Spatially Distinct Neutrophil Responses within the Inflammatory Lesions of Pneumonic Plague

Abstract

During pneumonic plague, the bacterium Yersinia pestis elicits the development of inflammatory lung lesions that continue to expand throughout infection. This lesion development and persistence are poorly understood. Here, we examine spatially distinct regions of lung lesions using laser capture microdissection and transcriptome sequencing (RNA-seq) analysis to identify transcriptional differences between lesion microenvironments. We show that cellular pathways involved in leukocyte migration and apoptosis are downregulated in the center of lung lesions compared to the periphery. Probing for the bacterial factor(s) important for the alteration in neutrophil survival, we show both in vitro and in vivo that Y. pestis increases neutrophil survival in a manner that is dependent on the type III secretion system effector YopM. This research explores the complexity of spatially distinct host-microbe interactions and emphasizes the importance of cell relevance in assays in order to fully understand Y. pestis virulence.

The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome

“…Moreover, YopM is required for the induction of systemic levels of the anti-inflammatory cytokine IL-10 (McPhee et al, 2012, McPhee et al, 2010), possibly through interaction with nuclear helicases and RSKs (Berneking et al, 2016). Lastly, YopM plays a key role in promoting neutrophil survival via processes independent of RSK and caspase-1 catalytic activities (Stasulli et al, 2015). Taken together, these findings indicate that YopM could have multiple functions depending on the infected cell type, host protein interaction, or subcellular localization.…”

The species-spanning family of LPX-motif harbouring effector proteins

“…Through these and probably other yet undetermined mechanisms, the LPX effector YopM contributes significantly to Yersinia virulence. Depending on the strain, the route of infection, and the infected host, a YopM‐mediated depletion of natural killer cells (Kerschen, Cohen, Kaplan, & Straley, ), colonisation of spleen, liver, and lungs (McCoy et al, ; McPhee et al, ), reduced secretion of pro‐inflammatory cytokines (Kerschen et al, ; Rüter, Buss, Scharnert, Heusipp, & Schmidt, ), induction of caspase‐3‐mediated apoptosis (Ye et al, ), or inhibition of apoptosis and migration (Stasulli et al, ) were observed.…”

“…The respective mechanisms are described in detail throughout Sections 1.2-1.3. NEL: novel class of E3 ubiquitin ligase(McCoy et al, 2010;McPhee et al, 2010), reduced secretion of pro-inflammatory cytokines(Kerschen et al, 2004;Rüter, Buss, Scharnert, Heusipp, & Schmidt, 2010), induction of caspase-3-mediated apoptosis(Ye et al, 2014), or inhibition of apoptosis and migration(Stasulli et al, 2015) were observed.1.2 | The Salmonella-derived LPX effectors SspH1, SspH2, and SlrPAs a major cause of foodborne illness throughout the world, Gramnegative, rod-shaped, and motile bacteria of the genus Salmonella include the two species Salmonella bongori and Salmonella enterica.The latter, in particular, is further divided into several subspecies and serovars. The typically orally acquired pathogens can cause disease syndromes such as food poisoning, typhoid fever, gastrointestinal inflammation, and bacteraemia, depending on the serovar and the host.…”

Immunomodulatory Yersinia outer proteins (Yops)–useful tools for bacteria and humans alike

“…Depending on the Yersinia strain, the route of infection, and the examined animal model, YopM-dependent colonization of spleen, liver and lungs, 45,46 depletion of natural killer cells, 47 reduction of pro-inflammatory cytokine secretion (including interleukins 1b, 12, 15, and 18, interferon-g and tumor necrosis factor-a), 13,47 induction of caspase 3-mediated apoptosis, 48 or inhibition of apoptosis and migration were observed. 49 Additionally, YopM was also suggested to induce elevated levels of the anti-inflammatory cytokine interleukin-10. 46 …”