登革熱是一種透過病媒蚊傳播的傳染性疾病，在全球的分布相當廣，主要則集中發生於熱帶及亞熱帶地區，不過近年來因為氣候變遷，在部分溫帶地區也陸續有個案的傳出。登革熱的傳播主要是透過被帶有病毒的埃及斑蚊叮咬，但是近期的研究也發現到輸血是另一條會進行傳染的路徑。登革病毒依據血清型做分型可以分為四型，每一型登革病毒都可以於臨床上造成不同程度的病徵，輕則可能無症狀，重則可能引起嚴重發燒(登革熱)，或是出血的症狀(登革出血熱)，最嚴重可能因此引發休克(登革休克熱)，最終造成死亡。登革熱患者在臨床上通常會被檢查出血液中的血小板數量低下，在文獻報導中則指出登革病毒會感染人類骨髓細胞中的血小板前驅細胞因此造成血小板數量低下。於流行病學的研究上也發現不同血清型的登革病毒於各地造成疫情爆發的頻率並不相同，造成的原因目前還尚未明瞭。透過之前的研究發現，人類骨髓細胞中的幹細胞或前驅細胞群相當容易被登革病毒所感染，因此我們假設不同血清型的登革病毒對於人類骨髓細胞的感染能力不同可能是造成這現象的原因。於本篇研究中，我們將受試者捐贈的新鮮人類骨髓細胞感染不同血清型的登革病毒，在固定細胞數量以及病毒感染量的條件下，於感染後不同時間點收取上清液並測量其中的病毒量後進行分析。同樣的實驗也利用已被證實可被不同血清型登革病毒感染的Meg01細胞株進行。從實驗結果中，可以發現到相同血清型的登革病毒對於感染宿主細胞後所引起的病毒量高峰，彼此間並沒有明顯的差異，但是不同血清型登革病毒對於宿主細胞的感染比率，彼此間卻存在著差異，其中第二型登革病毒的感染比率最高是84%，其次為第一型和第四型登革病毒的68%，最低為第三型登革病毒的44%。比較各血清型登革病毒對於男性及女性捐贈者骨髓檢體的感染比率，第一型登革病毒在男性組別中有著最高的90%感染比率，相較於在女性組別則是第二型及第四型登革病毒的感染比率最高為81.8%。綜合以上結果，說明了所有血清型的登革病毒對於人類骨髓細胞都擁有感染的能力，但是感染的比率卻會因為宿主的性別而有所不同。

Dengue is one the most important vector-borne human viral diseases globally. The disease can manifest with potential mortality symptoms as dengue hemorrhagic fever (DHF), categorized with plasma leakage resulting from an increase of vascular permeability, with or without dengue shock syndrome (DSS). The mechanisms leading to severe DHF/DSS remain an enigma despite many years of investigations. With glowing evidence suggests that human bone marrow (HBM) stem/progenitor cells are highly permissive for DNEV infection. Fifty freshly obtained human bone marrows from volunteers were infected with different DENV serotypes, respectively. As a control, Meg01 cells were utilized for DENV infection in parallel. Viral titers in the supernatants of collected samples were performed with plaque assay. Results revealed that all DENV serotypes were capable of infecting human bone marrow of both male and female origin, even though the frequency of infection rate was different.

1. Alcon S, Talarmin A, Debruyne M, Falconar A, Deubel V, et al. (2002) Enzyme-Linked Immunosorbent Assay Specific to Dengue Virus Type 1 Nonstructural Protein NS1 Reveals Circulation of the Antigen in the Blood during the Acute Phase of Disease in Patients Experiencing Primary or Secondary Infections. J. Clin. Microbiol. 40:376-381

2. Avirutnan P, Punyadee N, Noisakran S, Komoltri C, et al. (2006) Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement. J Infect Dis 193(8):1078-88

3. Avirutnan P, Fuchs A, Hauhart RE, Somnuke P, et al. (2010) Antagonism of the complement component C4 by flavivirus nonstructural protein NS1. J Exp Med 207(4): 793-806

4. Bargeron Clark K, Hsiao HM, Noisakran S, Tsai JJ, et al. (2012) Role of microparticles in dengue virus infection and its impact on medical intervention strategies. Yale J Biol Med 85(1):3-18

5. Bauer K, Esquilin IO, Santiago Cornier A, Thomas SJ, et al. (2015) A Phase II, Randomized, Safety and Immunogenicity Trial of a Re-Derived, Live-Attenuated Dengue Virus Vaccine in Healthy Children and Adults Living in Puerto Rico. Am J Trop Med Hyg doi:10.4269/ajtmh

6. Bente DA, Melkus MW, Garcia JV, Rico-Hesse R. (2005) Dengue fever in humanized NOD/SCID mice. J Virol. 79:13797–13799.

7. Bierman HR, Nelson ER.(1965) Hematodepressive virus diseases of Thailand. Ann Intern Med. 62:867–884.

8. Chaichana P, Okabayashi T, Puiprom O, Sasayama M, Sasaki T, et al. (2014) Low levels of antibody-dependent enhancement in vitro using viruses and plasma from dengue patients. PLoS One 9:3

9. Chamberlain G, Fox J, Ashton B, Middleton J (2007) Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25(11):2739-49

10. Cintia FM, Elzinandes LA, Amanda TC, Alessandro MS, et al. (2014) Down-Regulation of Complement Receptors on the Surface of Host Monocyte Even as In Vitro Complement Pathway Blocking Interferes in Dengue Infection. PLoS One 9(7):e102014

11. Cruz-Oliveira C, Freire JM, Conceição TM, Hiqa LM, et al. (2015) Receptors and routes of dengue virus entry into the host cells. FEMS Microbiol Rev 39(2):155-70

12. García G, Sierra B, Pérez AB, Aguirre E, Rosado I, et al. (2010) Asymptomatic dengue infection in a Cuban population confirms the protective role of the RR variant of the FcγRIIa polymorphism. Am J Trop Med Hyg 82: 1153–1156
13. Guzmán MG, Kouri GP, Bravo J, Soler M, Vazquez S, et al. (1990) Dengue hemorrhagic fever in Cuba, 1981: a retrospective seroepidemiologic study. Am J Trop Med Hyg 42: 179–184

14. Halstead SB, O’Rourke EJ (1977) Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody. J Exp Med 146: 201–217

15. Hayes JM, Rigau-Pérez JG, Reiter P, Effler PV, Pang L, et al. (2006) Risk factors for infection during a dengue-1 outbreak in Maui, Hawaii, 2001. Trans R Soc Trop Med Hyg. 100:559-566

16. Hotta, S. (1965): Twenty years of laboratory experience with dengue virus. p.228-256. In Saunders, M. and Lennette, E.H.(eds.), Medical and Applied Virology. Geen, St Louis.

17. Huang KJ, Lin YS, Liu HS, Yeh TM, Liu CC, et al. (2008) Anti-platelet and anti-endothelial cell autoantibodies in Vietnamese infants and children with dengue hemorrhagic fever. Am J Infect Dis. 4(1): 41-49

18. Kristina BC, Sansanee N, Nattawat O, Hsiao HM, et al. (2012) Multiploid CD61+ Cells Are the Pre-Dominant Cell Lineage Infected during Acute Dengue Virus Infection in Bone Marrow. PLoS One 7(12): e52902

19. Kuhn RJ, Zhang W, Rossmann MG, Platnev SV, Corver J, et al. (2002) Structure of dengue virus: implications for flavivirus organization, maturation, and fusion. Cell 108: 717–725
20. Kurosu T, Chaichana P, Yamate M, Anantapreecha S, et al. (2007) Secreted complement regulatory protein clusterin interacts with dengue virus nonstructural protein 1. Biochem Biophys Res Commun 362(4):1051-6

21. Lin CF, Lei HY, Liu CC, Liu HS, Yeh TM, et al. (2001) Generation of IgM anti-platelet autoantibody in dengue patients. J Med Virol 63:143-149

22. Luis AV, Diana PR, Sandra BL, Elsa S. (2007) Epidemiological Trends of Dengue Disease in Colombia (2000-2011): A Systematic Review. PLoS Negl Trop Dis 9(3):e0003499

23. Martha A, Yuzo Arima. (2011) Male–female differences in the number of reported incident dengue fever cases in six Asian countries. Western Pac Surveill Response J 2(2):17-23

24. Midgley CM, Bajwa-Joseph M, Vasanawathana S, Limpitikul W, Wills B, et al. (2011) An in-depth analysis of original antigenic sin in dengue virus infection. J Virol 85: 410–421

25. Nakao S, Lai CJ, Young NS. (1989) Dengue virus, a flavivirus, propagates in human bone marrow progenitors and hematopoietic cell lines. Blood. 74:1235–1240.

26. Navarro-Sánchez E, Desprès P, Cedillo-Barrón L. (2005) Innate immune responses to dengue virus. Arch Med Res 36(5):425-35

27. Nisalak A, Halstead SB, Singharaj P, Udomsakdi S, Nye SW, Vinijchaikul K. (1970) Observations related to pathogenesis of dengue hemorrhagic fever. 3. Virologic studies of fatal disease. Yale J Biol Med. 42:293–310.

28. Noisakran S, Onlamoon N, Hsiao HM, Clark KB, Villinger F, et al. (2013) Infection of bone marrow cells by dengue virus in vivo. Exp Hematol. 40(3): 250-259

29. Rekol Huy, Philippe Buchy, Anne Conan, Chantha Ngan, Sivuth Ong, et al. (2010) National dengue surveillance in Cambodia 1980–2008: epidemiological and virological trends and the impact of vector control. Bull World Health Organ. 88(9): 650-657

30. Sabchareon A, Sirivichayakul C, Limkittikul K, Chanthavanich P, Suvannadabba S, et al. (2012) Dengue Infection in Children in Ratchaburi, Thailand: A Cohort Study. I. Epidemiology of Symptomatic Acute Dengue Infection in Children, 2006–2009. PLoS Negl Trop Dis 6(7): e1732.
31. Sabin AB (1952) Research on dengue during World War II. Am J Trop Med Hyg 1: 30–50

32. Sangkawibha N, Rojanasuphot S, Ahandrik S, Viriyapongse S, Jatanasen S, et al. (1984) Risk factors in dengue shock syndrome: a prospective epidemiologic study in Rayong, Thailand. I. The 1980 outbreak. Am J Epidemiol 120: 653–669

33. Tsuda Y, Maekawa Y, Ogawa K, Itokawa K, Komagata O, et al. (2015) Biting density and distribution of Aedes albopictus during the September 2014 outbreak of dengue fever in Yoyogi Park and the vicinity in Tokyo Metropolis, Japan. Jpn J Infect Dis.

34. Tsai JJ, Liu LT, Chang K, Wang SH, Hsiao HM, et al. (2012) The importance of hematopoietic progenitor cells in dengue. Ther Adv Hematol 3(1): 59-71
35. van der Schaar HM, Wilschut JC, Smit JM (2009) Role of antibodies in controlling dengue virus infection. Immunobiology 214: 613–629

36. Villar L, Dayan GH, Arredondo-García JL, Rivera DM, et al. (2015) Efficacy of a Tetravalent Dengue Vaccine in Children in Latin America. N Engl J Med 372:113-123

37. World Health Organization. (2009) Dengue: guidelines for diagnosis, treatment, prevention, and control. World Health Organization, Genevam Switzerland

38. Young PR, Hilditch PA, Bletchly C, Halloran W. (2000) An Antigen Capture Enzyme-Linked Immunosorbent Assay Reveals High Levels of the Dengue Virus Protein NS1 in the Sera of Infected Patients. J. Clin. Microbiol. 38:1053-1057