Determination of viral factors associated with dengue virus infection and disease severity
Malaysia has experienced an unprecedented dengue outbreak between the years 2014 and 2015. The mortality rate of dengue was still higher in 2016 compared to 2014 indicating the continuity of the outbreak. There is an increasing concern that patient management and environmental control alone...
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| Format: | Thèse |
| Langue: | English |
| Publié: |
2019
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| Sujets: | |
| Accès en ligne: | http://psasir.upm.edu.my/id/eprint/85545/1/FPSK%28p%29%202019%201%20UPM%20ir.pdf |
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| Résumé: | Malaysia has experienced an unprecedented dengue outbreak between the
years 2014 and 2015. The mortality rate of dengue was still higher in 2016
compared to 2014 indicating the continuity of the outbreak. There is an
increasing concern that patient management and environmental control alone
are insufficient to overcome the current dengue epidemic in Malaysia.
Importantly, insight into the substantial progress of the disease burden despite
implementation of fogging and well-managed health care system should be
addressed. Could the answer lie within the dengue virus (DENV) itself? Has
the virus become virulent than we can imagine? Thus, the proposed study is
aimed to identify the viral factors contributing to dengue virus infection and
severity, especially during an outbreak period. The present study focused on
identifying the pattern of dengue serotype and genotype distribution
retrospectively from the year 2014 to 2017 in Malaysia. Dengue sera from
dengue confirmed patients were obtained from three localities, which include
Hospital Serdang, Hospital Ampang and Institute for Medical Research. The
study also attempted to associate the clinical spectrums and severity of
patients with the aforementioned serotype and genotype distribution.
Subsequently, viral replication and infectivity kinetics were compared between
dengue isolates from severe and non-severe cases as well as among
genotypes. Finally, dengue subgenomic RNA (sfRNA) was identified and
quantified using self-designed primers against all four serotypes to deduce the
role of the sfRNA in disease severity. The study findings indicated that DENV 1
genotype I was the predominant serotype and genotype during the recent
dengue outbreak in Malaysia. This reflected a serotype shift in replacing the
predominant DENV 2 that existed prior to the outbreak. The current trend
denotes that serotype replacement, is predicted to re-occur once the current
outbreak subsides. The re-emergence of DENV 3 genotype I was observed
during this period, where it should be cautiously monitored, as adaption to become more virulent is possible. Comparison between the dengue serotypes
and genotypes with disease spectrum revealed that the clinical characteristics
of dengue patients were serotype and genotype-specific. DENV 1 and DENV 3
were common in patients with mild infection whereas DENV 2-infected patients
significantly exhibited warning signs and presented with severe dengue. DENV
3 genotype I was frequently observed in patients with myalgia whereas DENV
3 genotype III was common in patients with arthralgia. The in-vitro phenotypic
characterization of dengue isolates from severe cases demonstrated a slow
and prolonged replication. The infectivity kinetics lasted up to day six whereas
the isolates from non-severe cases exhibited an early rise in the replication and
infectivity kinetics but unable to sustain towards the end. The replication and
infectivity kinetic trends varied with respect to dengue genotypes, consistent
with the circulating predominant genotypes. Involvement of sfRNA in the
disease severity was evidenced through higher copy numbers in severe
dengue than non-severe dengue isolates. In conclusion, the results
demonstrated that viral factors such as serotype shift, re-emergence of certain
genotypes, efficient replication and infectivity mechanism and sfRNA
collectively contribute towards dengue clinical manifestations and disease
severity. Complete eradication of these factors is difficult as they are rather
internal. Nonetheless, manipulating and predicting their behaviour may aid in
early detection of disease progression and developing deeper understanding
on dengue pathogenesis. Furthermore, the clinical symptoms of severe dengue
infection only manifest at later stage of dengue infection. Therefore, information
on the serotype or genotype-specific dengue manifestations and monitoring of
viral genomic copy numbers and sfRNA levels may serve as early surrogate
markers to predict the disease progression. |
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