Host response during Yersinia pestis infection of human bronchial epithelial cells involves negative regulation of autophagy and suggests a modulation of survival-related and cellular growth pathways

Abstract

Yersinia pestis (Yp) causes the re-emerging disease plague, and is classified by the CDC and NIAID as a highest priority (Category A) pathogen. Currently, there is no approved human vaccine available and advances in early diagnostics and effective therapeutics are urgently needed. A deep understanding of the mechanisms of host response to Yp infection can significantly advance these three areas. We employed the Reverse Phase Protein Microarray (RPMA) technology to reveal the dynamic states of either protein level changes or phosphorylation changes associated with kinase-driven signaling pathways during host cell response to Yp infection. RPMA allowed quantitative profiling of changes in the intracellular communication network of human lung epithelial cells at different times post infection and in response to different treatment conditions, which included infection with the virulent Yp strain CO92, infection with a derivative avirulent strain CO92 (Pgm-, Pst-), treatment with heat inactivated CO92, and treatment with LPS. Responses to a total of 111 validated antibodies were profiled, leading to discovery of 12 novel protein hits. The RPMA analysis also identified several protein hits previously reported in the context of Yp infection. Furthermore, the results validated several proteins previously reported in the context of infection with other Yersinia species or implicated for potential relevance through recombinant protein and cell transfection studies. The RPMA results point to strong modulation of survival/apoptosis and cell growth pathways during early host response and also suggest a model of negative regulation of the autophagy pathway. We find significant cytoplasmic localization of p53 and reduced LC3-I to LC3-II conversion in response to Yp infection, consistent with negative regulation of autophagy. These studies allow for a deeper understanding of the pathogenesis mechanisms and the discovery of innovative approaches for prevention, early diagnosis, and treatment of plague.

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

“…The present study added a time-resolved perspective to many of those molecular events, such as ubiquitin and microtubule functions that were reported previously in the context of Y . pestis pathogenesis [13, 14, 35, 39, 40]. In fact, our previous publication [4] upheld ubiquitin and microtubule functions as two major networks potentially manipulated by Y .…”

“…Y . pestis was found to block autophagosomes in vitro by altering the functions of AKT, AMPK and p53 signaling [39]. An in vivo study observed a slightly different mechanism, where Y .…”

Human bocavirus induces apoptosis and autophagy in human bronchial epithelial cells

“…Both pathways are associated with tumorigenesis and activated in a number of cancers (19). Yersinia pestis infection of HBECs has been associated with the negative regulation of autophagy via the observed decrease exhibited of p53 cytoplasmic localization and PI3K/AKT activation (31). Furthermore, plumbagin has been demonstrated to induce autophagy via the inhibition of the PI3K/AKT pathway in human non-small cell lung cancer cells (32) In the present study, the activation of p53 was significantly increased; however, AKT protein activation via phosphorylation was significantly decreased in pWHL-1-transfected HBECs when compared with the control and NC groups, indicating that HBoV induced HBEC autophagy predominantly through enhancing p53 activation and blocking AKT activation.…”

A Comprehensive Review of Autophagy and Its Various Roles in Infectious, Non-Infectious, and Lifestyle Diseases: Current Knowledge and Prospects for Disease Prevention, Novel Drug Design, and Therapy

“…Another bacterium, Yersinia pseudotuberculosis , replicates intracellularly inside specific compartments called Yersinia -containing vacuoles (YCVs), which contain autophagy markers; however, YCVs are not acidified and sustain bacterial replication [224]. During Y. pestis infection, LC3-I is conjugated with PE to recruit LC3-II, a marker of autophagy progression, to the phagosomal membrane [225]. A similar mechanism is used by Coxiella burnetii , the causative organism of Q fever.…”