New study reveals how high blood sugar makes lung infections worse; the findings may lead to a strategy for reversing this susceptibility
新研究揭露，高血糖如何使得肺部感染惡化；此些研究發現可能引領出一種，逆轉該種易感染性的策略。
For decades, it has been known that people with diabetes are at a substantially increased risk of developing severe lung disease if they become infected with viruses such as influenza, as well as with bacteria and fungi.
幾十年來，已是眾所周知，除了細菌及真菌外，糖尿病患者倘若也感染流感等病毒，則冒有實質增加罹患嚴重肺部疾病的風險。
When the COVID-19 pandemic started in early 2020, this mysterious phenomenon gained even more pressing importance: It became clear that people with diabetes were at a significantly higher risk of coming down with severe, even fatal, lung disease after developing a serious form of the virus, but no one understood why.
當2019冠狀病毒症(COVID-19：Coronavirus Disease-19)大流行病，於2020初開始時，此費解的事象增添了，更加急迫的重要性：很明顯，糖尿病患者，在感染一種嚴重的病毒後，冒有顯著罹患嚴重、甚至致命之肺部疾病的風險。不過，無人瞭解原因。
In fact, some 35 percent of people with COVID-19 who died during the pandemic had diabetes.
事實上，在該大流行病期間，死亡的COVID-19患者，大約35%具有糖尿病。
Now, research conducted at the Weizmann Institute of Science and published in Nature has revealed how, in diabetics, high levels of blood sugar disrupt the function of key cell subsets in the lungs that regulate the immune response. It also identifies a potential strategy for reversing this susceptibility and saving lives.
於以色列魏茨曼科學研究所進行，且目前發表於《自然》期刊的研究已經揭露，於糖尿病患者中，高水平的血糖如何擾亂，於肺部調節免疫反應之關鍵細胞子群的功能。這也確認了一種，逆轉該種易感染性及拯救生命的潛在策略。
Prof. Eran Elinav’s team in his lab at Weizmann, headed by Drs. Samuel Nobs, Aleksandra Kolodziejczyk and Suhaib K. Abdeen, subjected multiple mouse models of types 1 and 2 diabetes to a variety of viral lung infections.
Eran Elinav教授在其魏茨曼科學研究所實驗室，由Drs. Samuel Nobs、Aleksandra Kolodziejczyk及Suhaib K. Abdeen領導的團隊，使多隻1型及2型糖尿病小鼠模型，曝露於多種病毒性肺部感染。
Just as in diabetic humans, in all these models the diabetic mice developed a severe, fatal lung infection following exposure to lung pathogens such as influenza. The immune reaction, which in nondiabetics eliminates the infection and drives tissue healing, was severely impaired in the diabetic mice, leading to uncontrolled infection, lung damage and eventual death.
就如同具糖尿病的人類般，於所有此些模型中，在曝露於諸如流感等肺部病原體後，具糖尿病之小鼠出現了，嚴重的致命肺部感染。在不具糖尿病的小鼠中，消除感染並促進組織癒合的免疫反應，在具糖尿病的小鼠中，嚴重受損，導致不受控制的感染、肺部損傷及最終死亡。
Next, to decode the basis of this heightened risk, the team performed an evaluation of gene expression on the level of individual cells, in more than 150,000 single lung cells of infected diabetic and nondiabetic mice.
接著，為了破解這種高風險的原因，該團隊進行了，在多於15萬個感染糖尿病與不具糖尿病小鼠的單一肺細胞中，針對各個細胞層級之基因表現的評估。
The researchers also performed an extensive array of experiments involving immune and metabolic mechanisms, as well as an in-depth assessment of immune cell gene expression in infected diabetic mice.
除了於感染糖尿病小鼠中，進行免疫細胞基因表現的深入評估之外，此些研究人員也進行了，廣泛系列之涉及免疫力及代謝機制的實驗。
In the diabetic mice they identified a dysfunction of certain lung dendritic cells, the immune cells that orchestrate a targeted immune response against pathogenic infection.
於具糖尿病的小鼠中，他們確認了，某些肺部樹突狀細胞的一種功能障礙。此些免疫細胞協調，對抗病原體感染的標靶免疫反應。
“High blood sugar levels severely disrupt certain subsets of dendritic cells in the lung, preventing these gatekeepers from sending the molecular messages that activate the critically important immune response,” says Nobs, a postdoctoral fellow who was the study’s first author. “As a result, the infection rages on, uncontrolled.”
該項研究首要撰文人，博士後特別研究員，Nobs宣稱：「高血糖水平嚴重擾亂，肺部樹突狀細胞的某些子群，阻擾了此些守門細胞，發出激活至關重要之免疫反應的分子訊息。」
Importantly, the scientists discovered how high sugar levels in diabetic mice disrupt the normal function of lung dendritic cells during infection. Altered sugar metabolism in these cells led to the accumulation of metabolic byproducts that markedly disrupted the normal regulation of gene expression, leading to aberrant immune protein production.
重要的是，此些科學家發現了，於具糖尿病之小鼠中，在感染期間，高糖水平如何擾亂肺樹突狀細胞的正常功能。這改變了，於此些細胞中，糖的新陳代謝，致使顯著擾亂基因表現正常調節之代謝副產物的積累，而導致產生異常的免疫蛋白。
“This could explain why the functioning of these cells is disturbed in diabetes, and why the immune system is unable to generate an effective anti-infection defense,” says Kolodziejczyk, a postdoctoral fellow who co-led the study as a first coauthor.
共同領導該研究，兼首要合撰人的博士後特別研究員，Kolodziejczyk宣稱：「這能解釋，為何此些細胞的功能，在糖尿病中受到擾亂，及為何免疫系統無法產生，有效的抗感染防禦。」
The scientists next explored ways to prevent the harmful effects of high sugar levels in lung dendritic cells, as a means of lowering the infection’s risk in diabetic animals.
接著，此些科學家探索了，阻擾高糖水平，於肺部樹突狀細胞中，有害之影響的方法，作為於具糖尿病動物中，降低感染風險的一種方法。
Indeed, tight control of blood sugar levels by insulin supplementation prompted the dendritic cells to regain their capacity to generate a protective immune response that could prevent the cascade of events leading to a severe, life-threatening viral lung infection.
實際上，藉由補充胰島素，嚴格控制血糖水平促使了，樹突狀細胞恢復產生一種，能防止導致嚴重、危及生命的病毒性肺部感染之級聯事件的保護性免疫反應能力。
Alternatively, administration of small molecules reversing the sugar-induced regulatory impairment corrected the dendritic cells’ dysfunction and enabled them to generate a protective immune response despite the presence of high sugar levels.
要不，施予逆轉糖誘導之調節損傷的小分子矯正了，樹突狀細胞的功能障礙且使它們，儘管存在高糖水平，也能產生保護性免疫反應。
“Correcting blood sugar levels, or using drugs to reverse the gene regulatory impairment induced by high sugar, enabled our team to get the dendritic cells’ function back to normal,” says Abdeen, a senior intern who co-supervised the study. “This was very exciting because it means that it might be possible to block diabetes-induced susceptibility to viral lung infections and their devastating consequences.”
共同監督該研究的最高年級實習生，Abdeen宣稱：「矯正血糖水平，或使用藥物逆轉高糖引起的基因調控損傷，使咱們團隊能使樹突狀細胞的功能恢復正常。這是極令人振奮的。因為這意味著，或許有可能阻止，糖尿病引起之病毒性肺部感染的易感染性，及其破壞性後果。」
圖1. 糖尿病小鼠(右)的肺組織具有，比非糖尿病動物(左)更少的免疫細胞(紫色小點)
Lung tissue of a diabetic mouse (right) contains fewer immune cells (small purple dots) than that of a non-diabetic animal (left)
With over 500 million people around the world affected by diabetes, and with diabetes incidence expected to rise over the next decades, the new research has significant, promising clinical implications.
由於，全球超過5億人受到糖尿病侵襲，及預計於未來幾十年間，糖尿病發生率會上升。因此，該項新研究具有重要、有指望的臨床意涵。
“Our findings provide, for the first time, an explanation as to why diabetics are more susceptible to respiratory infection,” Elinav says. “Controlling sugar levels may make it possible to reduce this pronounced diabetes-associated risk.
Elinav宣稱：「我們的研究發現首次提供了，有關為何糖尿病患者，較容易受到呼吸道感染的一種解釋。控制血糖水平使其可能降低，這種明顯與糖尿病相關的風險。」
In diabetic patients whose sugar levels are not easily normalized, small molecule drugs may correct the gene alterations caused by high sugar levels, potentially alleviating or even preventing severe lung infection.
在血糖水平不易正常化的糖尿病患者中，小分子藥物可以矯正，高血糖引起的基因改變，從而潛在上減輕、或甚至防止嚴重的肺部感染。
Local administration of such treatments by inhalation may minimize adverse effects while enhancing effectiveness, and merits future human clinical testing.”
此類經由吸入之療法的局部施予，能使負面影響減至最少，同時提高有效性。因此，值得未來的人體臨床試驗。」
網址：https://wis-wander.weizmann.ac.il/life-sciences/why-people-diabetes-are-more-prone-respiratory-risk
翻譯：許東榮
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