The responses of lungs and adjacent lymph nodes in responding to Yersinia pestis infection: A transcriptomic study using a non-human primate model

Abstract

Initiation of treatment during the pre-symptomatic phase of Yersinia pestis ( Y . pestis ) infection is particularly critical. The rapid proliferation of Y . pestis typically couples with the manifestation of common flu-like early symptoms that often misguides the medical intervention. Our study used African green monkeys (AGM) that did not exhibit clear clinical symptoms for nearly two days after intranasal challenge with Y . pestis and succumbed within a day after showing the first signs of clinical symptoms. The lung, and mediastinal and submandibular lymph nodes (LN) accumulated significant Y . pestis colonization immediately after the intranasal challenge. Hence, organ-specific molecular investigations are deemed to be the key to elucidating mechanisms of the initial host response. Our previous study focused on the whole blood of AGM, and we found early perturbations in the ubiquitin-microtubule-mediated host defense. Altered expression of the genes present in ubiquitin and microtubule networks indicated an early suppression of these networks in the submandibular lymph nodes. In concert, the upstream toll-like receptor signaling and downstream NFκB signaling were inhibited at the multi-omics level. The inflammatory response was suppressed in the lungs, submandibular lymph nodes and mediastinal lymph nodes. We posited a causal chain of molecular mechanisms that indicated Y . pestis was probably able to impair host-mediated proteolysis activities and evade autophagosome capture by dysregulating both ubiquitin and microtubule networks in submandibular lymph nodes. Targeting these networks in a submandibular LN-specific and time-resolved fashion could be essential for development of the next generation therapeutics for pneumonic plague.

Gene-metabolite networks associated with impediment of bone fracture repair in spaceflight

“…Extraction of RNA from frozen tissues was carried out following an established protocol [44] . Frozen callus segments (or equivalent femora sections of sham mice) were cryogenically grounded using Cryomill (Retsh GmbH, Germany) and the amorphous materials were divided into two portions; one for transcriptomic and the other for metabolomic assays.…”

“…Dual dye microarray was performed using the SurePrint G3 mouse GE 8 × 60 k microarray kit (Agilent Technologies, Inc., CA, USA) following a well-established protocol [44] , [45] . This whole mouse genome microarray slides contains 41,000 mouse transcripts.…”

Yersinia remodels epigenetic histone modifications in human macrophages

“…The current understanding of how Yersinia modulates gene expression in macrophages is that it uses its effectors YopP and YopM to interfere with PAMP-induced MAP-kinase and NF-kB signaling to the nucleus [29]. Previous microarray or RNA-seq studies of Yersinia effects on gene expression were so far conducted in Y. pestis infected rat lymph nodes [50], African green monkeys [51,52] and neutrophils [53], in Y. pseudotuberculosis infected mouse cecum [54] and Peyer's patches [55] as well as in Y. enterocolitica infected epithelial and NK cells [56,57]. In macrophages systematic gene expression analysis was performed during Y. enterocolitica or Y. pseudotuberculosis infection of cultured mouse macrophages for up to 4 h and utilizing microarrays [30,[58][59][60].…”

“…Previous microarray or RNA-seq studies of Yersinia effects on gene expression were so far conducted in Y . pestis infected rat lymph nodes [ 50 ], African green monkeys [ 51 , 52 ] and neutrophils [ 53 ], in Y . pseudotuberculosis infected mouse cecum [ 54 ] and Peyer’s patches [ 55 ] as well as in Y .…”

Yersinia remodels epigenetic histone modifications in human macrophages

“…The current understanding of how Yersinia modulates gene expression in macrophages is that it uses its effectors YopP and YopM to interfere with PAMP-induced MAP-kinase and NF-kB signaling to the nucleus (Schubert et al, 2020). Previous microarray or RNA-seq studies of Yersinia effects on gene expression were so far conducted in Y. pestis infected rat lymph nodes (Comer et al, 2010), African green monkeys (Chakraborty et al, 2019;Hammamieh et al, 2016) and neutrophils (Subrahmanyam et al, 2001), in Y. pseudotuberculosis infected mouse cecum (Heine et al, 2018) and Peyer's patches (Nuss et al, 2017) as well as in Y. enterocolitica infected epithelial and NK cells (Bohn et al, 2004;Koch et al, 2013). In macrophages systematic gene expression analysis was performed during Y. enterocolitica or Y. pseudotuberculosis infection of cultured mouse macrophages for up to 4 h and utilizing microarrays Hoffmann et al, 2004;Auerbuch et al, 2009;Zhang et al, 2005).…”