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West Nile Virus Population Structure, Injury, and Interferon-Stimulated Gene Expression in the Brain From a Fatal Case of Encephalitis.

Grubaugh ND, Massey A, Shives KD, Stenglein MD, Ebel GD, Beckham JD - Open Forum Infect Dis (2015)

Bottom Line: Results.  We found that WNV populations in the injured subcortical brain regions exhibited increased amino acid variation and increased expression of specific interferon genes compared with cortical tissues despite similar viral burden.Conclusions.  These observational, patient-based data suggest that neuronal injury and the strength of viral selection pressure may be associated with the level of the innate immune responses.Further studies in human and animal models evaluating the role of innate immune responses on injury patterns and viral selection pressure are needed.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology Immunology and Pathology , College of Veterinary Medicine and Biomedical Sciences, Colorado State University , Fort Collins.

ABSTRACT
Background.  West Nile virus (WNV) infection in humans can result in severe, acute encephalitis typically involving subcortical gray matter brain regions. West Nile virus replication within specific human brain regions from a human case of acute encephalitis has not been studied. Methods.  We describe a fatal case of WNV encephalitis in which we obtained tissue from specific brain regions at autopsy to evaluate viral-host interactions using next-generation sequencing and immunohistochemistry analysis. Results.  We found that WNV populations in the injured subcortical brain regions exhibited increased amino acid variation and increased expression of specific interferon genes compared with cortical tissues despite similar viral burden. Conclusions.  These observational, patient-based data suggest that neuronal injury and the strength of viral selection pressure may be associated with the level of the innate immune responses. Further studies in human and animal models evaluating the role of innate immune responses on injury patterns and viral selection pressure are needed.

No MeSH data available.


Related in: MedlinePlus

Regional magnetic resonance imaging injury patterns associated with apoptosis and interferon-stimulated gene (ISG) expression. Magnetic resonance images (T2 sequences) showing increased signal intensity in the (A) midbrain substantia nigra and left mesial temporal lobe (arrows) and (B) the thalamus and right caudate nucleus (arrows). (C) Immunohistochemistry staining for cleaved-caspase 3 ([Cy3] red) and West Nile virus (WNV) envelope (ENV) antigen (TRITC, green) from indicated brain regions. Bar = 50 µm. Percentage of cells per high-power field positive for (D) CC3 and (E) WNV ENV antigen. *P < .0001, unpaired t test. (F) Reads per kilobase per million (RPKM) reads to interferon-stimulated genes from different brain regions were determined by next-generation sequencing. Gray bars indicate brain regions with neuronal injury.
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OFV182F1: Regional magnetic resonance imaging injury patterns associated with apoptosis and interferon-stimulated gene (ISG) expression. Magnetic resonance images (T2 sequences) showing increased signal intensity in the (A) midbrain substantia nigra and left mesial temporal lobe (arrows) and (B) the thalamus and right caudate nucleus (arrows). (C) Immunohistochemistry staining for cleaved-caspase 3 ([Cy3] red) and West Nile virus (WNV) envelope (ENV) antigen (TRITC, green) from indicated brain regions. Bar = 50 µm. Percentage of cells per high-power field positive for (D) CC3 and (E) WNV ENV antigen. *P < .0001, unpaired t test. (F) Reads per kilobase per million (RPKM) reads to interferon-stimulated genes from different brain regions were determined by next-generation sequencing. Gray bars indicate brain regions with neuronal injury.

Mentions: A 51-year-old female presented with 2 days of increasing altered mental status and decreasing responsiveness. Illness was preceded by 4 days of fever, nausea, and diarrhea. The patient's past medical history was remarkable for a history of rheumatoid arthritis treated with methotrexate and prednisone, and the last treatment was 1 year before presentation. The patient was evaluated in the emergency room, intubated for airway protection, and lumbar puncture was performed to obtain cerebral spinal fluid (CSF), which exhibited 163 white blood cells/mL with a differential of 99% lymphocytes. Magnetic resonance imaging (MRI) revealed increased signal in the insula, medial temporal lobe, medial left thalamus, and left cerebral peduncle (Figure 1A and B). The CSF was positive for WNV IgG (1.82, normal <1.29 intravenous [IV]) and IgM (8.74, normal <0.89 IV; Focus Diagnostics enzyme-linked immunosorbent assay), but CSF and serum WNV reverse transcription-polymerase chain reaction assays were negative for WNV RNA (ARUP Laboratories, Roche Molecular Systems Inc.). With these data, the patient was diagnosed with WNV encephalitis. During hospitalization in the intensive care unit, the patient was weaned from sedation, remained comatose, and had an electroencephalogram showing diffuse slowing. The patient did exhibit brain stem function but minimal peripheral responses with a physical exam consistent with loss of lower motor neuron function in all 4 extremities. An MRI of the spine exhibited no spinal cord lesions. Despite aggressive supportive care, the patient passed away after a cardiac arrest at day 11 of hospitalization. Autopsy was initiated 22 hours and 30 minutes after death and found no evidence of myocardial infarction or coronary artery disease. Brain tissue was collected at time of autopsy.Figure 1.


West Nile Virus Population Structure, Injury, and Interferon-Stimulated Gene Expression in the Brain From a Fatal Case of Encephalitis.

Grubaugh ND, Massey A, Shives KD, Stenglein MD, Ebel GD, Beckham JD - Open Forum Infect Dis (2015)

Regional magnetic resonance imaging injury patterns associated with apoptosis and interferon-stimulated gene (ISG) expression. Magnetic resonance images (T2 sequences) showing increased signal intensity in the (A) midbrain substantia nigra and left mesial temporal lobe (arrows) and (B) the thalamus and right caudate nucleus (arrows). (C) Immunohistochemistry staining for cleaved-caspase 3 ([Cy3] red) and West Nile virus (WNV) envelope (ENV) antigen (TRITC, green) from indicated brain regions. Bar = 50 µm. Percentage of cells per high-power field positive for (D) CC3 and (E) WNV ENV antigen. *P < .0001, unpaired t test. (F) Reads per kilobase per million (RPKM) reads to interferon-stimulated genes from different brain regions were determined by next-generation sequencing. Gray bars indicate brain regions with neuronal injury.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4697916&req=5

OFV182F1: Regional magnetic resonance imaging injury patterns associated with apoptosis and interferon-stimulated gene (ISG) expression. Magnetic resonance images (T2 sequences) showing increased signal intensity in the (A) midbrain substantia nigra and left mesial temporal lobe (arrows) and (B) the thalamus and right caudate nucleus (arrows). (C) Immunohistochemistry staining for cleaved-caspase 3 ([Cy3] red) and West Nile virus (WNV) envelope (ENV) antigen (TRITC, green) from indicated brain regions. Bar = 50 µm. Percentage of cells per high-power field positive for (D) CC3 and (E) WNV ENV antigen. *P < .0001, unpaired t test. (F) Reads per kilobase per million (RPKM) reads to interferon-stimulated genes from different brain regions were determined by next-generation sequencing. Gray bars indicate brain regions with neuronal injury.
Mentions: A 51-year-old female presented with 2 days of increasing altered mental status and decreasing responsiveness. Illness was preceded by 4 days of fever, nausea, and diarrhea. The patient's past medical history was remarkable for a history of rheumatoid arthritis treated with methotrexate and prednisone, and the last treatment was 1 year before presentation. The patient was evaluated in the emergency room, intubated for airway protection, and lumbar puncture was performed to obtain cerebral spinal fluid (CSF), which exhibited 163 white blood cells/mL with a differential of 99% lymphocytes. Magnetic resonance imaging (MRI) revealed increased signal in the insula, medial temporal lobe, medial left thalamus, and left cerebral peduncle (Figure 1A and B). The CSF was positive for WNV IgG (1.82, normal <1.29 intravenous [IV]) and IgM (8.74, normal <0.89 IV; Focus Diagnostics enzyme-linked immunosorbent assay), but CSF and serum WNV reverse transcription-polymerase chain reaction assays were negative for WNV RNA (ARUP Laboratories, Roche Molecular Systems Inc.). With these data, the patient was diagnosed with WNV encephalitis. During hospitalization in the intensive care unit, the patient was weaned from sedation, remained comatose, and had an electroencephalogram showing diffuse slowing. The patient did exhibit brain stem function but minimal peripheral responses with a physical exam consistent with loss of lower motor neuron function in all 4 extremities. An MRI of the spine exhibited no spinal cord lesions. Despite aggressive supportive care, the patient passed away after a cardiac arrest at day 11 of hospitalization. Autopsy was initiated 22 hours and 30 minutes after death and found no evidence of myocardial infarction or coronary artery disease. Brain tissue was collected at time of autopsy.Figure 1.

Bottom Line: Results.  We found that WNV populations in the injured subcortical brain regions exhibited increased amino acid variation and increased expression of specific interferon genes compared with cortical tissues despite similar viral burden.Conclusions.  These observational, patient-based data suggest that neuronal injury and the strength of viral selection pressure may be associated with the level of the innate immune responses.Further studies in human and animal models evaluating the role of innate immune responses on injury patterns and viral selection pressure are needed.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology Immunology and Pathology , College of Veterinary Medicine and Biomedical Sciences, Colorado State University , Fort Collins.

ABSTRACT
Background.  West Nile virus (WNV) infection in humans can result in severe, acute encephalitis typically involving subcortical gray matter brain regions. West Nile virus replication within specific human brain regions from a human case of acute encephalitis has not been studied. Methods.  We describe a fatal case of WNV encephalitis in which we obtained tissue from specific brain regions at autopsy to evaluate viral-host interactions using next-generation sequencing and immunohistochemistry analysis. Results.  We found that WNV populations in the injured subcortical brain regions exhibited increased amino acid variation and increased expression of specific interferon genes compared with cortical tissues despite similar viral burden. Conclusions.  These observational, patient-based data suggest that neuronal injury and the strength of viral selection pressure may be associated with the level of the innate immune responses. Further studies in human and animal models evaluating the role of innate immune responses on injury patterns and viral selection pressure are needed.

No MeSH data available.


Related in: MedlinePlus