NK cells and monocytes modulate primary HTLV-1 infection.
NK cells and monocytes modulate primary HTLV-1 infection.
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DOI：
10.1371/journal.ppat.1010416
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发表时间：
2022-04
期刊：
影响因子：
6.7
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中科院分区：
文献类型：
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我们研究了单核细胞、NK细胞和CD 8 + T细胞在原发性HTLV-1感染中的影响，方法是耗尽细胞亚群，并将猕猴暴露于HTLV-1野生型（HTLV-1 WT）或HTLV-1 p12 KO突变体（由于orf-I中的单点突变抑制其表达而无法感染完全动物）。orf-I编码的p8/p12蛋白抵消细胞毒性NK和CD 8 + T细胞，并有利于单核细胞中的病毒DNA持久性。在暴露于HTLV-1 WT的所有动物中，双重NK和CD 8 + T细胞或单独CD 8耗竭加速了血清转化。相比之下，HTLV-1 p12 KO感染性仅在NK细胞也被耗尽时才完全恢复，表明NK细胞在原发感染中的关键作用。单核细胞/巨噬细胞耗竭导致所有暴露于HTLV-1 WT的动物血清转化加速，但病毒抗体滴度较低且不持久。在暴露于HTLV-1 p12 KO的大多数动物中未发生血清转化。在人原代单核细胞或THP-1细胞中比较HTLV-1 WT和HTLV-1 p12 KO的体外实验证明，orf-I表达与原代细胞中炎性小体活化的抑制、病毒感染细胞中CD 47“不要吃我”信号表面表达的增加以及感染细胞的单核细胞吞噬的减少有关。总的来说，我们的数据表明先天性NK细胞在原发性感染中的关键作用，并表明单核细胞在原发性感染中的双重作用。一方面，orf-I表达通过使受感染细胞免于吞噬细胞而增加病毒传播的机会，另一方面可以通过调节炎性小体活化来保护被吞噬的受感染细胞。这些数据还表明，一旦感染建立，orf-1表达的化学计量可能有助于慢性炎症观察HTLV-1感染通过调节单核细胞巨噬细胞。抑制或促进HTLV-1感染的免疫细胞仍然未知，它们的鉴定对于了解病毒发病机制和开发有效的HTLV-1疫苗至关重要。中和抗体在天然HTLV-1感染中产生，但它们的影响可能受到病毒通过病毒突触、细胞导管和生物膜从细胞传播到细胞的能力的阻碍。通过消耗血液中的特定免疫细胞亚群，我们发现NK细胞在早期HTLV-1感染的遏制中起着关键作用。此外，单核细胞/巨噬细胞的瞬时消耗导致早期但不持续的血清转化，这表明单核细胞的早期参与可能是长期生产性感染所必需的。被HTLV-1感染的凋亡T细胞的吞噬可能代表了在宿主中持续存在的病毒策略，因为由orf-I和orf-II编码的病毒蛋白质影响受体和参与细胞增殖的蛋白质的功能。这些结果表明，有效的HTLV-1疫苗还必须引起持久的先天性应答，能够通过吞噬受感染的T细胞迅速清除单核细胞的病毒入侵，以避免建立导致慢性炎症的恶性循环。
We investigated the impact of monocytes, NK cells, and CD8+ T-cells in primary HTLV-1 infection by depleting cell subsets and exposing macaques to either HTLV-1 wild type (HTLV-1WT) or to the HTLV-1p12KO mutant unable to infect replete animals due to a single point mutation in orf-I that inhibits its expression. The orf-I encoded p8/p12 proteins counteract cytotoxic NK and CD8+ T-cells and favor viral DNA persistence in monocytes. Double NK and CD8+ T-cells or CD8 depletion alone accelerated seroconversion in all animals exposed to HTLV-1WT. In contrast, HTLV-1p12KO infectivity was fully restored only when NK cells were also depleted, demonstrating a critical role of NK cells in primary infection. Monocyte/macrophage depletion resulted in accelerated seroconversion in all animals exposed to HTLV-1WT, but antibody titers to the virus were low and not sustained. Seroconversion did not occur in most animals exposed to HTLV-1p12KO. In vitro experiments in human primary monocytes or THP-1 cells comparing HTLV-1WT and HTLV-1p12KO demonstrated that orf-I expression is associated with inhibition of inflammasome activation in primary cells, with increased CD47 “don’t-eat-me” signal surface expression in virus infected cells and decreased monocyte engulfment of infected cells. Collectively, our data demonstrate a critical role for innate NK cells in primary infection and suggest a dual role of monocytes in primary infection. On one hand, orf-I expression increases the chances of viral transmission by sparing infected cells from efferocytosis, and on the other may protect the engulfed infected cells by modulating inflammasome activation. These data also suggest that, once infection is established, the stoichiometry of orf-I expression may contribute to the chronic inflammation observed in HTLV-1 infection by modulating monocyte efferocytosis. The immune cells that inhibit or favor HTLV-1 infection are still unknown and their identification is critical for understanding viral pathogenesis and for the development of an effective HTLV-1 vaccine. Neutralizing antibodies are produced in natural HTLV-1 infection, but their impact is likely hampered by the virus’s ability to be transmitted from cell to cell via the virological synapse, cellular conduits, and biofilms. By depleting specific immune cell subsets in blood, we found that NK cells play a critical role in the containment of early HTLV-1 infection. Moreover, transient depletion of monocytes/macrophages results in early, but not sustained seroconversion, suggesting that early engagement of monocytes may be necessary for long-term productive infection. The engulfment of apoptotic T-cells infected by HTLV-1 may represent a viral strategy to persist in the host since the viral proteins encoded by orf-I and orf-II affect the function of receptors and proteins involved in efferocytosis. These results suggest that effective HTLV-1 vaccines must also elicit durable innate responses able to promptly clear virus invasion of monocytes through engulfment of infected T-cells to avoid the establishment of a vicious cycle that leads to chronic inflammation.
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DOI：
10.3390/v3091532
发表时间：
2011-09
期刊：
Viruses
影响因子：
--
作者：
Araya N;Sato T;Yagishita N;Ando H;Utsunomiya A;Jacobson S;Yamano Y
通讯作者：
Yamano Y
影响因子：
14.5
作者：
Bangham CR;Cook LB;Melamed A
通讯作者：
Melamed A
影响因子：
20.3
作者：
Fukumoto, Risaku;Andresen, Vibeke;Franchini, Genoveffa
通讯作者：
Franchini, Genoveffa
影响因子：
20.3
作者：
Enose-Akahata, Yoshimi;Oh, Unsong;Jacobson, Steven
通讯作者：
Jacobson, Steven
影响因子：
5.4
作者：
Albrecht, B;D'Souza, CD;Lairmore, MD
通讯作者：
Lairmore, MD