Abstract
Primary varicella-zoster virus (VZV) infection in adults is often complicated by severe pneumonia, which is difficult to treat and is associated with high morbidity and mortality. Here, the simian varicella virus (SVV) nonhuman primate (NHP) model was used to investigate the pathogenesis of varicella pneumonia. SVV infection resulted in transient fever, viremia, and robust virus replication in alveolar pneumocytes and bronchus-associated lymphoid tissue. Clearance of infectious virus from lungs coincided with robust innate immune responses, leading to recruitment of inflammatory cells, mainly neutrophils and lymphocytes, and finally severe acute lung injury. SVV infection caused neutrophil activation and formation of neutrophil extracellular traps (NETs) in vitro and in vivo. Notably, NETs were also detected in lung and blood specimens of varicella pneumonia patients. Lung pathology in the SVV NHP model was associated with dysregulated expression of alveolar epithelial cell tight junction proteins (claudin-2, claudin-10, and claudin-18) and alveolar endothelial adherens junction protein VE-cadherin. Importantly, factors released by activated neutrophils, including NETs, were sufficient to reduce claudin-18 and VE-cadherin expression in NHP lung slice cultures. Collectively, the data indicate that alveolar barrier disruption in varicella pneumonia is associated with NET formation.
Highlights
Most adults worldwide are infected with the human alphaherpesvirus varicella-zoster virus (VZV) [1]
simian varicella virus (SVV) DNA load in bronchoalveolar lavage (BAL) cells peaked at 4 dpi and declined slowly thereafter (Figure 1D)
Intratracheal SVV infection of cynomolgus macaques leads to a brisk self-limiting virus replication in the lung, which was associated with clinical signs and gross lung pathology that closely resembled VZV-induced pneumonia in humans [11, 12]
Summary
Most adults worldwide are infected with the human alphaherpesvirus varicella-zoster virus (VZV) [1]. VZV causes varicella (chickenpox) as a primary infection, establishes a lifelong latent infection in ganglionic neurons, and reactivates in one-third of latently infected individuals to cause herpes zoster (shingles) [2]. While primary VZV infection is generally benign in children, varicella is more severe and frequently accompanied by complications in adults and immunocompromised individuals [2]. Pneumonia is the most common and serious complication of chickenpox in adults, with an incidence of 1.0 to 2.3 cases per 400 varicella patients [3, 4]. Mild pneumonitis may be even more prevalent as radiographic abnormalities are detected in 16% of adult varicella patients [5]. Prompt administration of antivirals strongly reduces mortality rates, about 20% of patients succumb to the disease due to secondary bacterial infections or acute respiratory distress syndrome (ARDS) [6]
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