由於尚未完全明瞭登革病毒的致病機制，目前對於登革病毒所造成的疾病仍缺乏有效的預防疫苗、治療藥物、以及預後方法。我們先前發現，人類細胞質中的先天免疫因子TMEM173會被登革病毒蛋白酶NS2B3所切割而削弱宿主的抗病毒能力。在本研究中，我們選殖出兩種不同的人類TMEM173單倍體：MITA和STING並探討對於登革病毒蛋白酶的感受性是否發生改變。我們發現，無論在病毒感染或是細胞表現病毒蛋白酶NS2B3的情況下，雖然STING和MITA都能被蛋白酶切割，但MITA的被切割效率高於STING。我們進一步以免疫共沉澱法發現，NS2B3和MITA的交互作用能力較STING強，顯示TMEM173的被切割效率和NS2B3交互作用能力相關。有趣的是環狀質體DNA、細胞全部DNA、線性PCR產物和人造雙股DNA-poly（dA:dT）都可以增強NS2B3切割MITA的效率，而且切割效率和MITA的活化程度相關，但NS2B3切割STING的效率以及交互作用程度都不會因為這些刺激而增強。因此宿主DNA滲漏，致病原多重感染，特別是人與人之間TMEM173的單倍體差異都可能會影響宿主先天免疫反應。這項發現有助我們理解登革病毒的致病機制以及在人類族群內造成多樣化病徵的原因，有望發展成登革熱相關疾病預後指標。

Dengue virus (DENV) infection is a serious problem in tropical and subtropical area with no effective therapeutic, reliable vaccine, and prognostic biomarker. Despite the DENV pathogenesis is not fully understood, the interactions between DENV and innate immunity-related factors would contribute to the consequences in response to DENV infection. Previously, we found that human TMEM173, a cytosolic DNA sensor, was functionally impaired by DENV protease cleavage. In this study, we found that two nature haplotypes of human TMEM173, namely MITA and STING respectively, were both cleaved by either DENV infection or DENV protease NS2B3 overexpression but with different efficiency: STING is more resistant than MITA to the cleavage. By immunoprecipitation, we found that the interaction between DENV protease and MITA haplotype was much stronger than that between the protease and STING haplotype. Since the DENV protease-mediated TMEM173 cleavage can be enhanced by cytosolic DNA stimuli, we checked whether this phenomenon is restricted by particular DNA species. Interestingly, the interaction between dengue protease and MITA can be further enhanced and then facilitate MITA cleavage in response to several DNA species stimuli, including cellular total DNA, circular plasmid DNA, linear PCR products, and synthetic dsDNA analog poly(dA:dT). In the case of STING, none of the TMEM173 agonists we tested can enhance STING cleavage. Therefore, host DNA leakage, bacterial superinfection, and particular human single-nucleotide polymorphism of TMEM173 may alter the host innate responses and contribute to DENV pathogenesis. These parameters might explain the diverse syndromes of DENV infection in human population and provide prognostic markers for forewarning DENV-related disease in the future.

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