Habbick Marin R, Bushmaker Trenton, Singh Reema, Sharma Pryanka, Munster Vincent J, van Doremalen Neeltje, Rasmussen Angela L
Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada.
Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK, Canada.
bioRxiv. 2025 Jun 19:2025.06.19.660369. doi: 10.1101/2025.06.19.660369.
Middle East respiratory syndrome coronavirus (MERS-CoV) causes a spectrum of disease outcomes in infected humans, ranging from asymptomatic or tolerant to lethal. While the virus itself contributes to pathogenesis, disease severity is primarily influenced by the host's response to infection. One factor observed to impact the host response is sex, as epidemiological data indicates that male persons have a higher case fatality rate than females infected with MERS-CoV. However, the mechanism underlying this sex bias is unknown and disease course remains difficult to predict. This study investigates how male and female transgenic mice expressing humanized dipeptidyl peptidase-4 (hDPP4) respond to MERS-CoV infection following exposure to either a tolerance-inducing low dose or lethal high dose. We observed that female hDPP4 mice display dose-dependent tolerance to infection and males experienced uniformly lethal disease in both dosing groups. Longitudinal transcriptomic analysis revealed that males suppress innate and inflammatory responses early after infection, causing delayed induction of the host antiviral response. In contrast, high dose females mount an immediate and sustained interferon and inflammatory response, activating antiviral effectors and interferon-stimulated genes. Tolerant females displayed the greatest transcriptional control, showing no pathway enrichment and minimal changes in weight throughout infection. Our results suggest that the magnitude of the response is driven by dose while the nature of the response in shaped by sex. Females mount a more robust response to MERS-CoV infection, allowing females to tolerate low-dose infection but causing uncontrolled inflammation after high dose infection. In contrast, males experienced lethal outcomes regardless of dose. By examining the dynamics of sex-biased host transcriptional responses in determining disease severity, this study highlights the importance of sex as a biological variable in coronavirus pathogenesis research.
中东呼吸综合征冠状病毒（MERS-CoV）在受感染的人类中会导致一系列疾病结果，从无症状或耐受性感染到致命性感染。虽然病毒本身会引发发病机制，但疾病的严重程度主要受宿主对感染的反应影响。观察到影响宿主反应的一个因素是性别，因为流行病学数据表明，感染MERS-CoV的男性病死率高于女性。然而，这种性别差异背后的机制尚不清楚，疾病进程仍然难以预测。本研究调查了表达人源化二肽基肽酶4（hDPP4）的转基因雄性和雌性小鼠在暴露于诱导耐受性的低剂量或致死性高剂量后对MERS-CoV感染的反应。我们观察到，雌性hDPP4小鼠对感染表现出剂量依赖性耐受性，而在两个给药组中雄性均经历了一致的致死性疾病。纵向转录组分析显示，雄性在感染后早期抑制先天性和炎症反应，导致宿主抗病毒反应的诱导延迟。相比之下，高剂量组的雌性会立即产生持续的干扰素和炎症反应，激活抗病毒效应器和干扰素刺激基因。耐受性雌性表现出最大程度的转录控制，在整个感染过程中没有通路富集，体重变化最小。我们的结果表明，反应的强度由剂量驱动，而反应的性质由性别决定。雌性对MERS-CoV感染的反应更强，这使得雌性能够耐受低剂量感染，但在高剂量感染后会导致不受控制的炎症。相比之下，无论剂量如何，雄性都会出现致命结果。通过研究性别偏向的宿主转录反应动态在确定疾病严重程度中的作用，本研究强调了性别作为冠状病毒发病机制研究中的一个生物学变量的重要性。
