Brockhurst Jacqueline K, Salciccioli Brittany E, Griffin Diane E
Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
J Virol. 2025 Apr 15;99(4):e0188024. doi: 10.1128/jvi.01880-24. Epub 2025 Mar 27.
Measles virus (MeV) is an extremely infectious respiratory virus and a major cause of childhood morbidity and mortality worldwide. MeV infection of the respiratory epithelium induces shedding of multinucleate epithelial cells from the apical surface of the epithelium without compromising epithelial barrier integrity. To study the mechanisms driving the apical extrusion of MeV-infected respiratory epithelial cells, we used primary differentiated tracheal epithelial cell cultures (rhTECs) and respiratory samples from rhesus macaques infected with wild-type MeV (WT MeV) or live-attenuated MeV (LAMV). We show that sphingosine-1-phosphate (S1P) signaling, rather than cell death or inflammasome activation, plays a key role in WT MeV and LAMV-induced cell shedding. Inhibiting S1P signaling resulted in delayed shedding of clusters of infected cells and higher viral titers within the epithelium, suggesting that cell extrusion impacts viral dynamics within the respiratory tract. We also found that shedding of individual infected cells began early after apical infection, prior to the formation of infected cell clusters within the epithelium. These findings offer new insights into MeV biology and pathogenesis within the respiratory tract.
Despite the availability of a safe and effective vaccine, measles virus (MeV) still has a significant global impact, and in 2022 alone led to over 136,000 deaths. MeV is one of the most contagious known viruses and spreads via the respiratory route. When respiratory epithelial cells are infected, they are shed into the lumen of the respiratory tract, but this process is poorly understood. Here, we use primary differentiated respiratory epithelial cells from rhesus macaques to show that sphingosine-1-phosphate (S1P) signaling, and not cell death or inflammasome activation, plays a role in cell shedding during both wild-type and live-attenuated MeV infection. Through this mechanism, MeV-infected cells are extruded without disrupting the integrity of the respiratory epithelium. Inhibiting S1P signaling resulted in delayed shedding of infected cells and higher viral titers in the epithelium. These findings indicate that host cellular responses play an important role in MeV infectivity.
麻疹病毒（MeV）是一种极具传染性的呼吸道病毒，是全球儿童发病和死亡的主要原因。呼吸道上皮细胞感染MeV会诱导多核上皮细胞从上皮顶端表面脱落，而不会损害上皮屏障的完整性。为了研究驱动感染MeV的呼吸道上皮细胞顶端挤出的机制，我们使用了原代分化的气管上皮细胞培养物（rhTECs）以及感染野生型MeV（WT MeV）或减毒活MeV（LAMV）的恒河猴的呼吸道样本。我们发现，鞘氨醇-1-磷酸（S1P）信号传导，而非细胞死亡或炎性小体激活，在野生型MeV和减毒活MeV诱导的细胞脱落中起关键作用。抑制S1P信号传导导致受感染细胞簇的脱落延迟，且上皮内病毒滴度更高，这表明细胞挤出会影响呼吸道内的病毒动态。我们还发现，单个受感染细胞的脱落在上皮顶端感染后早期就开始了，早于上皮内受感染细胞簇的形成。这些发现为MeV在呼吸道中的生物学特性和发病机制提供了新的见解。
尽管有安全有效的疫苗，但麻疹病毒（MeV）仍然对全球有重大影响，仅在2022年就导致超过13.6万人死亡。MeV是已知传染性最强的病毒之一，通过呼吸道传播。当呼吸道上皮细胞被感染时，它们会脱落到呼吸道腔内，但这个过程目前还知之甚少。在这里，我们使用来自恒河猴的原代分化呼吸道上皮细胞表明，鞘氨醇-1-磷酸（S1P）信号传导，而非细胞死亡或炎性小体激活，在野生型和减毒活MeV感染期间的细胞脱落中起作用。通过这种机制，感染MeV的细胞被挤出而不会破坏呼吸道上皮的完整性。抑制S1P信号传导导致受感染细胞的脱落延迟，且上皮内病毒滴度更高。这些发现表明宿主细胞反应在MeV感染性中起重要作用。
