Transcriptomic characterization provides insights into Hantavirus Cardiopulmonary Syndrome (HCPS) severity

Abstract

Hantaviruses are important human pathogens that cause a severe zoonotic disease called hantavirus cardiopulmonary syndrome (HCPS), presenting a case fatality rate up to 40%. Clinical course of HCPS may present as a mild condition with moderate respiratory failure or progress rapidly to a severe condition with cardiopulmonary shock that can be fatal. However, the role of the host's responses in this progression towards HCPS and their association with severity remains elusive. In this study, a transcriptome approach combined with clinical laboratory data was applied to gain a better insight into factors associated with HCPS severity. For this, total RNA was extracted from peripheral blood mononuclear (PBMCs) isolated from hantavirus infected patients in acute and convalescent phases. Healthy subjects were used as control. Severe patients are defined as those who develop cardiopulmonary shock and need to receive vasoactive drugs and mechanical ventilation as a treatment and in the most severe cases, they also receive extracorporeal membrane oxygenation (ECMO). Mild clinical course is defined as a disease characterized only by prodromal symptoms or who progress to a minor cardiorespiratory failure that does not require mechanical ventilation and remains hemodynamically stable. Samples from 18 patients (12 severe and 6 mild) and 9 healthy controls were sequenced and analyzed. Differential expression was evaluated by comparing the patient samples grouped by severity in acute and convalescent phase versus the healthy controls. Our results showed that proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and serum levels are increased and could contribute to proinflammatory response in severe HCPS patients. PCSK9 has two FDA approved inhibitors and could be a potential therapeutic target for HCPS. Also showed that hantaviruses can become insensitive to type I IFN response, which contributes to a more severe HCPS outcome