Airborne Rabies Transmission in a Laboratory Worker

Winkler, William G.; Fashinell, Thomas R.; Leffingwell, Lois; Howard, P. J. A.; Conomy, John P.

doi:10.1001/jama.1973.03230100043011

Cited by 159 publications

(40 citation statements)

References 7 publications

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“…RABV infects epithelial cells in the final stages of disease, when virus spreads from the CNS to a variety of extraneural tissues through innervation routes. Epithelial-cell infection is also a primary and necessary step in intranasal or oral infections in animals and in accidental exposures of laboratory workers to RABV (37)(38)(39)(40). The BS-C-1 cells used in this study do not express the putative RABV receptors p75 neurotrophin receptor (p75 NTR ) and neural cell adhesion molecule (NCAM), as both were undetectable by reverse transcription (RT)-PCR (data not shown).…”

Section: Discussionmentioning

confidence: 88%

Uptake of Rabies Virus into Epithelial Cells by Clathrin-Mediated Endocytosis Depends upon Actin

Piccinotti

Kirchhausen

Whelan

2013

J Virol

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dRabies virus (RABV) causes a fatal zoonotic encephalitis. Disease symptoms require replication and spread of the virus within neuronal cells; however, in infected animals as well as in cell culture the virus replicates in a broad range of cell types. Here we use a single-cycle RABV and a recombinant vesicular stomatitis virus (rVSV) in which the glycoprotein (G) was replaced with that of RABV (rVSV RABV G) to examine RABV uptake into the African green monkey kidney cell line BS-C-1. Combining biochemical studies and real-time spinning-disk confocal fluorescence microscopy, we show that the predominant entry pathway of RABV particles into BS-C-1 cells is clathrin dependent. Viral particles enter cells in pits with elongated structures and incomplete clathrin coats which depend upon actin to complete the internalization process. By measuring the time of internalization and the abundance of the clathrin adaptor protein AP2, we further show that the pits that internalize RABV particles are similar to those that internalize VSV particles. Pharmacological perturbations of dynamin or of actin polymerization inhibit productive infection, linking our observations on particle uptake with viral infectivity. This work extends to RABV particles the finding that clathrin-mediated endocytosis of rhabdoviruses proceeds through incompletely coated pits which depend upon actin. R abies virus (RABV) is the prototypical member of the zoonotic lyssavirus genus responsible for fatal encephalitis in animals and humans. A single-stranded negative-sense RNA virus, RABV encases its RNA genome in a bullet-shaped, enveloped particle that incorporates a single surface glycoprotein (G). RABV G mediates all internalization steps from cell binding to membrane fusion. In addition, G is a major determinant of RABV neurotropism (1). Conjugation or pseudotyping with the ectodomain of pathogenic RABV G or peptides derived from receptor-binding regions allows retargeting of biologically active molecules to the central nervous system (CNS) for drug delivery or as neurotracers (2, 3). Since a large part of RABV pathogenesis is reliant on the virus garnering access to neurons and the CNS, G is also a determining factor in RABV virulence. The pathogenicity of attenuated strains can be effectively increased by replacing the glycoprotein with one from a neurotropic, virulent strain (4).Like other rhabdoviruses, RABV gains access to the cellular interior by endocytosis and subsequent low pH-dependent fusion (5-7). Electron micrographs of viral particles in vesicles with electron-dense coats suggest that clathrin-coated pits mediate the uptake of RABV in both neuronal and nonneuronal cells (8, 9). However, static images cannot inform on the fate of such particles or the relevance of these interactions for subsequent infection. High-resolution live-imaging techniques permit tracking of viral uptake into coated pits (10-15). Fluorescence tagging of coatedpit components and quantitative analysis methods have revealed differences for the pits engaging fluoresc...

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Section: Discussionmentioning

confidence: 88%

Uptake of Rabies Virus into Epithelial Cells by Clathrin-Mediated Endocytosis Depends upon Actin

Piccinotti

Kirchhausen

Whelan

2013

J Virol

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“…While contamination via aerosolization remains exceptional and has been reported in only two laboratory cases (14,15), the presence of rabies virus in human bronchial secretions has never been reported. In our patient, the detection of viral RNA in bronchial aspirates, together with unsuccessful attempts to isolate the virus from those specimens, suggests that this potential source remains at very limited risk for rabies transmission.…”

Section: Case Reportmentioning

confidence: 99%

Severe Ketoalkalosis as Initial Presentation of Imported Human Rabies in France

et al. 2015

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eWe report a patient with an unusual initial metabolic presentation of imported human rabies who became symptomatic within 2 weeks of returning from Mali to France. This is the single case of imported human rabies identified in France within the past 11 years and the first report of viral RNA in bronchial secretions. CASE REPORTA 57-year-old male without past medical history presented to an emergency room in March 2014 because of fever and generalized pain. He had been a resident of France for the previous 15 years and had returned 2 weeks earlier following a 6-month stay in Mali. Approximately 1 month before his return to France, he underwent a right foot injury from a tree branch which eventually healed with local care.On admission, he was conscious and cooperative but appeared anxious; he had fever (38.2°C) and abundant sweating and complained of generalized pain, mostly in the lower limbs. A clean, noninflammatory wound scar was noted on the right foot. He had marked tachypnea (rate, 40 inspirations/minute) and periodic deeper inspirations. Chest examination results were unremarkable. Arterial blood gas measurements while the patient was breathing room air were as follows: pH 7.79; partial pressure of carbon dioxide (PaCO 2 ), 11 mm Hg; PaO 2 , 136 mm Hg; bicarbonates, 16 mmol/liter; and lactate, 3.7 mmol/liter. The capillary blood glucose was measured at 12 mmol/liter, and a urine dipstick revealed glycosuria (3ϩ) and ketonuria (3ϩ). Serum creatinine was at 94 mol/liter and sodium at 136 mmol/liter. Thick and thin blood smears were negative for malaria. Chest X-ray results were normal. The patient was transferred to our intensive care unit (ICU) with a presumptive diagnosis of uncontrolled diabetes and unexplained severe respiratory alkalosis. He received intravenous fluids, continuous insulin infusion, and tetanus prevention with vaccination and serotherapy. Hyperventilation, ketonuria, and metabolic abnormalities resolved within 2 days, with normalization of pH and PaCO 2 . Glycated hemoglobin was 6.5%, and the patient required no further insulin administration during his ICU stay.Two days after ICU admission, he developed bouts of hyperactivity, disorientation, and delirium with thoughts of impending death associated with persecution ideas, alternating with periods of drowsiness and returns to normal behavior when he seemed aware of his disorder and criticized it. Hypersalivation was remarkable, and the patient occasionally spat on ICU personnel. Motor weakness, deep tendon reflexes, and limb sensory perceptions were normal. The results of a computed tomography scan and magnetic resonance imaging (MRI) of the brain were unremarkable. Electroencephalogram results showed no epileptic activity. The cerebrospinal fluid (CSF) test result was normal, with a negative PCR test for herpes simplex virus 1 (HSV-1) and HSV-2. Serological tests for human immunodeficiency virus type 1 (HIV-1) and HIV-2 and HIV-1 p24 antigen were negative. Thyroid-stimulating hormone and ammonia levels were in the normal range. Syphili...

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“…Inhalation of aerosolized rabies virus was previously reported as an accidental event in a laboratory worker, who was infected while grinding rabid sheep brains for vaccine production [17], and by people in caves inhabited by numerous infected bats [18].…”

Section: Viral Transmissionmentioning

confidence: 99%

Perspectives in Diagnosis and Treatment of Rabies Viral Encephalitis: Insights from Pathogenesis

et al. 2016

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Rabies viral encephalitis, though one of the oldest recognized infectious disease of humans, remains an incurable, fatal encephalomyelitis, despite advances in understanding of its pathobiology. Advances in science have led us on the trail of the virus in the host, but the sanctuaries in which the virus remains hidden for its survival are unknown. Insights into host-pathogen interactions have facilitated evolving immunologic therapeutic strategies, though we are far from a cure. Most of the present-day knowledge has evolved from in vitro studies using fixed (attenuated) laboratory strains that may not be applicable in the clinical setting. Much remains to be unraveled about this elusive virus. This review attempts to re-examine the current advances in understanding of the pathobiology of the rabies virus that modulate the diagnosis, treatment, and prevention of this fatal disease.

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Airborne Rabies Transmission in a Laboratory Worker

Cited by 159 publications

References 7 publications

Uptake of Rabies Virus into Epithelial Cells by Clathrin-Mediated Endocytosis Depends upon Actin

Uptake of Rabies Virus into Epithelial Cells by Clathrin-Mediated Endocytosis Depends upon Actin

Severe Ketoalkalosis as Initial Presentation of Imported Human Rabies in France

Perspectives in Diagnosis and Treatment of Rabies Viral Encephalitis: Insights from Pathogenesis

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