Hemagglutinin Cleavability, Acid Stability, and Temperature Dependence Optimize Influenza B Virus for Replication in Human Airways
Hemagglutinin Cleavability, Acid Stability, and Temperature Dependence Optimize Influenza B Virus for Replication in Human Airways
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DOI：
10.1128/jvi.01430-19
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发表时间：
2020-01-01
影响因子：
5.4
通讯作者：
Naesens, Lieve
中科院分区：
文献类型：
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作者：
Laporte, Manon;Stevaert, Annelies;Naesens, Lieve
甲型流感病毒（IAV）和B流感病毒（IBV）每年都会引起流行病，具有显著的发病率和死亡率。当人畜共患IAV进入人群时，病毒血凝素（HA）需要适应以实现持续的病毒传播。相比之下，IBV已经在其唯一宿主人类中传播了很长一段时间。这是否需要IBV HA适应人类气道尚不清楚。为了解决这个问题，我们比较了两种季节性IAV（A/H1N1和A/H3 N2）和两种IBV（B/维多利亚和B/Yamagata谱系）关于HA作为病毒进入期间膜融合的介体的宿主依赖性活性。我们首先通过覆盖所有II型跨膜丝氨酸蛋白酶（TTSP）和激肽释放酶来研究HA的蛋白水解激活，其中许多被证明存在于人呼吸道上皮中。IBV HAO前体被一组更广泛的TTSP切割，并以比IAV HAO高得多的效率活化。因此，敲低单一蛋白酶TMPRSS 2可消除IAV而非IBV在人呼吸道上皮细胞中的传播。第二，HA融合pH值被证明对于IBV和人类适应的IAV是相似的（除了1918 IAV的HA）。第三，IBV HA在33 ℃（B/维多利亚HA的膜融合所需的温度）下表现出更高的表达。这表明IBV HA对人类上呼吸道的温和酸性pH和较冷温度的显著适应。这些独特的和内在的IBV HA的特点是兼容的广泛的宿主适应在此呼吸道病毒在人群中的长期循环。重要性流感流行是由甲型流感和流感B病毒（分别为IAV和IBV）引起的。IBV会导致严重疾病;然而，对它的研究远少于IAV。虽然IAV起源于动物宿主，但IBV仅在人类中传播。病毒传播需要病毒血凝素（HA）在人体气道中具有活性并足够稳定。我们在这里解决这些机制之间的不同IBV和IAV。尽管人类IAV依赖于一种特定的蛋白酶来激活HA，但IBV的情况并非如此。几种蛋白酶对IBV的上级活化作用应能增强感染性颗粒的脱落。IBV HA表现出酸稳定性和对33 ° C的偏好，表明对人上呼吸道的显著适应，其中pH为弱酸性并且存在较冷的温度。IBV在人类中的长期存在使这些适应性特征合理化，并且可能对理解呼吸道病毒的生物学和进化具有更广泛的相关性。
Influenza A virus (IAV) and influenza B virus (IBV) cause yearly epidemics with significant morbidity and mortality. When zoonotic IAVs enter the human population, the viral hemagglutinin (HA) requires adaptation to achieve sustained virus transmission. In contrast, IBV has been circulating in humans, its only host, for a long period of time. Whether this entailed adaptation of IBV HA to the human airways is unknown. To address this question, we compared two seasonal lAVs (A/H1N1 and A/H3N2) and two IBVs (B/Victoria and B/Yamagata lineages) with regard to host-dependent activity of HA as the mediator of membrane fusion during viral entry. We first investigated proteolytic activation of HA by covering all type II transmembrane serine protease (TTSP) and kallikrein enzymes, many of which proved to be present in human respiratory epithelium. The IBV HAO precursor is cleaved by a broader panel of TTSPs and activated with much higher efficiency than IAV HAO. Accordingly, knockdown of a single protease, TMPRSS2, abrogated spread of IAV but not IBV in human respiratory epithelial cells. Second, the HA fusion pH values proved similar for IBV and human-adapted IAVs (with one exception being the HA of 1918 IAV). Third, IBV HA exhibited higher expression at 33 degrees C, a temperature required for membrane fusion by B/Victoria HA. This indicates pronounced adaptation of IBV HA to the mildly acidic pH and cooler temperature of human upper airways. These distinct and intrinsic features of IBV HA are compatible with extensive host adaptation during prolonged circulation of this respiratory virus in the human population.IMPORTANCE Influenza epidemics are caused by influenza A and influenza B viruses (IAV and IBV, respectively). IBV causes substantial disease; however, it is far less studied than IAV. While IAV originates from animal reservoirs, IBV circulates in humans only. Virus spread requires that the viral hemagglutinin (HA) is active and sufficiently stable in human airways. We resolve here how these mechanisms differ between IBV and IAV. Whereas human IAVs rely on one particular protease for HA activation, this is not the case for IBV. Superior activation of IBV by several proteases should enhance shedding of infectious particles. IBV HA exhibits acid stability and a preference for 33 degrees C, indicating pronounced adaptation to the human upper airways, where the pH is mildly acidic and a cooler temperature exists. These adaptive features are rationalized by the long existence of IBV in humans and may have broader relevance for understanding the biology and evolution of respiratory viruses.