眼睛表面的常居微生物可以保护角膜免受感染

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眼睛表面的常居微生物可以保护角膜免受感染

原创 2017-08-02 SIFIC热点团队 SIFIC感染官微

检索丨刘金淑

翻译丨陈燕琼

审核丨刘金淑、陈志锦

乳杆菌(C. mast)

新研究显示，眼睛表面的常居微生物在保护眼睛免受感染的免疫应答中至关重要。发表在7月11日的《免疫》杂志上的这项研究，证明了存在于眼睛的一种常居微生物可增强免疫系统以抵御病原体。该研究是在美国国立卫生研究院眼科研究所（NEI）进行的。

NEI实验室高级研究员Rachel Caspi博士解释说：“这是眼部表面有常居菌的首个证据，所以这项研究解决了眼部表面是否存在常居微生物群这个存在已久的问题。”

多年来，由于眼睛表面存在一种称为溶菌酶的酶，这种酶具有抗菌肽，可以破坏细菌以及其它可能从空气或我们的手指上落到眼睛上的微生物，所以眼表被认为是无菌的。

Caspi实验室研究员Anthony Leger博士能够从小鼠结膜中培养出细菌，他发现了几种常在皮肤上发现的葡萄球菌和乳杆菌（C.mast），但还不清楚这些微生物是刚刚落到眼睛上的，或是正被消除，还是长期居住在眼睛上的。

研究人员在对小鼠眼结膜免疫细胞进行培养时，发现了乳杆菌诱导免疫细胞产生了白细胞介素（IL）-17，这是一种对宿主防御至关重要的信号蛋白。经进一步研究，他们发现IL-17由γδT细胞产生，这是一种在粘膜组织中发现的免疫细胞。IL-17诱导了结膜中其他免疫细胞-中性粒细胞（最丰富的白细胞类型）将抗微生物蛋白质释放到泪液中。研究人员目前正在研究可以使得乳杆菌抵抗自身引起的免疫反应而能持续存在于眼睛内的独特之处。

为了确定乳杆菌是否有助于小鼠的免疫应答，St. Leger设立了两个小组，一组是眼结膜中有乳杆菌的小鼠，另一组是用抗生素治疗以杀死眼睛中乳杆菌和其他细菌的小鼠，然后让真菌和白色念珠菌作用于两组小鼠的眼部。使用抗生素的小鼠的结膜免疫应答降低，不能消除白色念珠菌，从而导致全身感染。另一方面，具有正常乳杆菌的小鼠能够抵御真菌。

然而，St. Leger注意到，来自NIH动物中心的小鼠在他们的眼睛上有乳杆菌，但来自缅因州杰克逊实验室（JAX）和其他商业供应商的小鼠却没有。这个偶然的发现使得研究人员难以确定乳杆菌是眼睛的常居菌还是刚好在外界环境中掉落到眼睛上的微生物。他们给眼结膜内没有乳杆菌的小鼠进行乳杆菌接种，并确定在几周后是否可以从这些小鼠眼睛内培养出乳杆菌，还要确定乳杆菌是否可以很容易地通过环境进行传播。

当给JAX小鼠接种乳杆菌后，小鼠产生了可释放IL-17的结膜γδT细胞，且经过几周后还可以从小鼠的眼睛上培养出乳杆菌。相比之下，其他几个菌株被接种到JAX小鼠的眼睛上后就消失了，更没有诱导局部免疫。但乳杆菌在眼睛表面定植的原因仍不得而知。

有趣的是，即使经过8周的共居，乳杆菌也没有传播给同一个笼子内的其他小鼠。然而，乳杆菌可以从母鼠传给幼崽。这两个观察结果支持了下面这个论点：乳杆菌是宿主的共生体，而不是通过皮肤和外界环境植入到眼睛的细菌。研究人员目前正在研究是否还有其他细菌可在调节眼睛免疫上发挥作用。

Leger指出：“尽管乳杆菌似乎会引起有益的免疫应答，但也有可能引起疾病。例如老年人往往存在免疫抑制，这可能会导致乳杆菌增长失控而引起疾病。该研究已经给“眼中央存在微生物”这个观点建立了证据。众所周知，肠道内益生菌可调节肠道的免疫应答。现在我们可以看到这种关系也存在于眼睛里，这对我们如何治疗眼部疾病很重要。

目前还不清楚如何把这些研究结果转换化为对人类健康和免疫力，因此患者使用抗生素治疗眼部感染时，应遵循眼科专业人员的建议。

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原文：

Microbes Living on the Surface of theEye Protect Cornea From Infections

Corynebacterium mastitidis (C. mast)

Resident microbes living on the eye are essential for immune responsesthat protect the eye from infection, new research shows. The study, whichappears in the journal Immunity on July 11, demonstrates the existence of aresident ocular microbiome that trains the developing immune system to fend offpathogens. The research was conducted at the National Eye Institute (NEI), partof the National Institutes of Health.

“This is the first evidence that a bacterium lives on the ocular surfacelong-term,” explained Rachel Caspi, PhD, senior investigator in NEI’sLaboratory of Immunology. “This work addresses a longstanding question aboutwhether there is a resident ocular microbiome.”  

For years, the ocular surface was thought to be sterile because of thepresence of an enzyme called lysozyme that destroys bacteria, antimicrobialpeptides, and other factors that rid the eye of microbes that may land from theair (or from our fingers) onto the surface of the eye.

Anthony St. Leger, PhD, research fellow in Caspi’slaboratory, was able toculture bacteria from the mouse conjunctiva, the membrane that lines theeyelids. He found several species of Staphylococci, which are commonly found onthe skin, and Corynebacterium mastitidis (C. mast). But it wasn’t clear whetherthose microbes had just arrived on the eye and were en route to beingdestroyed, or whether they lived on the eye for extended periods of time.

The researchers found that C. mast, when cultured with immune cells fromthe conjunctiva, induced the production of interleukin (IL)-17, a signalingprotein critical for host defense. Upon further investigation, they found thatIL-17 was produced by gamma delta T cells, a type of immune cell found inmucosal tissues. IL-17 attracted other immune cells called neutrophils—the mostabundant type of white blood cell—to the conjunctiva and induced the release ofanti-microbial proteins into the tears. The researchers are currentlyinvestigating the unique features that can make C. mast resistant to the immuneresponse that it itself provokes and allow it to persist in the eye.

To determine whether the microbe was contributing to the immune responsein mice, St. Leger formed two groups, one control (with C. mast) and onetreated with an antibiotic to kill C. mast and other ocular bacteria, and thenchallenged them with the fungus, Candida albicans. The mice receivingantibiotics had a reduced immune response in their conjunctiva and were notable to eliminate C. albicans, leading to full-blown ocular infection. Thecontrol mice with normal C. mast on the other hand were able to fend off thefungus.

St. Leger noticed that mice from the NIH animal facility had C. mast ontheir eyes, but mice from the Jackson Laboratory (JAX) in Maine and othercommercial vendors did not. This fortuitous observation allowed the researchersto determine if C. mast was truly a resident microbe, as opposed to a transientmicrobe that lands on the eye from the environment. They did this byinoculating C. mast-free mice with the microbe and determining if the microbecould be cultured from those animals’ eyes many weeks later. They alsodetermined whether the microbe could easily be transmitted among cagemates.

When inoculated with C. mast, JAX mice produced conjunctival gamma delta Tcells that released IL-17. Bacteria could still be cultured from their eyesafter many weeks. By contrast, several other strains of bacteria inoculatedonto the eyes of JAX mice disappeared without inducing local immunity. “Westill don’t know what enables C. mast to successfully establish itself in theeye, whereas other similar bacteria fail to colonize,” Caspi said.

Interestingly, C. mast was not spread to cage-mates even after eight weeksof co-housing; however, C. mast can be passed from mother to pup. Both of theseobservations support the notion that C. mast is a resident commensal, not abacterium that is continually re-introduced to the eye from the skin or theenvironment, Caspi explained.

Although C. mast appears to stimulate a beneficial immune response, theremay be situations in which it could cause disease, St. Leger noted. Forinstance, the elderly tend to have suppressed immune systems, which might allowC. mast to grow out of control and cause disease.

The researchers are currently investigating whether other bacteria play arole in regulating eye immunity.

“We’ve established the proof of concept of a central ocular microbiome,”St. Leger said. “It's well known that there are good bacteria in the gut thatmodulate the immune response. Now we show that this relationship exists in theeye. That's important for how we think about treating ocular disease.”

It’s unclear how these results may translate to human health and immunity.Patients should follow their eye care professional’s advice when usingantibiotics for infections of the eye.

Reference: St. Leger AJ, Desai JV, Drummond RA, Kugadas A, Almaghrabi F,Raychaudhuri K, GadjevaM, Iwakura Y, Lionakis MS, Caspi RR. 2017. An ocularcommensal protects from corneal infection by driving an IL-17 response frommucosal gd T cells. Immunity XXX

Sources: NIH, National Eye Institute (NEI)

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图文编辑：独白

审稿：赵静 孙庆芬

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路过学习

一路向前2016

路过学习了，谢谢老师分享！

小白天使

太好了。和肠道益生菌是一样的道理吧