different from the survival time after SB i.m. infection (p>0.05, Figure 1B). Although the disease onset as indicated by the loss of body weight was alike in both SB groups (Figure 1A), mice infected i.v. with SB did not develop hind limb paralysis. Of note, i.v. injected SB caused disease symptoms similar to those reported for intracerebral inoculation [11].

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