Abstract
Dengue virus (DENV) infection remains a major public health concern in many parts of the world, including Southeast Asia and the Americas. Sri Lanka experienced its largest dengue outbreak in 2017. Neurological symptoms associated with DENV infection have increasingly been reported in both children and adults. Here, we characterize DENV type 2 (DENV-2) strains, which were isolated from cerebrospinal fluid (CSF) and/or serum of patients with dengue encephalitis. Acute serum and CSF samples from each patient were subjected to dengue-specific non-structural protein 1 (NS1) antigen test, IgM and IgG enzyme-linked immunosorbent assay (ELISA), virus isolation, conventional and real-time polymerase chain reaction (PCR), and next-generation sequencing (NGS). Among the 5 dengue encephalitis patients examined, 4 recovered and 1 died. DENV-2 strains were isolated from serum and/or CSF samples of 3 patients. The highest viral genome levels were detected in the CSF and serum of the patient who succumbed to the illness. A phylogenetic tree revealed that the DENV-2 isolates belonged to a new clade of cosmopolitan genotype and were genetically close to strains identified in China, South Korea, Singapore, Malaysia, Thailand, and the Philippines. According to the NGS analysis, greater frequencies of nonsynonymous and synonymous mutations per gene were identified in the nonstructural genes. The full genomes of serum- and CSF-derived DENV-2 from the same patient shared 99.7% similarity, indicating that the virus spread across the blood-brain barrier. This is the first report to describe neurotropic DENV-2 using whole-genome analysis and to provide the clinical, immunological, and virological characteristics of dengue encephalitis patients during a severe dengue outbreak in Sri Lanka in 2017.
Highlights
Dengue is one of the most globally prevalent, arthropod-borne, viral diseases in humans [1]
During the 2017 severe dengue outbreak in Sri Lanka, 295 patients suspected with dengue infection were admitted to the Kandy Teaching Hospital in Kandy, Sri Lanka
Paired serum and cerebrospinal fluid (CSF) samples were collected from these patients (2 children and 3 adults) who were diagnosed with severe dengue (SD) (Table 1)
Summary
Dengue is one of the most globally prevalent, arthropod-borne, viral diseases in humans [1]. The causative agent, dengue virus (DENV), which includes four distinct, but closely related serotypes, belongs to the genus Flavivirus in the family Flaviviridae [3]. There has been an increase in the number of reported cases of neurological manifestations associated with dengue infections. Neurological signs were first reported in 1976 as atypical symptoms of dengue infection, and their incidence rates have varied from 0.5% to 20% in recent years [7, 8]. Dengue serotypes 2 and 3 are most commonly associated with neurological symptoms [10, 11]. Confirmed dengue cases with neurological manifestations have been confirmed by assessing the presence of the virus and/or antibody in the cerebrospinal fluid (CSF) [6, 12]. Molecular and biological characterizations of neurotropic DENV strains have been extremely limited, despite their important roles in the neuropathogenesis of dengue
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