PNNL

Abstract

Understanding viral pathogenesis is challenging due to confounding factors, including nonabrasive access to infected tissues and high abundance of inflammatory mediators that may mask mechanistic details. In diseases such as influenza and smallpox, where the primary cause of mortality results from complications in the lung, the characterization of lung fluid offers a unique opportunity to study host-pathogen interactions with minimal affect on infected animals. This investigation characterizes the global proteome response in the pulmonary fluid, broncheoalveolar lavage fluid (BALF), of macaques during upper respiratory infection by Monkeypox virus (MPXV), a close relative of the causative agent of smallpox, Variola virus. These results are compared and contrasted against Vaccinia virus (VV) infections, a low pathogenic relative of MPXV, and with extracellular fluid from MPXV-infected HeLa cells. To identify changes in the pulmonary protein compartment, macaque lung fluid was sampled twice prior to infection, serving as baseline, and up to 6 times following intrabronchial infection with either MPXV or VV. Increased expression of inflammatory proteins was observed in response to both viruses. While the increased expression resolved for a subset of proteins, such as C-reactive protein, S100A8, and S100A9, high expression levels persisted for other proteins, including Vitamin-D-binding protein and fibrinogen gamma. Structural and metabolic proteins were substantially decreased in lung fluid exclusively during MPXV, and not VV infection. Decreases in structural and metabolic proteins were similarly observed in the extracellular fluid of MPXV-infected HeLa cells. Results from this study suggest the host inflammatory response may not be the only facilitator of viral pathogenesis, but rather maintaining pulmonary structural integrity could be a key factor influencing disease progression and mortality.