The Role of NS1 Gene Mutations in Dengue Virus Serotype 2 and Their Association with Clinical Severity of Dengue Hemorrhagic Fever: A Systematic Review
DOI:
https://doi.org/10.54259/sehatrakyat.v4i3.5243Kata Kunci:
Dengue Virus Serotype 2, Disease Severity, NS1 Mutations, Vascular LeakageAbstrak
NS1 gene of Dengue Virus Serotype 2 (DENV-2) plays a significant role in the pathogenesis and clinical severity of dengue infections, including Dengue Hemorrhagic Fever. Mutations in the NS1 gene of DENV-2 are closely associated with the clinical severity of dengue. Methods: This review article employs a systematic review methodology, utilizing Scopus, PubMed and Web of Science from 2015 to 2025. Results: The T164S mutation was consistently associated with increased severity through elevated secreted NS1 (sNS1) production, complement activation, and inflammation. Conversely, the S103T mutation appeared in milder cases. NS1 mutations also correlated with immune hyperactivation, vascular leakage, and, in some cases, neurological symptoms such as encephalitis. Despite these findings, direct causality between specific mutations and clinical outcomes requires further investigation. Conclusion: Mutations in the NS1 gene of DENV-2 affect the stability, secretion, and immunogenic properties of the NS1 protein, leading to increased vascular leakage and severe disease outcomes
Unduhan
Referensi
Beatty, P. R., Puerta-Guardo, H., Killingbeck, S. S., Glasner, D. R., Hopkins, K., & Harris, E. (2015). Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination. Science Translational Medicine, 7(304). https://doi.org/10.1126/scitranslmed.aaa3787
Bhatt, S., Gething, P. W., Brady, O. J., Messina, J. P., Farlow, A. W., Moyes, C. L., Drake, J. M., Brownstein, J. S., Hoen, A. G., Sankoh, O., Myers, M. F., George, D. B., Jaenisch, T., William Wint, G. R., Simmons, C. P., Scott, T. W., Farrar, J. J., & Hay, S. I. (2013). The global distribution and burden of dengue. Nature, 496(7446), 504–507. https://doi.org/10.1038/nature12060
Canari, C. J. L., Paz-Soldan, V. A., Lescano, A. G., & Morrison, A. C. (2024). Circulation of DENV-2 serotype associated with increased risk of cumulative incidence of severe dengue and dengue with warning signs: A 16-year retrospective study in Peru. In medRxiv (Vol. 1, Issue 165, pp. 1–13). https://doi.org /10.1101/2024.05.02.24306735
Carlson, R. (2023). DENGUE OUTBREAKS. Vax LLC. https://www.vax-before-travel.com/dengue-outbreaks
Chan, K. W. K., Watanabe, S., Jin, J. Y., Pompon, J., Teng, D., Alonso, S., Vijaykrishna, D., Halstead, S. B., Marzinek, J. K., Bond, P. J., Burla, B., Torta, F., Wenk, M. R., Ooi, E. E., & Vasudevan, S. G. (2019). A T164S mutation in the dengue virus NS1 protein is associated with greater disease severity in mice. Science Translational Medicine, 11(498). https://doi.org/10.1126/scitranslmed.aat7726
Choy, M. M., Ng, D. H. L., Siriphanitchakorn, T., Ng, W. C., Sundstrom, K. B., Tan, H. C., Zhang, S. L., Chan, K. W. K., Manuel, M., Kini, R. M., Chan, K. R., Vasudevan, S. G., & Ooi, E. E. (2020). A Non-structural 1 Protein G53D Substitution Attenuates a Clinically Tested Live Dengue Vaccine. Cell Reports, 31(6), 107617. https://doi.org/10.1016/j.celrep.2020.107617
Fang, E., Li, M., Liu, X., Hu, K., Liu, L., Zhang, Z., Li, X., Peng, Q., & Li, Y. (2023). NS1 Protein N-Linked Glycosylation Site Affects the Virulence and Pathogenesis of Dengue Virus. Vaccines, 11(5). https://doi.org/10.3390/vaccines11050959
Feng, S.-J., Liu, Y., Chen, J., Duan, S.-Q., Rao, Q., Chen, J.-Y., & Guan, J.-Q. (2020). Identification and analysis of nonstructural protein 1 gene of dengue virus type 2 isolated in Hunan Province, China in 2018. Chinese Journal of Biologicals, 33(12), 1357–1362. https://doi.org/10045503 (ISSN)
Ghosh, A., Sukla, S., Nath, H., Saha, R., De, A., & Biswas, S. (2022). Non-structural protein 1 (NS1) variants from dengue virus clinical samples revealed mutations that influence NS1 production and secretion. European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology, 41(5), 803–814. https://doi.org/10.1007/s10096-022-04441-4
Glasner, D. R., Puerta-Guardo, H., Beatty, P. R., & Harris, E. (2018). The Good, the Bad, and the Shocking: The Multiple Roles of Dengue Virus Nonstructural Protein 1 in Protection and Pathogenesis. Annual Review of Virology, 5(1), 227–253. https://doi.org/10.1146/annurev-virology-101416-041848
Glasner, D. R., Ratnasiri, K., Puerta-Guardo, H., Espinosa, D. A., Beatty, P. R., & Harris, E. (2017). Dengue virus NS1 cytokine independent vascular leak is dependent on endothelial glycocalyx components. PLoS Pathogens, 13(11), 1–22. https://doi.org/10.1371/journal.ppat.1006673
Hapuarachchi, H. C., Chua, R. C. R., Shi, Y., Thein, T. L., Lee, L. K., Lee, K. S., Lye, D. C., Ng, L. C., & Leo, Y. S. (2015). Clinical outcome and genetic differences within a monophyletic dengue virus type 2 population. PLoS ONE, 10(3). https://doi.org/10.1371/journal.pone.0121696
Hee, J.-R., Cheng, D., Chen, Y.-H., Wang, S.-H., Chao, C.-H., Huang, S.-W., Ling, P., Wan, S.-W., Chang, C.-P., Chu, J. J. H., Yeh, T.-M., & Wang, J.-R. (2025). A non-structural protein 1 substitution of dengue virus enhances viral replication by interfering with the antiviral signaling pathway. Journal of Biomedical Science, 32(1), 25. https://doi.org/10.1186/s12929-024-01116-4
Katzelnick, L. C., Fonville, J. M., Gromowski, G. D., Arriaga, J. B., Green, A., James, S. L., Lau, L., Montoya, M., Wang, C., VanBlargan, L. A., Russell, C. A., Thu, H. M., Pierson, T. C., Buchy, P., Aaskov, J. G., Munoz, J. L., Vasilakis, N., Gibbons, R. V., Tesh, R. B., Smith, D. J. (2015). Dengue viruses cluster antigenically but not as discrete serotypes. Science, 349(6254), 1338–1343. https://doi.org/10.1126/science.aac5017
Katzelnick, L. C., Gresh, L., Halloran, M. E., Mercado, J. C., Kuan, G., Gordon, A., Balmaseda, A., & Harris, E. (2017). Antibody-dependent enhancement of severe dengue disease in humans. Science, 358(6365), 929–932. https://doi.org/10.1126/science.aan6836
Ko, H. Y., Li, Y. T., Yu, H. P., Li, Y. Y., Chiang, M. T., Simanjuntak, Y., Lee, Y. L., Dai, S. S., Chung, P. J., Yu, G. Y., Chao, D. Y., & Lin, Y. L. (2024). Emergence and increased epidemic potential of dengue variants with the NS5V357E mutation after consecutive years of transmission. IScience, 27(11), 110899. https://doi.org/10.1016/j.isci.2024.110899
Kraivong, R., Traewachiwiphak, S., Nilchan, N., Tangthawornchaikul, N., Pornmun, N., Poraha, R., Sriruksa, K., Limpitikul, W., Avirutnan, P., Malasit, P., & Puttikhunt, C. (2022). Cross-reactive antibodies targeting surface exposed non structural protein 1 (NS1) of dengue virus-infected cells recognize epitopes on the spaghetti loop of the β-ladder domain. PLoS ONE, 17(5 May), 1–24. https://doi.org/10.1371/journal.pone.0266136
Muller, D. A., & Young, P. R. (2013). The flavivirus NS1 protein: Molecular and structural biology, immunology, role inpathogenesis and application asadiagnostic biomarker. Antiviral Research, 98(2), 192–208. https://doi.org/10.1016/j.antiviral.2013.03.008
Mushtaq, S., Khan, M. T., Javed, H., Ansari, M. A., Syed, R., Waheed, Y., & Khan, M. I. U. (2024). Mutational Frequencies in the Immune System Interacting Proteins NS2A and NS2B in Dengue Virus Isolates. Journal of Biological Regulators and Homeostatic Agents, 38(7), 5507–5517. https://doi.org/10.23812/j.biol.regul.homeost.agents.20243807.442
Nwe, K. M., Ngwe Tun, M. M., Muthugala, R., Nabeshima, T., Balingit, J. C., Rajamanthri, L., Jayawardana, D., Attanayake, S., Inoue, S., Takamatsu, Y., Urano, T., & Morita, K. (2023). Clinical, Virological, and Immunological Features in Cosmopolitan Genotype DENV-2 Infected Patients during a Large Dengue Outbreak in Sri Lanka in 2017. The American Journal of Tropical Medicine and Hygiene, 109(4), 917–925. https://doi.org/10.4269/ajtmh.22-0780
Ogire, E., Diaz, O., Vidalain, P.-O., Lotteau, V., Despres, P., & Roche, M. (2021). Instability of the NS1 Glycoprotein from La Reunion 2018 Dengue 2 Virus (Cosmopolitan-1 Genotype) in Huh7 Cells Is Due to Lysine Residues on Positions 272 and 324. International Journal of Molecular Sciences, 22(4), 1951. https://doi.org/10.3390/ijms22041951
Ogire, E., El-Kalamouni, C., Despres, P., & Roche, M. (2023). Stability of Dengue 2 Nonstructural Glycoprotein 1 (NS1) Is Affected by the Nature of Basic Residue at Position NS1-324. Current Issues in Molecular Biology, 45(2), 1644–1654. https://doi.org/10.3390/cimb45020106
OhAinle, M., Balmaseda, A., Macalalad, A. R., Tellez, Y., Zody, M. C., Saborio, S., Nuñez, A., Lennon, N. J., Birren, B. W., Gordon, A., Henn, M. R., & Harris, E. (2011). Dynamics of Dengue Disease Severity Determined by the Interplay Between Viral Genetics and Serotype-Specific Immunity. Science Translational Medicine, 3(114), 320–330. https://doi.org/10.1126/scitranslmed.3003084
Puerta, G. H., Glasner, D. R., & Harris, E. (2016). Dengue Virus NS1 Disrupts the Endothelial Glycocalyx, Leading to Hyperpermeability. PLOS Pathogens, 12(7), e1005738. https://doi.org/10.1371/journal.ppat.1005738
Ravi, V., Imran, M., Khare, K., Mishra, P., Mohite, R., Kanika, Khan, M. A., Swaminathan, A., Yadav, A., Sinha, S., Shukla, R., Chattopadhyay, P., Soni, J., Maurya, R., Sethi, T., Tarai, B., Budhiraja, S., & Pandey, R. (2025). Clinico-genomic study reveals association of dengue virus genome high frequency mutations with dengue disease severity. Scientific Reports, 15(1), 18724. https://doi.org/10.1038/s41598-025-00462-z
Rodriguez, A. E. D., Martinez, B. J., Juarez, P. L., Alvarado, D. A., Gonzalez, B. C. R., & Rodriguez, M. H. (2022). Genetic diversity and spatiotemporal dynamics of DENV-1 and DENV-2 infections during the 2012–2013 outbreak in Mexico. Virology, 573(April), 141–150. https://doi.org/10.1016/j.virol.2022.06.011
Samune, Y., Saito, A., Sasaki, T., Koketsu, R., Srimark, N., Phadungsombat, J., Yokoyama, M., Kotani, O., Sato, H., Yamanaka, A., Haga, S., Okamoto, T., Kurosu, T., Nakayama, E. E., & Shioda, T. (2024). Genetic regions affecting the replication and pathogenicity of dengue virus type 2. PLoS Neglected Tropical Diseases, 18(1), 1–27. https://doi.org/10.1371/journal.pntd.0011885
Sanchez, V. L. A., Mathew, A., Salje, H., Sousa, D., Casale, N. A., Farmer, A., Buddhari, D., Anderson, K., Iamsirithaworn, S., Kaewhiran, S., Friberg, H., Currier, J. R., & Rothman, A. L. (2024). Protective Role of NS1 Specific Antibodies in the Immune Response to Dengue Virus Through Antibody Dependent Cellular Cytotoxicity. The Journal of Infectious Diseases, 230(5), 1147–1156. https://doi.org/10.1093/infdis/jiae137
Scaturro, P., Cortese, M., Chatel-Chaix, L., Fischl, W., & Bartenschlager, R. (2015). Dengue Virus Non-structural Protein 1 Modulates Infectious Particle Production via Interaction with the Structural Proteins. PLoS Pathogens, 11(11), e1005277. https://doi.org/10.1371/journal.ppat.1005277
Singh, S., Anupriya, M. G., & Sreekumar, E. (2017). Comparative whole genome analysis of dengue virus serotype-2 strains differing in transendothelial cell leakage induction in vitro. Infection, Genetics and Evolution, 52, 34–43. https://doi.org/10.1016/j.meegid.2017.04.022
Torres, M. C., Lima de Mendonça, M. C., Damasceno Dos Santos Rodrigues, C., Fonseca, V., Ribeiro, M. S., Brandão, A. P., Venâncio da Cunha, R., Dias, A. I., Santos Vilas Boas, L., Felix, A. C., Pereira, M. A., Pinto, L. M. de O., Sakuntabhai, A., & de Filippis, A. M. B. (2021). Dengue virus serotype 2 intrahost diversity in patients with different clinical outcomes. Viruses, 13(2), 1–20. https://doi.org/10.3390/v13020349
Tun, M. M. N., Muthugala, R., Nabeshima, T., Soe, A. M., Dumre, S. P., Rajamanthri, L., Jayawardana, D., Attanayake, S., Inoue, S., & Morita, K. (2020). Complete genome analysis and characterization of neurotropic dengue virus 2 cosmopolitan genotype isolated from the cerebrospinal fluid of encephalitis patients. PLoS ONE, 15(6 June), 1–15. https://doi.org/10.1371/journal.pone.0234508
Wang, T., Bu, C. H., Hildebrand, S., Jia, G., Siggs, O. M., Lyon, S., Pratt, D., Scott, L., Russell, J., Ludwig, S., Murray, A. R., Moresco, E. M. Y., & Beutler, B. (2018). Probability of phenotypically detectable protein damage by ENU induced mutations in the Mutagenetix database. Nature Communications, 9(1). https://doi.org/10.1038/s41467-017-02806-4
Unduhan
Diterbitkan
Cara Mengutip
Terbitan
Bagian
Lisensi
Hak Cipta (c) 2025 Nyoman Cahyadi Tri Setiawan, Rozikin Rozikin

Artikel ini berlisensi Creative Commons Attribution 4.0 International License.
Hak cipta pada setiap artikel adalah milik penulis.
Penulis mengakui bahwa SEHATRAKYAT (Jurnal Kesehatan Masyarakat) sebagai publisher yang mempublikasikan pertama kali dengan lisensi Creative Commons Attribution 4.0 International License.
Penulis dapat memasukan tulisan secara terpisah, mengatur distribusi non-ekskulif dari naskah yang telah terbit di jurnal ini kedalam versi yang lain, seperti: dikirim ke respository institusi penulis, publikasi kedalam buku, dan lain-lain. Dengan mengakui bahwa naskah telah terbit pertama kali pada SEHATRAKYAT (Jurnal Kesehatan Masyarakat).





















