為什麼 2022 年猴痘會在社區擴大傳播？
資料來源：www.thelancet.com/microbe。 2022 年 8 月 5 日 https://doi.org/10.1016/S2666-5247(22)00200-2 / 財團法人台灣紅絲帶基金會編譯
在《刺胳針微生物》中，Akanyene Otu 及其同事呼籲為 2022 年猴痘爆發採取緊急公共衛生行動，並指出自 2022 年 5 月 7 日以來非洲以外的病例已超過 1970 年至今在流行地區以外發現的病例爆發總數。當我們考慮到過去 2 個月的病例大大超過了整個 20 世紀確診或疑似人類猴痘病例的數量時，最新的人類感染率更加令人擔憂。Isidro 及其同事的定序顯示，正在傳播的猴痘病毒來自 2017 年至 2019 年間在奈及利亞、新加坡、以色列和英國的病例樣本中採樣的進化枝。Happi 及其同事描述了一種新的進化枝系統，並將循環病毒臨時命名為人類猴痘病毒 1 (hMPXV1)。此外，Nextstrain 的hMPXV1 的分子時鐘分析顯示後代譜系 A.1、A.2、A.1.1 和 B.1 具有廣泛的多樣性。 O’Toole 和 Rambaut 觀察到，一種稱為載脂蛋白 B 編輯複合物 (APOBEC3) 的胞苷脫氨酶可能正在推動 hMPXV1.4 胞苷脫氨酶改變 DNA 的近期快速地進化，胞苷脫氨酶改變 DNA，從而導致開關區域雙鏈斷裂。在人類細胞中，一種胞苷脫氨酶被稱為「活化誘導的胞苷脫氨酶」驅動Ｊ對產生新抗體至關重要的體細胞突變。 APOBEC3 蛋白對反轉錄病毒至關重要，在細小病毒、B型肝炎和皰疹病毒等 DNA 病毒的單鏈 DNA 調控中發揮重要作用。儘管了解是什麼驅動了突變變化是有幫助的，但了解基因改變如何促進人與人之間的傳播同樣重要。透過了解變化如何改變功能，這可能有助於預測現有醫療對策的潛在問題，並將促進新抗病毒工具的生產。了解哪些分子功能不同將使我們能夠針對這些分子採取適當的對策。檢測已知會改變發病機制的猴痘蛋白功能的變化將使我們能夠靶向這些分子，以減少疾病和可能的傳播。該小組概述了建議的未來研究，以確定 hMPXV1 的突變變化如何改變人類的病毒發病機制。這些研究可以為有助於阻止猴痘在人類中傳播的工具提供極好的線索。
小組討論：建議未來的研究以確定 hMPXV1 的突變變化是如何在人類宿主中提供優勢
改進進入人體細胞（速度、質量和進入機制的多樣性）
改進病毒複製
• 增強使用宿主的機制進行病毒複製（例如，更兼容地使用密碼子，更好地利用宿主細胞的能量，例如使用脂質）
• 避免宿主細胞內的分解代謝機制之增強
• 改變對 pH、溫度或離子濃度等微環境變化的耐受性
改善胞吐作用
• 增強用於從細胞中退出的包裝
• 細胞裂解與形成的成熟病毒粒子的最佳釋放上更好地協調
• 成熟病毒粒子的比例發生變化，這些病毒粒子變成包裹的病毒粒子，然後作為包膜病毒粒子退出
•釋放能重組細胞骨架元素及其功能的分子
改進逃避先天性防禦機制
• 細胞或可溶性模式識別受體的抑製劑，或改變模式識別受體或其功能的誘餌分子
• 釋放能改變從顆粒中釋放物質功能的分子，例如趨化因子、激肽或類花生酸
改善對適應性防禦機制的規避
• 誘餌分子
• 改變的病毒分子規避現有的 B 細胞受體或抗體和 T 細胞受體
• 改變細胞因子和趨化因子功能的分子
提高在宿主外的穩定性
• 減少 DNA 衰變的因素（例如，增加對 pH、濕度或溫度變化的耐受性）
聲明沒有競爭利益。版權所有 © 2022 作者。由 Elsevier Ltd. 出版。這是 CC BY-NC-ND 4.0 許可下的開放獲取文章。 Aileen M Marty amarty@fiu.edu，美國佛羅里達州邁阿密佛羅里達國際大學內科
Why is there expanding community transmission of monkeypox in 2022?
資料來源：www.thelancet.com/microbe. August 5, 2022 https://doi.org/10.1016/S2666-247(22)00200-2
In The Lancet Microbe, Akaninyene Otu and colleagues1 called for urgent public health action for the 2022 monkeypox outbreak, noting that cases outside of Africa since May 7, 2022, have exceeded the overall number of cases detected outside of endemic areas from 1970 to the current outbreak. The newest rate of human infections is even more alarming when we consider that cases in the last 2 months vastly exceeded the number of confirmed or suspected human monkeypox cases in the entire 20th century. Sequencing by Isidro and colleagues revealed that the circulating monkeypox virus descended from a clade sampled in cases in Nigeria, Singapore, Israel, and the UK between 2017 and 2019. Happi and colleagues described a new clade system and gave the circulating virus the provisional name human monkeypox virus 1 (hMPXV1). Furthermore, Nextstrain’s molecular clock analysis of hMPXV1 shows extensive diversity in the descendant lineages A.1, A.2, A.1.1, and B.1. O’Toole and Rambaut observed that a cytidine deaminase called apolipoprotein B editing complex (APOBEC3) could be driving the recent rapid evolution of hMPXV1. Cytidine deaminases alter DNA, leading to double-stranded breaks at switch regions. In human cells, a cytidine deaminase known as activation induced cytidine deaminase drives somatic mutations crucial for producing new antibodies. APOBEC3 proteins are essential for retroviruses and play important roles in single strand DNA regulation of DNA viruses such as parvovirus, hepatitis B, and herpes viruses. Although it is helpful to know what is driving the mutational changes, it is equally crucial to understand how genetic alterations are facilitating human-to-human transmission. By understanding how changes alter functions, this might help predict potential problems with existing medical countermeasures and will facilitate the production of new antiviral tools. Knowing which molecules function differently will allow us to target those molecules with appropriate countermeasures. Detecting changes in the function of monkeypox proteins known to alter pathogenesis would allow us to target those molecules to decrease disease and possibly transmission. The panel provides an overview of suggested future studies to identify how mutational changes in hMPXV1 could alter viral pathogenesis in humans. These studies could provide excellent clues for tools that can help halt the spread of monkeypox in humans.
Panel: Suggested future studies to establish how mutational changes in hMPXV1 might provide an advantage in a human host
Improved entry into human cells (speed, quality, and variety of entry mechanisms)
Improved viral replication
• Enhanced use of host machinery for viral replication (eg, more compatible use of codons, better use of energy from host cells such as the use of lipids)
• Enhanced avoidance of catabolic mechanisms within the host cell
• Altered tolerance to microenvironmental changes in pH, temperature, or ion concentrations
Improved exocytosis
• Enhanced packaging for exit from cells
• Cell lysis better coordinated with the optimal release of formed mature virions
• Alteration in proportions of mature virions that become wrapped virions and then exit as enveloped virions
• Release of molecules that reorganise cytoskeletal elements and their functions
Improved evasion of innate defences mechanisms
• Inhibitors of cellular or soluble pattern recognition receptors, or decoy molecules that alter pattern recognition receptors or their functions
• Release of molecules that alter the functions of substances released from granules such as chemokines, kinins, or eicosanoids
Improved evasion of adaptive defence mechanisms
• Decoy molecules
• Altered viral molecules that evade existing B-cell receptors or antibodies and T-cell receptors
• Molecules that alter the function of cytokines and chemokines
Improved stability outside of a host
• Factors that reduce decay of DNA (eg, increased tolerance to changes in pH, humidity, or temperature
I declare no competing interests. Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Aileen M Marty amarty@fiu.edu Division of Internal Medicine, Florida International University, Miami, FL 33199, USA