Host transcriptional programs underlying lesion development in contagious bovine pleuropneumonia
Contagious bovine pleuropneumonia (CBPP), caused by Mycoplasma mycoides subsp. mycoides (Mmm), remains a major burden to cattle health and the agricultural industry. Mmm is an atypical bacterial pathogen that appears to lack classical virulence factors that cause direct tissue injury (i.e. toxins), and little is known about the mechanisms driving its pathogenicity. The host immune response is believed to be implicated in CBPP pathology, though the molecular mechanisms underlying lesion initiation, progression and chronicity are poorly defined. Classical pathology describes a continuum of lung lesions starting from early inflammation to more mature necrotic lesions and formation of fibrotic sequestra. However, the host transcriptional response driving this potentially immunopathological progression during Mmm infection has never been resolved in vivo. Here, we performed lesion-stage-resolved transcriptomic profiling of pathological lung tissue collected from experimentally infected animals and compared to healthy lung tissue collected from unchallenged controls. Differential gene expression and functional enrichment analyses were used to identify biological pathways relevant to Mmm infection and pathological lesion formation. Early infection was dominated by interferon-stimulated genes and cytokine-responsive pathways, creating a primarily antiviral-like response environment despite the bacterial etiology. Red hepatization showed strong induction of neutrophil chemoattractants, epithelial remodeling markers, and early matrix-remodeling enzymes. Consolidation, spanning red and grey stages, was enriched for innate immune activation, leukocyte adhesion, extracellular matrix organization, and persistent interferon signaling. Grey hepatization reflected late-stage consolidation with heightened neutrophil effector activity, oxidative and proteolytic injury, and macrophage and fibroblast-linked collagen processing. Necrosis/Sequestra lesions showed reduced inflammatory signaling, robust extracellular matrix organization, adhesion, and morphogenetic pathways consistent with encapsulation and sequestrum formation. Our data indicate that the dynamic continuum of CBPP lung pathology is initiated by interferon-primed myeloid recruitment and amplified by neutrophil-driven injury and macrophage- and fibroblast-mediated matrix remodeling. These data further substantiate the role of dysregulated immunity in the development of disease during Mmm infection.