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Aim: To develop a trivalent DNA vaccine candidate encapsulated in Chitosan-TPP nanoparticles against hand foot and mouth disease (HFMD) and assess its immunogenicity in mice. Materials & methods: Trivalent plasmid carrying the VP1 and VP2 genes of EV-A71, VP1 gene of CV-A16 was encapsulated in Chitosan-TPP nanoparticles through ionic gelation. In vitro characterization and in vivo immunization studies of the CS-TPP-NPs (pIRES-VP121) were performed. Results: Mice administered with CS-TPP NPs (pIRES-VP121) intramuscularly were observed to have the highest IFN-γ response. Sera from mice immunized with the naked pDNA and CS-TPP-NPs (pIRES-VP121) demonstrated good viral clearance against wild-type EV-A71 and CV-A16 in RD cells. Conclusion: CS-TPP-NPs (pIRES-VP121) could serve as a prototype for future development of multivalent HFMD DNA vaccine candidates.
[Box: see text].
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Nipah virus (NiV) is an emerging pathogen that causes encephalitis and a high mortality rate in infected subjects. This systematic review aimed to comprehensively analyze the global epidemiology and research advancements of NiV to identify the key knowledge gaps in the literature. Articles searched using literature databases, namely PubMed, Scopus, Web of Science, and Science Direct yielded 5,596 articles. After article screening, 97 articles were included in this systematic review, comprising 41 epidemiological studies and 56 research developments on NiV. The majority of the NiV epidemiological studies were conducted in Bangladesh, reflecting the country's significant burden of NiV outbreaks. The initial NiV outbreak was identified in Malaysia in 1998, with subsequent outbreaks reported in Bangladesh, India, and the Philippines. Transmission routes vary by country, primarily through pigs in Malaysia, consumption of date palm juice in Bangladesh, and human-to-human in India. However, the availability of NiV genome sequences remains limited, particularly from Malaysia and India. Mortality rates also vary according to the country, exceeding 70% in Bangladesh, India, and the Philippines, and less than 40% in Malaysia. Understanding these differences in mortality rate among countries is crucial for informing NiV epidemiology and enhancing outbreak prevention and management strategies. In terms of research developments, the majority of studies focused on vaccine development, followed by phylogenetic analysis and antiviral research. While many vaccines and antivirals have demonstrated complete protection in animal models, only two vaccines have progressed to clinical trials. Phylogenetic analyses have revealed distinct clades between NiV Malaysia, NiV Bangladesh, and NiV India, with proposals to classify NiV India as a separate strain from NiV Bangladesh. Taken together, comprehensive OneHealth approaches integrating disease surveillance and research are imperative for future NiV studies. Expanding the dataset of NiV genome sequences, particularly from Malaysia, Bangladesh, and India will be pivotal. These research efforts are essential for advancing our understanding of NiV pathogenicity and for developing robust diagnostic assays, vaccines and therapeutics necessary for effective preparedness and response to future NiV outbreaks.
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BACKGROUND AND PURPOSE: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited disorder of fatty acid oxidation that causes lipid storage myopathy (LSM). This is the first report on MADD that describes the phenotypic and genetic features of a Malaysian cohort. METHODS: Among the >2,500 patients in a local muscle biopsy database, patients with LSM were identified and their genomic DNA were extracted from muscle samples and peripheral blood. All 13 exons of the electron-transfer flavoprotein dehydrogenase gene (ETFDH) were subsequently sequenced. Fifty controls were included to determine the prevalence of identified mutations in the normal population. RESULTS: Fourteen (82%) of the 17 LSM patients had MADD with ETFDH mutations. Twelve (86%) were Chinese and two were Malay sisters. Other unrelated patients reported that they had no relevant family history. Nine (64%) were females. The median age at onset was 18.5 years (interquartile range=16-37 years). All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography. Three patients experienced a metabolic crisis at their presentation. Sanger sequencing of ETFDH revealed nine different variants/mutations, one of which was novel: c.998A>G (p.Y333C) in exon 9. Notably, 12 (86%) patients, including the 2 Malay sisters, carried a common c.250G>A (p.A84T) variant, consistent with the hotspot mutation reported in southern China. All of the patients responded well to riboflavin therapy. CONCLUSIONS: Most of our Malaysian cohort with LSM had late-onset, riboflavin-responsive MADD with ETFDH mutations, and they demonstrated phenotypic and genetic features similar to those of cases reported in southern China. Furthermore, we report a novel ETFDH mutation and possibly the first ever MADD patients of Malay descent.
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Dengue virus is a flavivirus transmitted by the mosquitoes, Aedes aegypti and Aedes albopictus. Dengue infection by all four serotypes (DEN 1 to 4) is endemic globally in regions with tropical and subtropical climates, with an estimated 100-400 million infections annually. Among those hospitalized, the mortality is about 1%. Neurological involvement has been reported to be about 5%. The spectrum of neurological manifestations spans both the peripheral and central nervous systems. These manifestations could possibly be categorized into those directly related to dengue infection, i.e. acute and chronic encephalitis, indirect complications leading to dengue encephalopathy, and post-infectious syndrome due to immune-mediated reactions, and manifestations with uncertain mechanisms, such as acute transverse myelitis, acute cerebellitis and myositis. The rising trend in global dengue incidence calls for attention to a more explicit definition of each neurological manifestation for more accurate epidemiological data. The actual global burden of dengue infection with neurological manifestation is essential for future planning and execution of strategies, especially in the development of effective antivirals and vaccines against the dengue virus. In this article, we discuss the recent findings of different spectrums of neurological manifestations in dengue infection and provide an update on antiviral and vaccine development and their challenges.
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Aedes , Encefalopatias , Dengue , Viroses , Animais , Humanos , Dengue/complicações , Dengue/epidemiologiaRESUMO
Background: The Malayan pangolin (Manis javanica) is a placental mammal and is listed as Critically Endangered on the IUCN Red List of Threatened Species. Most previous attempts to breed pangolins in captivity have met with little success because of dietary issues, infections, and other complications, although a previous study reported breeding pangolins in captivity to the third generation. In our previous pangolin genome sequencing data analysis, we obtained a considerable amount of bacterial DNA from a pregnant female Malayan pangolin (named "UM3"), which was likely infected by Paraburkholderia fungorum-an agent of biodegradation and bioremediation in agriculture. Methodology: Here, we further confirmed and characterized this bacterial species using PCR, histological staining, whole-genome sequencing, and bioinformatics approaches. PCR assays with in-house designed primer sets and 16S universal primers showed clear positive bands in the cerebrum, cerebellum, lung, and blood of UM3 suggesting that UM3 might have developed septicaemia. Histological staining showed the presence of Gram-negative rod-shaped bacteria in the pangolin brain and lungs, indicating the colonization of the bacteria in these two organs. In addition, PCR screening of UM3's fetal tissues revealed the presence of P. fungorum in the gastrocnemius muscle, but not in other tissues that we examined. We also sequenced and reconstructed the genome of pangolin P. fungorum, which has a genome size of 7.7 Mbps. Conclusion: Our study is the first to present detailed evidence of the presence of P. fungorum in a pangolin and her fetus (although preliminary results were presented in our previous article). Here, we raise the concern that P. fungorum may potentially infect humans, especially YOPI (young, old, pregnant, and immunocompromised) people. Therefore, caution should be exercised when using this bacterial species as biodegradation or bioremediation agents in agriculture.
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Mamíferos , Pangolins , Humanos , Gravidez , Animais , Feminino , Pangolins/genética , Mamíferos/genética , Placenta , Eutérios/genética , Análise de SequênciaRESUMO
Radiology-pathology correlation is essential for multidisciplinary collaboration in diagnosis and understanding the mechanism of CNS damage in infectious processes. The microscopic acute inflammatory processes are well established and are supplemented by a variety of less-invasive microbial and immunohistochemical investigations. Understanding the pathogenesis of pathogen spread and neuroinvasion, vascular and immune-mediated brain, and spinal cord damage are essential for interpreting radiological images.
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Radiologia , Humanos , Inflamação , Encéfalo/diagnóstico por imagemRESUMO
BACKGROUND: With progress made in neurogenetics and neuroinflammation, the indications and value of nerve biopsies in the diagnostic evaluation of peripheral neuropathies are less clear. In this study, we aimed to evaluate the diagnostic yield of nerve biopsies in patients with peripheral neuropathies. METHODS: We performed a retrospective review of nerve biopsy reports from April 1998 to June 2021 of patients with peripheral neuropathies presenting to the Department of Pathology, University of Malaya Medical Centre, Kuala Lumpur, Malaysia. The diagnostic value of the biopsies was determined based on the criteria by Midroni and Bilbao as follows: contributive (essential and helpful), non-contributive and inadequate. RESULTS: A total of 107 nerve biopsies were analysed. Sixty-four (60 %) were males and the mean age was 52 years, ranging from 13 to 86 years. Ninety-four (88 %) were sural nerve biopsies; and only one patient (1 %) each had superficial peroneal and superficial radial nerve biopsy. The indications for the procedure were vasculitis (34 %), peripheral neuropathy of unknown aetiology (34 %), amyloidosis (14 %) and chronic inflammatory demyelinating polyneuropathy (10 %). In 68 (63 %) biopsies, the diagnostic value was contributive. Of these, 28 (26 %) were essential and 40 (37 %) were helpful. In contrast, 35 (33 %) biopsies were non-contributive and 4 (4 %) were inadequate. In 66 % (71/107) of cases, the nerve biopsy did not reveal a definite pathological diagnosis. However, in the remainder, a diagnosis of vasculitis (18 %, 19/107), followed by amyloidosis (10 %, 11/107) could be determined. For 32/71 biopsies with undetermined pathological diagnosis, neuropathy remained cryptogenic in 22 % (7/32) upon follow up. CONCLUSIONS: With the exception of vasculitis and amyloidosis, there is limited value in performing nerve biopsies in the evaluation of patients with peripheral neuropathy. However, this should be interpreted with caution as the number of patients with a clinical diagnosis of vasculitis and amyloidosis were relatively larger than patients with other diagnosis. Refinement and careful selection of cases are required to increase the diagnostic yield of nerve biopsy.
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Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Vasculite , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Biópsia/métodos , Nervo Radial/patologia , Vasculite/diagnóstico , Estudos Retrospectivos , Nervo Sural/patologiaRESUMO
OBJECTIVES: Acute Nipah (NiV) encephalitis is characterised by a dual pathogenetic mechanism of neuroglial infection and ischaemia-microinfarction associated with vasculitis-induced thrombotic occlusion. We investigated the contributions of these two mechanisms in fatal cases. MATERIALS AND METHODS: We analysed brain tissues (cerebrum, brainstem and cerebellum) from 15 autopsies using light microscopy, immunohistochemistry (IHC), in situ hybridisation and quantitative methods. RESULTS: Three types of discrete plaque-like parenchymal lesions were identified: Type 1 with neuroglial IHC positivity for viral antigens and minimal or no necrosis; Type 2 with neuroglial immunopositivity and necrosis; and Type 3 with necrosis but no viral antigens. Most viral antigen/RNA-positive cells were neurons. Cerebral glial immunopositivity was rare, suggesting that microinfarction played a more important role in white matter injury. Type 1 lesions were also detected in the brainstem and cerebellum, but the differences between cerebral cortex and these two regions were not statistically significant. In the cerebral cortex, Type 1 lesions overwhelmingly predominated, and only 14% Type 1 vs 69% Type 2 lesions were associated with thrombosis. This suggests that neuronal infection as a mechanism of pathogenesis was more important than microinfarction, both in general and in Type 1 lesions in particular. Between the 'early' group (<8-day fever) and the 'late' group (≥8-day fever), there was a decrease of Type 1 and Type 2 lesions with a concomitant increase of Type 3 lesions, suggesting the latter possibly represented late-stage microinfarction and/or neuronal infection. CONCLUSION: Neuronal infection appears to play a more important role than vasculopathy-induced microinfarction in acute NiV encephalitis.
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Encefalite , Infecções por Henipavirus , Encefalite/patologia , Infecções por Henipavirus/patologia , Humanos , Imuno-Histoquímica , Neurônios/patologiaRESUMO
AIMS: Enterovirus A71 (EV-A71) is an etiological agent of hand foot and mouth disease (HFMD) and has the potential to cause severe neurological infections in children. L-SP40 peptide was previously known to inhibit EV-A71 by prophylactic action. This study aimed to identify the mechanism of inhibition in Rhabdomyosarcoma (RD) cells and in vivo therapeutic potential of L-SP40 peptide in a murine model. MAIN METHODS: A pull-down assay was performed to identify the binding partner of the L-SP40 peptide. Co-immunoprecipitation and co-localization assays with the L-SP40 peptide were employed to confirm the receptor partner in RD cells. The outcomes were validated using receptor knockdown and antibody blocking assays. The L-SP40 peptide was further evaluated for the protection of neonatal mice against lethal challenge by mouse-adapted EV-A71. KEY FINDINGS: The L-SP40 peptide was found to interact and co-localize with nucleolin, the key attachment receptor of Enteroviruses A species, as demonstrated in the pull-down, co-immunoprecipitation and co-localization assays. Knockdown of nucleolin from RD cells led to a significant reduction of 3.5 logs of viral titer of EV-A71. The L-SP40 peptide demonstrated 80% protection of neonatal mice against lethal challenge by the mouse-adapted virus with a drastic reduction in the viral loads in the blood (~4.5 logs), skeletal muscles (1.5 logs) and brain stem (1.5 logs). SIGNIFICANCE: L-SP40 peptide prevented severe hind limb paralysis and death in suckling mice and could serve as a potential broad-spectrum antiviral candidate to be further evaluated for safety and potency in future clinical trials against EV-A71.
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Enterovirus Humano A/efeitos dos fármacos , Enterovirus Humano A/metabolismo , Infecções por Enterovirus/tratamento farmacológico , Infecções por Enterovirus/metabolismo , Fragmentos de Peptídeos/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Animais Recém-Nascidos , Camundongos , Camundongos Endogâmicos ICR , Fragmentos de Peptídeos/administração & dosagem , Ligação Proteica/fisiologia , Resultado do Tratamento , NucleolinaRESUMO
We report the clinical and genetic characteristics of hereditary transthyretin amyloidosis in the multi-ethnic Malaysian population. Subjects with genetically confirmed transthyretin amyloidosis seen between 2001 till August 2020 were included. There were 30 patients and 14 asymptomatic carriers, of which 26 (59.1%) were men. The majority (86.7%) were ethnic Chinese while two (6.7%) each were Malay and Sri Lankan Tamil ethnicity respectively. Among patients, mean age of symptom-onset was 55.9⯱â¯9.8 years with mean duration from symptom-onset to diagnosis of 3.2⯱â¯2.5 years. Common presenting symptoms were sensory symptoms of upper limbs (43.3%), symmetric sensory symptoms of both lower limbs (16.7%) and autonomic symptoms (16.7%). Nerve conduction studies showed sensorimotor polyneuropathy in 25 (83.3%) patients (22, axonal). Abnormal echocardiograms were seen in 24 (80%) patients, although 15 were asymptomatic. Of six different TTR mutations found, Ala97Ser was the commonest, and found exclusively in 84.6% of Chinese patients. Other mutations among Chinese patients were Val30Met, Ala25Thr and Asp39Val. Our Malay and Tamil patients had Glu54Lys and Gly47Val mutations respectively. In conclusion, TTR Ala97Ser is the commonest mutation among ethnic Chinese Malaysians which presented with late-onset progressive sensorimotor polyneuropathy, autonomic dysfunction and subclinical cardiac involvement.
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Neuropatias Amiloides Familiares/genética , Etnicidade/genética , Adulto , Idoso , Povo Asiático/genética , Feminino , Humanos , Malásia , Masculino , Pessoa de Meia-Idade , Mutação , Exame Neurológico , FenótipoRESUMO
Asymptomatic electrophysiological peripheral neuropathy is described in systemic lupus erythematosus (SLE) patients. To determine if SLE could have an even earlier effect on peripheral nerve function even before the development of electrophysiological abnormalities, we compared nerve conduction studies (NCS) of SLE patients without electrophysiological or clinical peripheral neuropathy with healthy controls. Consecutive SLE patients without clinical neuropathy (or other known causes of neuropathy) underwent sensory and motor NCS of all four limbs. Results of 61 patients without electrophysiological criteria of neuropathy were compared with age- and gender-matched controls. Although still within the laboratory's range of normal values, significant differences were found in several NCS parameters between patients and controls. SLE patients had lower amplitudes for ulnar, fibular, and tibial compound muscle action potentials (CMAP) and sural sensory nerve action potentials (SNAP); slower conduction velocities for median, ulnar, and fibular motor nerves, and median, ulnar and sural sensory nerves. SLE patients also had longer minimum F-wave latencies for median, ulnar, fibular, and tibial nerves. H reflexes were more often absent in patients. Correlations were found between the number of disease relapses and motor conduction velocities of the fibular and tibial nerves. SLE may have early effect on peripheral nerve function in patients even before they develop electrophysiological or clinical neuropathy.
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Lúpus Eritematoso Sistêmico/complicações , Condução Nervosa , Polineuropatias/etiologia , Adulto , Idoso , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nervos Periféricos/fisiopatologia , Índice de Gravidade de DoençaRESUMO
Coxsackievirus A16 (CV-A16) is one of the major causes of mild and self-limiting hand-foot-and-mouth disease (HFMD) in young children, which may occasionally leads to serious neurological complications. In this study, we had developed a novel, consistent, orally infected CV-A16 HFMD hamster model with encephalomyelitis. Four groups of 7-day-old hamsters in a kinetic study were orally infected with mouse-adapted CV-A16 strains and sacrificed at 1-4 days post infection (dpi), respectively. Tissues were studied by light microscopy, immunohistochemistry to detect viral antigens, in situ hybridization to detect viral RNA, and by viral titration. In a separate transmission experiment, orally infected index hamsters were housed together with contact hamsters to investigate oral and fecal viral shedding by virus culture and reverse transcription polymerase chain reaction (RT-PCR). At severe infection/death endpoints, index and contact hamster infection were also histopathologically analyzed. In the kinetic study, infected hamsters developed signs of infection at 4 dpi. Viral antigens/RNA were localized to brainstem (medulla/pons; reticular formation and motor trigeminal nucleus) and spinal cord anterior horn neurons, oral squamous epithelia and epidermis from 3 to 4 dpi. Salivary and lacrimal glands, myocardium, brown adipose tissue, intestinal smooth muscle, and skeletal muscle infection was also demonstrated. Viremia at 1 dpi and increasing viral titers in various tissues were observed from 2 dpi. In the transmission study, all contact hamsters developed disease 3-5 days later than index hamsters, but demonstrated similar histopathological findings at endpoint. Viral culture and RT-PCR positive oral washes and feces confirmed viral shedding. Our hamster model, orally infected by the natural route for human infection, confirmed CV-A16 neurotropism and demonstrated squamous epitheliotropism reminiscent of HFMD, attributes not found in other animal models. It should be useful to investigate neuropathogenesis, model person-to-person transmission, and for testing antiviral drugs and vaccines.
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Cricetinae/virologia , Modelos Animais de Doenças , Encefalomielite/virologia , Enterovirus Humano A/fisiologia , Doença de Mão, Pé e Boca/virologia , Boca/virologia , Animais , Antígenos Virais/metabolismo , Criança , Encefalomielite/diagnóstico , Enterovirus Humano A/genética , Enterovirus Humano A/metabolismo , Fezes/virologia , Doença de Mão, Pé e Boca/diagnóstico , Humanos , Imuno-Histoquímica , Hibridização In Situ , Boca/patologia , Mucosa Bucal/patologia , Mucosa Bucal/virologia , RNA Viral/genética , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Several studies on clinical practice for Duchenne muscular dystrophy (DMD) have been conducted in Western countries. However, there have been only a few similar studies in Asia and Oceania. Here, we investigate the steroid therapy-related clinical practice for DMD among the local experts. In 2015, we conducted a DMD expert survey in Asia and Oceania to acquire information regarding patients with DMD and to assess current clinical practice with the cooperation of Asian and Oceanian Myology Centre, a neuromuscular disease research network. RESULTS: We obtained survey responses from 87 out of 148 clinicians (62%) from 13 countries and regions. In China, 1385 DMD patients were followed-up by 5 respondent neurologists, and 84% were between 0 and 9 years of age (15% were 10-19 years, 1% > 19 years). While in Japan, 1032 patients were followed-up by 20 clinicians, and the age distribution was similar between the 3 groups (27% were 0-9 years, 35% were 10-19 years, 38% were >19 years). Most respondent clinicians (91%) were aware of DMD standard of care recommendations. Daily prednisolone/prednisone administration was used most frequently at initiation (N = 45, 64%). Inconsistent opinion on steroid therapy after loss of ambulation and medication for bone protection was observed. CONCLUSIONS: Rare disease research infrastructures have been underdeveloped in many of Asian and Oceanian countries. In this situation, our results show the snapshots of current medical situation and clinical practice in DMD. For further epidemiological studies, expansion of DMD registries is necessary.
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Distrofia Muscular de Duchenne/tratamento farmacológico , Padrões de Prática Médica/estatística & dados numéricos , Prednisolona/uso terapêutico , Prednisona/uso terapêutico , Esteroides/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , China , Pesquisas sobre Atenção à Saúde , Humanos , Lactente , Japão , Masculino , Oceania , Sociedades Médicas/estatística & dados numéricos , Adulto JovemRESUMO
INTRODUCTION: Malignant astrocytomas are composed of heterogeneous cell populations. Compared to grade IV glioblastoma, low-grade astrocytomas have more differentiated cells and are associated with a better prognosis. Therefore, inducing cellular differentiation to alter the behaviour of high-grade astrocytomas may serve as a therapeutic strategy. The nuclear factor one (NFI) transcription factors are essential for normal astrocytic differentiation. Here, we investigate whether family members NFIA and NFIB act as effectors of cellular differentiation in glioblastoma. METHODS: We analysed expression of NFIA and NFIB in mRNA expression data of high-grade astrocytoma and with immunofluorescence co-staining. Furthermore, we induced NFI expression in patient-derived subcutaneous glioblastoma xenografts via in vivo electroporation. RESULTS: The expression of NFIA and NFIB is reduced in glioblastoma as compared to lower grade astrocytomas. At a cellular level, their expression is associated with differentiated and mature astrocyte-like tumour cells. In vivo analyses consistently demonstrate that expression of either NFIA or NFIB is sufficient to promote tumour cell differentiation in glioblastoma xenografts. CONCLUSION: Our findings indicate that both NFIA and NFIB may have an endogenous pro-differentiative function in astrocytomas, similar to their role in normal astrocyte differentiation. Overall, our study establishes a basis for further investigation of targeting NFI-mediated differentiation as a potential differentiation therapy.
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Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Glioblastoma/patologia , Fatores de Transcrição NFI/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fatores de Transcrição NFI/genética , Gradação de Tumores , Neurogênese , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Distal acquired demyelinating symmetric neuropathy (DADS) is a variant of chronic inflammatory demyelinating polyneuropathy (CIDP) characterized by symmetrical, distal, sensory or sensorimotor involvement. DADS with M-protein (DADS-M) is less responsive to immunotherapy compared to those without M-protein (DADS-I). We report a case of DADS-I with severe clinical presentation viz. early hand involvement with marked wasting, inexcitable peripheral nerves on neurophysiology and poor response to immunotherapy. Despite the unusual presentation, ancillary tests including cerebrospinal fluid analysis, nerve biopsy and nerve ultrasound were supportive of an inflammatory demyelinating polyneuropathy. This case demonstrated the heterogeneity of the disorder and expands the clinical spectrum of DADS neuropathy.
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Imunoglobulina M , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Azatioprina/uso terapêutico , Eletrodiagnóstico , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Condução Nervosa/fisiologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/imunologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/fisiopatologia , Prednisolona/uso terapêutico , Resultado do TratamentoRESUMO
Japanese encephalitis (JE) is a known CNS viral infection that often involves the thalamus early. To investigate the possible role of sensory peripheral nervous system (PNS) in early neuroinvasion, we developed a left hindlimb footpad-inoculation mouse model to recapitulate human infection by a mosquito bite. A 1-5 days postinfection (dpi) study, demonstrated focal viral antigens/RNA in contralateral thalamic neurons at 3 dpi in 50% of the animals. From 4 to 5 dpi, gradual increase in viral antigens/RNA was observed in bilateral thalami, somatosensory, and piriform cortices, and then the entire CNS. Infection of neuronal bodies and adjacent nerves in dorsal root ganglia (DRGs), trigeminal ganglia, and autonomic ganglia (intestine, etc.) was also observed from 5 dpi. Infection of explant organotypic whole brain slice cultures demonstrated no viral predilection for the thalamus, while DRG and intestinal ganglia organotypic cultures confirmed sensory and autonomic ganglia susceptibility to infection, respectively. Early thalamus and sensory-associated cortex involvement suggest an important role for sensory pathways in neuroinvasion. Our results suggest that JE virus neuronotropism is much more extensive than previously known, and that the sensory PNS and autonomic system are susceptible to infection.