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2021年12月15日：香港大學(xué)醫(yī)學(xué)院：奧密克戎變異株比德爾塔更快更易感染人類支氣管，但肺部的感染較輕

由香港大學(xué)李嘉誠醫(yī)學(xué)院的研究人員領(lǐng)導(dǎo)的一項(xiàng)研究，首次提供了關(guān)于新冠新型關(guān)切變異株（VOC）——奧密克戎——如何感染人類呼吸道的信息。研究人員發(fā)現(xiàn)，奧密克戎感染人類支氣管的速度比德爾塔變異株和原始的新冠毒株快了?70 倍，這可能解釋了為什么奧密克戎在人與人之間的傳播速度比以前的變異株快。他們的研究還顯示，奧密克戎造成的肺部感染明顯低于原始的新冠毒株，這個(gè)指標(biāo)可能說明疾病的嚴(yán)重程度較低。這項(xiàng)研究目前正在接受同行評(píng)議，待發(fā)表。

研究發(fā)現(xiàn)

香港科技園公共衛(wèi)生學(xué)院副教授及免疫及感染研究中心首席研究員陳智威（Chan Chi-wai）博士，以及香港大學(xué)醫(yī)學(xué)院病理科教授John Nicholls教授，自 2007 年起率先使用體外呼吸道培養(yǎng)，來調(diào)查許多新出現(xiàn)的病毒感染，例如禽流感、中東呼吸綜合征(MERS)的冠狀病毒等。現(xiàn)在，他們使用這項(xiàng)技術(shù)去搞清為什么奧密克戎變異株在傳播和疾病嚴(yán)重程度上可能與其他新冠變異株不同。

這種方法利用因治療需被切除的肺組織來調(diào)查呼吸道的病毒性疾病，這些組織如不使用則通常會(huì)被廢棄。陳博士和他的團(tuán)隊(duì)成功地分離出了奧密克戎變異株，并使用這個(gè)實(shí)驗(yàn)?zāi)Ｐ蛯⒏腥九c 2020 年最初的新冠毒株、德爾塔變異株和最近的奧密克戎進(jìn)行了比較。他們發(fā)現(xiàn)，在人類支氣管中，新的奧密克戎變異株比最初的新冠毒株和德爾塔變異株復(fù)制得更快。在感染 24 小時(shí)后，奧密克戎變異株的復(fù)制率比德爾塔變異株和最初的新冠毒株高約70倍。相比之下，奧密克戎變異株在人類肺部組織中的復(fù)制效率較低（比最初的新冠毒株低 10 倍以上），這可能意味著疾病的嚴(yán)重程度較低。

陳博士說:“值得注意的是，人類疾病的嚴(yán)重程度不僅取決于病毒復(fù)制，還取決于宿主對(duì)感染的免疫反應(yīng)，這可能導(dǎo)致先天免疫系統(tǒng)失調(diào)，即‘細(xì)胞因子風(fēng)暴’?！薄斑€需要指出的是，一種傳染性很強(qiáng)的病毒會(huì)感染更多的人，從而導(dǎo)致更嚴(yán)重的疾病和死亡，盡管這種病毒本身的致病性可能較低。”因此，結(jié)合我們最近的研究表明，奧密克戎變異株可以部分逃脫疫苗和過去感染的免疫，奧密克戎變異株的總體威脅可能非常重大?！?/p>

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2022 年 1 月 5 日：《自然》：奧密克戎對(duì)肺部的弱攻擊可能會(huì)降低它的危險(xiǎn)性

動(dòng)物研究中越來越多的證據(jù)表明，奧密克戎在肺組織中不易繁殖，而在感染其他變異株的人身上，肺組織可能會(huì)受到嚴(yán)重破壞。

來自南非和英國的初步跡象表明，快速傳播的新冠奧密克戎變異株相較之前的德爾塔，危險(xiǎn)性較小?，F(xiàn)在，一系列的實(shí)驗(yàn)室研究為這種差異提供了一個(gè)說得通的解釋：奧密克戎感染肺部深處的細(xì)胞，并不會(huì)像它感染上呼吸道那樣容易。

“這是一個(gè)非常有吸引力的觀察結(jié)果，或許可以解釋我們?cè)诓∪松砩峡吹降默F(xiàn)象，”加州舊金山格萊斯頓病毒學(xué)研究所的病毒學(xué)家 Melanie Ott 說。她沒有參與這項(xiàng)研究。但是她補(bǔ)充說：奧密克戎的高度傳染性意味著醫(yī)院很快就會(huì)人滿為患——盡管它所導(dǎo)致的疾病的嚴(yán)重程度有所降低。

南非當(dāng)局于 12 月 30 日宣布，該國已度過奧密克戎高峰，死亡人數(shù)沒有出現(xiàn)大幅上升。英國政府 12 月 31 日的一份報(bào)告說，在英格蘭，因感染奧密克戎病毒而需要住院治療或緊急護(hù)理的人的比例，約為感染德爾塔病毒的人的一半。

但是，通過疫苗接種、感染或通過兩者同時(shí)獲得新冠免疫保護(hù)的人數(shù)，隨著時(shí)間的推移而增加，這使得很難確定奧密克戎是否在本質(zhì)上比早期的變異株更溫和，導(dǎo)致的病癥更輕。為了找到答案，研究人員將目光轉(zhuǎn)向了動(dòng)物和實(shí)驗(yàn)室培養(yǎng)皿中的細(xì)胞。

密蘇里州圣路易斯華盛頓大學(xué)的病毒學(xué)家 Michael Diamond 和他的同事們用奧密克戎和其他新冠變異株感染倉鼠和小鼠，以跟蹤疾病的發(fā)展。這種差異是驚人的：幾天后，感染奧密克戎的動(dòng)物，肺部的病毒濃度至少比感染其他變異株的嚙齒動(dòng)物低 10 倍。其他團(tuán)隊(duì)也注意到，與之前的變異株相比，奧密克戎在肺組織中的水平降低了。

Diamond說：他特別震驚地看到，被奧密克戎感染的動(dòng)物體重并沒有變化，而其他動(dòng)物的體重卻迅速下降，后者表明感染導(dǎo)致了嚴(yán)重的疾病?！爸暗拿糠N新冠毒株都很容易感染倉鼠，感染程度很高。但很明顯，奧密克戎對(duì)倉鼠來說是不同的。肺部是冠狀病毒造成大部分損害的地方，肺部感染可以引發(fā)炎癥性免疫反應(yīng)，破壞受感染和未受感染的細(xì)胞，導(dǎo)致組織瘢痕化和缺氧。受感染的肺細(xì)胞越少，表明病癥較輕?！?/p>

另一個(gè)研究小組發(fā)現(xiàn)：在感染肺細(xì)胞和被稱為有機(jī)物的微型肺模型方面，奧密克戎的成功程度遠(yuǎn)不如之前的變異株。這些實(shí)驗(yàn)還發(fā)現(xiàn)了一個(gè)可能的原因：一種名為 TMPRSS2 的蛋白質(zhì)，它突出在肺部和其他器官的許多細(xì)胞表面，但在大多數(shù)鼻和喉嚨細(xì)胞的表面明顯缺失。

之前的變異株已經(jīng)利用這種蛋白質(zhì)來感染細(xì)胞，但研究人員注意到奧密克戎不能與 TMPRSS2 很好地結(jié)合。相反，它往往會(huì)在被細(xì)胞攝取時(shí)進(jìn)入細(xì)胞。

奧密克戎更容易感染上呼吸道

英國劍橋大學(xué)病毒學(xué)家 Ravindra Gupta 是 TMPRSS2 研究的合著者之一。他表示：難以進(jìn)入肺細(xì)胞，可能有助于解釋為什么奧密克戎更容易引發(fā)上呼吸道感染，而不是肺部感染。Gupta說，這個(gè)理論也可以解釋，為什么根據(jù)一些估計(jì)，奧密克戎的傳染性幾乎和麻疹一樣，而麻疹是高傳染性的基準(zhǔn)。如果變異株停留在上呼吸道，病毒顆?？赡軙?huì)很容易“搭乘”從鼻子和嘴巴排出的物質(zhì)，從而讓病毒找到新的宿主。其他數(shù)據(jù)提供了直接證據(jù)，表明奧密克戎在上呼吸道比在肺部更容易復(fù)制。

Ott說，最新的結(jié)果可能意味著“病毒在上呼吸道形成了非常局部的感染，在肺部造成嚴(yán)重破壞的機(jī)會(huì)更少”。這將是一個(gè)令人高興的消息。但是宿主的免疫反應(yīng)在疾病的嚴(yán)重程度中扮演著重要的角色，如果科學(xué)家們想要了解奧密克戎的基本生物性如何影響其在人類中的疾病進(jìn)展，他們需要更多的臨床數(shù)據(jù)。

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2022 年 1 月 8 日：奧密克戎是“大號(hào)流感”？張文宏：不是！它會(huì)咬人

https://www.shantou.gov.cn/stswsj/gkmlpt/content/2/2014/post_2014378.html#3521

感染新冠病毒奧密克戎變異株后，生命健康受到的影響有多大？

1月8日，國家傳染病醫(yī)學(xué)中心主任、復(fù)旦大學(xué)附屬華山醫(yī)院感染科主任張文宏表示，一些自媒體說奧密克戎引發(fā)的是“大號(hào)流感”，這是缺乏科學(xué)依據(jù)的，他研究奧密克戎感染者的醫(yī)學(xué)影像后認(rèn)為，這種變異株“會(huì)咬人”。一個(gè)國家和地區(qū)需要強(qiáng)大的免疫屏障和醫(yī)療資源，才能抵御奧密克戎的威脅。

“今天上午8點(diǎn)半，我還輕輕撫摸過奧密克戎的片子。”張文宏告訴聽眾，“自媒體說這個(gè)變異株引起的是‘大號(hào)流感’，這是不足為據(jù)的，我們復(fù)旦校友可不要人云亦云?！睋?jù)介紹，奧密克戎是新冠病毒在人體免疫壓力下的自然選擇結(jié)果，“可以說，奧密克戎在與免疫系統(tǒng)斗爭后贏了”。目前，這種首先在南非發(fā)現(xiàn)的變異株已肆虐全球，導(dǎo)致很多國家和地區(qū)的感染人數(shù)大幅上升。

張文宏認(rèn)為，西方國家之所以在“硬闖”這波疫情，其底氣主要來自疫苗，其效果有待進(jìn)一步評(píng)估。目前，美國的新冠疫苗接種率接近70%，三針疫苗接種率是22%，所以大多數(shù)健康的年輕人有望平安“闖”過這波疫情，但免疫力低下的人群呢？前景不容樂觀。英國近期每天新增確診人數(shù)超過20萬，但病死率沒有明顯上升。究其原因，是英國的新冠疫苗接種率達(dá)到80%，三針疫苗接種率超過50%，且尚未出現(xiàn)嚴(yán)重的醫(yī)療資源擠兌情況。

在亞洲，新加坡的兩針及以上新冠疫苗接種率高達(dá)90%以上，目前病死率控制在非常低的水平。以色列近期每天新增確診人數(shù)超過1萬，但病死率也非常低，其主要原因也是疫苗接種率高，三針接種率達(dá)到50%。以色列政府規(guī)定，60歲以上老年人必須接種第三針疫苗。

“我們?cè)试S關(guān)于疫苗接種的爭論，但要看到，疫苗在新冠疫情防控中的作用是不可低估的?！睆埼暮暾f，“如果我們不積極接種疫苗，筑起強(qiáng)大的免疫屏障，就會(huì)回到1918年那次全球疫情?！痹谒磥?，雖然疫苗屏障沒有完全防住新冠病毒的傳播，但它已讓病毒的毒性大幅下降，降低了感染者的病死率。

除了不斷提高疫苗兩針及以上的接種率，一個(gè)國家或地區(qū)還要確保醫(yī)療資源的充分供給，這樣才能對(duì)免疫力低下的感染者進(jìn)行充分救治?！叭绻t(yī)療資源不夠，奧密克戎是會(huì)‘咬人’的?！睆埼暮暾f，“我國各地都要確保醫(yī)療資源的充分和平等?！?/p>

在演講結(jié)束前，他表示，“已看到漫漫長夜的曙光。世界何時(shí)重新開放？一是要筑起強(qiáng)大的免疫屏障，二是把病死率控制得很低?！?/p>

原文

香港大學(xué)醫(yī)學(xué)院：

http://www.med.hku.hk/en/news/press/20211215-omicron-sars-cov-2-infection

hkUMed finds Omicron SARS-CoV-2 can infect faster and better than Delta in human bronchus but with less severe infection in lung

A study led by researchers from the LKS Faculty of Medicine at The University of Hong Kong (hkUMed) provides the first information on how the novel Variant of Concern (VOC) of SARS-CoV-2, the Omicron SARS-CoV-2 infect human respiratory tract. The researchers found that Omicron SARS-CoV-2 infects and multiplies 70 times faster than the Delta variant and original SARS-CoV-2 in human bronchus, which may explain why Omicron may transmit faster between humans than previous variants. Their study also showed that the Omicron infection in the lung is significantly lower than the original SARS-CoV-2, which may be an indicator of lower disease severity. This research is currently under peer review for publication.

Research findings

Dr Michael Chan Chi-wai, Associate Professor of School of Public Health and Principal Investigator, Centre for Immunology and Infection (C2i), Hong Kong Science and Technology Park (hkSTP) and Professor John Nicholls, Professor of Department of Pathology, hkUMed have pioneered the use of ex vivo cultures of the respiratory tract for investigating many emerging virus infections since 2007, such as avian influenza, coronavirus of the Middle East Respiratory Syndrome (MERS). Now this technique has been applied to understand why the Omicron variant may differ in transmission and disease severity from other SARS-CoV-2 variants.

This method uses lung tissue removed for treatment of the lung, which is normally discarded, for investigating virus diseases of the respiratory tract. Dr Chan and his team successfully isolated the Omicron SARS-CoV-2 variant and used this experimental model to compare infection with the original SARS-CoV-2 from 2020, the Delta variant and the recent Omicron variant. They found that the novel Omicron variant replicates faster than the original SARS-CoV-2 virus and Delta variant in the human bronchus. At 24 hours after infection, the Omicron variant replicated around 70 times higher than the Delta variant and the original SARS-CoV-2 virus. In contrast, the Omicron variant replicated less efficiently (more than 10 times lower) in the human lung tissue than the original SARS-CoV-2 virus, which may suggest lower severity of disease.

‘It is important to note that the severity of disease in humans is not determined only by virus replication but also by the host immune response to the infection, which may lead to dysregulation of the innate immune system, i.e. “cytokine storm”,’ said Dr Chan. ‘It is also noted that, by infecting many more people, a very infectious virus may cause more severe disease and death even though the virus itself may be less pathogenic. Therefore, taken together with our recent studies showing that the Omicron variant can partially escape immunity from vaccines and past infection, the overall threat from Omicron variant is likely to be very significant.’

《自然》：

https://www.nature.com/articles/d41586-022-00007-8

Omicron's feeble attack on the lungs could make it less dangerous

Mounting evidence from animal studies suggests that Omicron does not multiply readily in lung tissue, which can be badly damaged in people infected with other variants.

Early indications from South Africa and the United Kingdom signal that the fast-spreading Omicron variant of the coronavirus SARS-CoV-2 is less dangerous than its predecessor Delta. Now, a series of laboratory studies offers a tantalizing explanation for the difference: Omicron does not infect cells deep in the lung as readily as it does those in the upper airways.

“It’s a very attractive observation that might explain what we see in patients,” says Melanie Ott, a virologist at the Gladstone Institute of Virology in San Francisco, California, who was not involved in the research. But she adds that Omicron’s hyper-transmissibility means that hospitals are filling quickly — despite any decrease in the severity of the disease it causes.

Authorities in South Africa announced on 30 December that the country had passed its Omicron peak without a major spike in deaths. And a 31 December UK government report said that people in England who were infected with Omicron were about half as likely to require hospitalization or emergency care as were those infected with Delta.

But the number of people who have gained immune protection against COVID-19 through vaccination, infection or both has grown over time, making it difficult to determine whether Omicron intrinsically causes milder disease than earlier variants. For answers, researchers have turned to animals and to cells in laboratory dishes.

How the coronavirus infects cells — and why Delta is so dangerous

Michael Diamond, a virologist at Washington University in St. Louis, Missouri, and his colleagues infected hamsters and mice with Omicron and other variants to track disease progression. The differences were staggering: after a few days, the concentration of virus in the lungs of animals infected with Omicron was at least ten times lower than that in rodents infected with other variants1. Other teams have also noted that compared with previous variants, Omicron is found at reduced levels in lung tissue2,3.

Diamond says he was especially shocked to see that the Omicron-infected animals nearly maintained their body weight, whereas the others quickly lost weight — a sign that their infections were causing severe disease. “Every strain of SARS-CoV-2 has infected hamsters very easily, to high levels,” he says, “and it’s clear that this one is different for hamsters.” The lungs are where the coronavirus does much of its damage, and lung infection can set off an inflammatory immune response that ravages infected and uninfected cells alike, leading to tissue scarring and oxygen deprivation. Fewer infected lung cells could mean milder illness.

Another group found that Omicron is much less successful than previous variants at infecting lung cells and miniature lung models called organoids4. These experiments also identified a plausible player in the difference: a protein called TMPRSS2, which protrudes from the surfaces of many cells in the lungs and other organs, but is notably absent from the surfaces of most nose and throat cells.

Previous variants have exploited this protein to infect cells, but the researchers noticed that Omicron doesn’t bind to TMPRSS2 so well. Instead, it tends to enter cells when it is ingested by them5,6.

Upper airway preferred

Difficulty entering lung cells could help to explain why Omicron does better in the upper airways than in the lungs, says Ravindra Gupta, a virologist at the University of Cambridge, UK, who co-authored one of the TMPRSS2 studies4. This theory could also explain why, by some estimates, Omicron is nearly as transmissible as measles, which is the benchmark for high transmissibility, says Diamond. If the variant lingers in the upper airways, viral particles might find it easy to hitch a ride on material expelled from the nose and mouth, allowing the virus to find new hosts, says Gupta. Other data provide direct evidence that Omicron replicates more readily in the upper airways than in the lungs2,5.

The latest results could mean that “the virus establishes a very local infection in the upper airways and has less chance to go and wreak havoc in the lungs”, Ott says. That would be welcome news — but a host’s immune response plays an important part in disease severity, and scientists need more clinical data if they are to understand how Omicron’s basic biology influences its disease progression in humans.

Omicron’s course of infection could also have implications for children, says Audrey John, a specialist in paediatric infectious disease at the Children’s Hospital of Philadelphia in Pennsylvania. Young children have relatively small nasal passages, and babies breathe only through their noses. Such factors can make upper respiratory conditions more serious for children than for adults, John says. But she adds that she has not seen data suggesting an uptick in the numbers of young children hospitalized for croup and other conditions that could indicate a severe infection of the upper respiratory tract.

Although there is still much to learn about the new variant, Gupta says that fears raised in late November by the multitude of mutations in Omicron’s genome have not been completely borne out. He says the initial alarm offers a cautionary tale: it’s difficult to predict how a virus will infect organisms from its genetic sequence alone.

doi: https://doi.org/10.1038/d41586-022-00007-8

References

1.

Diamond, M. et al. Preprint at Research Square https://doi.org/10.21203/rs.3.rs-1211792/v1 (2021).

2.

McMahan, K. et al. Preprint at bioRxiv https://doi.org/10.1101/2022.01.02.474743 (2022).

3.

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