論文題目：Dengue virus and the host innate immune response
scholar 引用：13
頁數：12
發表時間：10 Oct 2018
發表刊物：Emerging Microbes & Infections
作者：Naoko Uno & Ted M. Ross
摘要：
Dengue virus (DENV, 登革熱病毒) is a mosquito-borne(蚊蟲傳播) Flavivirus(黃病毒屬) that is endemic(地方性的) in many tropical and sub-tropical countries where the transmission vectors Aedes spp.(伊蚊) mosquitoes resides. There are four serotypes(血清型) of the virus. Each serotype is antigenically(抗原性) different, meaning they elicit heterologous antibodies. Infection with one serotype will create neutralizing antibodies to the serotype. Cross-protection from other serotypes is not long term, instead heterotypic infection can cause severe disease. This review will focus on the innate immune response to DENV infection and the virus evasion of the innate immune system by escaping recognition or inhibiting the production of an antiviral state. Activated innate immune pathways includes type I interferon(干擾素), complement, apoptosis(細胞凋亡), and autophagy(細胞自噬), which the virus can evade or exploit to exacerbate disease. It is important to understand out how the immune system reacts to infection and how the virus evades immune response in order to develop effective antivirals and vaccines.
結論：
- The NS proteins are responsible for viral replication and host innate immune evasion. NS蛋白負責病毒複製和宿主先天免疫逃避。
- The innate immune response to DENV is not well characterized nor are the exact roles of the NS proteins in evading the immune response. NS蛋白在DENV感染的先天免疫反應機制還不太清楚
- The main innate immune response is type I IFN and the main evasion mechanism of the virus is to target against the type I IFN response. 主要的innate immune response是跟type I IFN(I型干擾素)，病毒的主要逃避機制是針對I型干擾素應答。
- Other innate immune responses include complement activation, apoptosis, autophagy, and RNAi. 其他的一些innate immune response
- It is important to understand the host innate immune response to infection and how the virus evades or exploits this in order to develop effective antivirals and vaccines.想要研發有效的抗病毒藥物和疫苗，搞清楚 host innate immune response to infection和how the virus evades or exploits是非常重要的。
正文組織架構：
1. Dengue virus
1.1 Epidemiology(流行病學)
1.2 The virion(病毒粒子)
1.3 Viral life cycle
2. Innate immune responses
2.1 Viral sensing
2.2 Type I IFN response
2.3 Complement system response
2.4 Other innate immune responses
2.5 Innate immunity associated with severe disease
3. Innate immune evasion
3.1 Inhibition and evasion of type I IFN response
3.2 Other immune evasion mechanisms
4. Future directions
5. Conclusion
正文部分內容摘錄：
1. Dengue virus
1.1 Epidemiology(流行病學)
- Primary infections may cause a rash and fever, but many infections are asymptomatic.原發感染有發燒和皮疹，但是還有很多感染並無症狀。
- Secondary infections, however, are known to cause severe disease, specifically after a heterotypic infection. 繼發性感染，特別是異性感染會引起嚴重的疾病。
- The exact cause of this is unknown, but the phenomenon of antibody-dependent enhancement (ADE,抗體依賴性增強) may cause increased pathogenicity and virulence. ADE增強會增加致病性和病毒性。
- ADE occurs when antibodies from a previous heterotypic infection do not neutralize a secondary infection with a different subtype but still bind to viral proteins.
- 抗體依賴的增強作用（antibody dependent enhancement，ADE）某些病毒特異性抗體（一般多爲非中和抗體）與病毒結合後，結合了病毒的抗體可通過其Fc段與某些表面表達FcR的細胞結合從而介導病毒進入這些細胞，從而增強了病毒的感染性的過程,如登革熱病毒。
- This creates a virus–antibody complex phagocytosed by cells that are not usually infected via Fcγ receptors, specifically monocytes via FcγIIa receptor.
- Severe disease is seen in only 1% of DENV cases; however, mortality in severe cases can have a rate of up to 20%.
1.2 The virion(病毒粒子)
- They are enveloped(包膜) and spherical(球型), with a positive-sensed and single-stranded RNA (ssRNA) genome that encodes one open reading frame with three structural (capsid(衣殼), precursor membrane (prM,前驅膜), and envelope) and seven nonstructural (NS) proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5).黃病毒屬的特點
- The genome is approximately 11,000 kb in length, containing a type I cap at the 5′ end and lacking a 3′ poly(A) tail
- The virus structure consists of a well-organized outer shell with an icosahedral(二十面體的) symmetry, a lipid bilayer, and a poorly ordered nucleocapsid core that encapsulates the RNA genome
- Out of the three structural proteins, the envelope glycoprotein (E) is the main target for neutralizing antibodies and is responsible for receptor binding and fusion 包膜糖蛋白E
- The NS proteins are responsible for viral replication and host immune evasion.
1.3 Viral life cycle
- The virus binds to host cell receptors (exact receptors are unknown)
- (1) and enters the host cell (DENV permissive cells include keratinocytes(角質細胞), dendritic cells(樹突狀細胞), endothelial cells(內皮細胞), fibroblasts(纖維母細胞), macrophage(巨噬細胞), and mast cells), via receptor-mediated endocytosis
- (2). Acidification(酸化) of the endosome(核內體) induces conformational change of the E glycoprotein(糖蛋白) causing the virus to fuse with the endosomal(核內體的) membrane and release its genomic RNA material into the cytoplasm(細胞質)
- (3). DENV RNA translation and replication occur at the endoplasmic reticulum (ER,內質網)
- (4). The host ribosome directly translates the genomic RNA into a polyprotein(聚合蛋白), where host and viral proteases(蛋白酶) cleave the nascent protein(初生蛋白) into structural (blue) and nonstructural (red) proteins
- (5). RNA replication occurs in virus-induced membrane vesicles(膜囊泡) by the viral replication complex, with the transmembrane NS2a, NS2b, NS4a, and NS4b proteins acting as the scaffold
- (6). The viral genome is packaged into the immature virus particles during assembly
- (7). These particles are transported through the Golgi apparatus, where host furin-like proteases cleave the prM peptide
- (8), and the nascent viral particles exit the cell via exocytosis(胞外分泌) as fully mature virions
- (9). Some pr peptides are not cleaved resulting in immature, non-infectious virions or partially mature virions. The soluble NS1 hexamer is also secreted
2. Innate immune responses
2.1 Viral sensing
- The PRRs that are associated with DENV recognition are cytoplasmic retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), along with endosomal Toll-like receptor 3 (TLR3) and TLR7.
- RIG-I and MDA5 are an essential part of the innate immune response against virus, sensing viral replication in the cytoplasm.
- Two TLRs critical in the innate response to DENV infection are TLR3 and TLR7. TLR3, which is the primary TLR for DENV, recognizes dsRNA in endosomal compartments and TLR7 recognizes ssRNA in DC endosomal compartments.
- the cGAS-STING is activated by mitochondrial DNA (mtDNA) released in the cytosol
2.2 Type I IFN response
- Production of type I IFNs inhibits DENV infection of other monocytes.
2.3 Complement system response
- The complement system is also an important part of innate immune response to the virus.
2.4 Other innate immune responses
- RNA interference (RNAi) for antiviral defense in plants and invertebrates have been well characterized, including the DENV vector Aedes aegypti
- Autophagy inhibits replication in monocytes, specifically under ADE conditions, which make these cells highly susceptible to infection
- DENV proteins have been shown to activate apoptosis inside infected cells.
2.5 Innate immunity associated with severe disease
- Some immune responses are implicated with disease severity.
3. Innate immune evasion
3.1 Inhibition and evasion of type I IFN response
- 各種簡稱，好多啊。。。記不住
3.2 Other immune evasion mechanisms
- The phosphatidylinositol 3 kinase/Akt (PI3K/Akt) pathway plays an important role in cell survival, regulating proliferation, and inhibiting apoptosis 這個pathway也許後續我分析會涉及到
4. Future directions
- 目前還沒有有效的疫苗，新型化合物是未來研究方向之一。