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English to Indonesian: How immune cells kill bacteria with acid General field: Science
Source text - English The first line of immune defense against invading pathogens like bacteria are macrophages, immune cells that engulf every foreign object that crosses their way. After enclosing it in intracellular membrane vesicles, a process called phagocytosis, macrophages kill their prey with acid. However, it is not yet entirely understood how the acidification process is established. In their quest to systematically study proteins that transport chemicals across cellular membranes, researchers at CeMM characterized the critical role for transporter SLC4A7 in this process, providing valuable new insights for many pathologic conditions from inflammation to cancer.
Among the many different kinds of immune cells that patrol the body, macrophages are the first when it comes to fight against a foreign threat. With their flexible and versatile surface, they engulf every microorganism or particle that could be harmful for the health of the organism, and enclose it in an intracellular membrane vesicle called phagosome. To eliminate the threat and break it down to its constituents, the interior of the phagosome needs to be effectively and progressively acidified. For this crucial part of phagocytosis, the macrophages must undergo multiple metabolic changes, which are not yet entirely understood.
The team of Giulio Superti-Furga, Scientific Director of the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, discovered in their latest study that a membrane protein belonging to the family of "solute carriers" (SLCs) plays an essential role in phagocytosis and phagosome acidification. Their work was published in the journal Cell Host & Microbe.
SLCs represent the largest group of transporter proteins responsible for the movement of chemical molecules across cellular membranes. As phagocytosis and the acidification of phagosomes require the exchange of ions and nutrients, the scientists in Superti-Furga´s laboratory hypothesized that SLCs might be essential for macrophages to undergo those processes. To test their hypothesis, the researchers developed an essay with special cells in which they impaired the 391 human SLC genes individually using CRISPR/Cas9 gene editing technology.
Those cells, each of them carrying a single defective SLC gene, were subsequently tested on how they performed during phagocytosis. Strikingly, among all SLCs, SLC4A7, a sodium bicarbonate transporter, was the only one who turned out to be essential for macrophages to undergo phagocytosis and acidification. Cells with impaired SLC4A7 were unable to acidify their phagosomes and by consequence decreased their capacity to kill bacteria.
Having identified their prime candidate SLC4A7, the scientists, in collaboration with the laboratory of Nicolas Demaurex of the University of Geneva, investigated further and unveiled the mechanism causing the impaired phagosome acidification. "SLC4A7 is located on the surface of macrophages and necessary for bicarbonate import from the environment into the cell cytoplasm" Giulio Superti-Furga, senior author of the study explains. "The SLC4A7-driven bicarbonate import is essential for buffering the cellular pH during phagocytosis. If SLC4A7 was lost, the activation of macrophages led to accumulation of protons in their cytoplasm, which further inhibited the acidification of phagosomes."
The results of this study do not only provide new fundamental insights into the molecular functioning of one of the most important cells of the immune system. As phagocytosis plays a significant role in various pathologic conditions from inflammation to cancer, these new insights are likely of relevance beyond the context of infectious diseases. The effort to understand the role of the different cellular transporters, supported by a grant of the European Research Council (ERC).
Translation - Indonesian Lini pertama bagi pertahanan kekebalan di dalam tubuh kita saat menerima serangan patogen seperti bakteri adalah makrofag.
Makrofag inilah kumpulan sel-sel imunitas di dalam tubuh yang bekerja melawannya dengan cara menelan setiap benda asing yang melintasi mereka. Setelah membungkusnya dalam vesikel membran intraseluler, proses yang disebut fagositosis, makrofag kemudian membunuh mangsanya dengan asam.
Meski demikian, belum sepenuhnya dipahami bagaimana proses pengasaman itu terjadi di dalam makrofag tersebut.
Sebagai bagian upaya mempelajari secara sistematis protein yang mengangkut bahan kimia melalui membran sel, para peneliti di CeMM melihat peran penting pada protein pengirim SLC4A7 dalam proses ini, yang memberikan wawasan baru berharga bagi banyak kondisi patologis, mulai dari peradangan hingga ke kanker.
Di antara berbagai jenis sel-sel kekebalan tubuh yang berpatroli di tubuh, makrofag adalah yang pertama berhadapan dengan ancaman asing. Dengan permukaannya yang fleksibel dan serbaguna, mereka menelan setiap mikroorganisme atau partikel yang bisa membahayakan kesehatan organisme, dan mengurungnya dalam vesikel membran intraseluler yang disebut fagosom.
Untuk menghilangkan ancaman dan memecahnya hingga pada ke tingkat unsurnya, bagian interior fagosom haruslah efektif dan diasamkan secara progresif. Pada bagian krusial dari fagositosis ini, makrofag harus mengalami beberapa perubahan metabolik, yang belum sepenuhnya dipahami.
Tim Giulio Superti-Furga, Direktur Ilmiah Pusat Penelitian CeMM Kedokteran Molekuler dari Akademi Ilmu Pengetahuan Austria, menemukan dalam penelitian terbaru mereka bahwa protein membran milik keluarga “pembawa larutan zat” (SLC) memainkan peran penting dalam fagositosis dan pengasaman fagosom. Penelitian mereka dipublikasikan di jurnal Cell Host & Microbe.
SLC mewakili kelompok terbesar protein pengirim yang bertanggung jawab pada pergerakan molekul kimia yang melintasi membran sel. Karena fagositosis dan pengasaman fagosom membutuhkan pertukaran ion dan nutrisi, para ilmuwan di laboratorium Superti-Furga membuat hipotesis bahwa SLC mungkin penting bagi makrofag untuk menjalani proses tersebut. Untuk menguji hipotesis mereka, para peneliti mengembangkan esai dengan sel-sel khusus dengan 391 gen SLC manusia mereka lemahkan secara individu menggunakan teknologi pengeditan gen CRISPR/Cas9.
Sel-sel tersebut, yang masing-masing membawa gen SLC cacat tunggal, kemudian diuji bagaimana mereka melakukan fagositosis. Secara mencolok, di antara semua SLC, SLC4A7, pengangkut natrium bikarbonat, adalah satu-satunya yang ternyata penting bagi makrofag untuk menjalani fagositosis dan pengasaman. Sel-sel dengan SLC4A7 yang terganggu tidak dapat mengasamkan fagosom mereka dan konsekuensinya menurunkan kapasitas mereka untuk membunuh bakteri.
Setelah mengidentifikasi kandidat utama mereka SLC4A7, para ilmuwan, bekerja sama dengan laboratorium Nicolas Demaurex dari Universitas Jenewa, menyelidiki lebih lanjut dan meluncurkan mekanisme yang menyebabkan gangguan pengasaman fagosome.
“SLC4A7 terletak di permukaan makrofag dan diperlukan untuk impor bikarbonat dari lingkungan ke dalam sitoplasma sel,” kata Giulio Superti-Furga, peneliti senior studi ini menjelaskan. “Impor bikarbonat SLC4A7 sangat penting bagi buffering pH sel selama fagositosis. Jika SLC4A7 hilang, aktivasi makrofag menyebabkan akumulasi proton di sitoplasma mereka, yang selanjutnya menghambat pengasaman fagosom.”
Hasil penelitian ini tidak hanya memberikan wawasan mendasar baru ke dalam fungsi molekul dari salah satu sel terpenting dari sistem kekebalan. Karena fagositosis memainkan peran penting dalam berbagai kondisi patologis mulai dari peradangan hingga ke kanker, wawasan baru ini tampaknya memiliki relevansi di luar konteks penyakit menular. Upaya untuk memahami peran protein pengirim sel-se yang berbeda didukung oleh hibah dari European Research Council (ERC).
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