Transcriptomic evidence of cytokine storm and sepsis in little brown bats exposed to white-nose syndrome

Abstract

Much progress has been made in understanding the pathophysiology of white-nose syndrome (WNS), a devastating disease that has impacted North American hibernating bats for nearly two decades. Growth of the causative fungal pathogen, Pseudogymnoascus destructans, on exposed epidermal tissue of bats creates an immune reaction that disrupts natural hibernation physiology and leads to premature expenditure of energy reserves and often death. Past work has highlighted the similarities between WNS and immune reconstitution inflammatory syndrome, but other conditions that have not been considered yet may also be relevant. We performed a transcriptomic analysis of wing tissue from naïve and exposed bats to further investigate the implications of observed differential gene expression patterns. For this analysis, we collected wing biopsy samples from 41 individuals prior to WNS emergence and 58 individuals 2-5 years after WNS emergence. We generated poly-A enriched tag-Seq libraries to compare gene expression between these groups. We then linked our findings and those of past studies to other disease systems to build hypotheses regarding mechanisms of WNS pathophysiology. We found an overrepresentation of functions related to programmed cell death and cytokine activity among upregulated genes. Importantly, we also identified upregulation of three S100 damage-associated molecular patterns (DAMPs) in exposed populations. Taken together, our findings and those of past studies suggest that infected bats experience a feedback loop of cell death among immune cells, the release of DAMPs and the stimulation of cytokine release that may act to maintain pathological immune activity. This feedback loop likely relates to cytokine storms in individuals with severe infection and possibly deteriorates into sepsis over time. Given the pathophysiology of sepsis, multiple organ dysfunction potentially contributes to the physiological disruption associated with WNS.

Keywords: Bats; Pseudogymnoascus destructans; gene expression; immune dysregulation; immune response; inflammation; pathophysiology.

Figure 1

A map of the Eastern United States showing the counties from which samples were collected.

Figure 2

Volcano plot showing the results of the differential expression analysis. The x-axis shows the log 2-fold change of each gene between pre- and post-WNS samples and the y-axis is the -log10(FDR) of each relationship.

Figure 3

PCA biplot showing the first two standardized principal components grouped by WNS status.

Figure 4

Boxplots comparing the normalized read counts of the genes most correlated with the first two principal components between samples collected pre- and post-WNS. The midline represents the median, the hinges show the first and third quartiles and the whiskers extend from the first and third quartiles to 1.5 × the interquartile range.