Tissue‐specific expression patterns of tau and ubiquitin proteins coordinated with Yersinia pestis pathogenesis in a non‐human primate model

Abstract

Early identification of molecular markers in conjunction with pathogenic exposure offers a potential means to initiate treatment during a timeframe when it would most be effective. The identification of molecular markers could also allow for novel therapeutic strategies, which become all the more critical as antibiotic resistance continually becomes more widespread. In order to examine pre‐symptomatic illness, African green monkeys were challenged intranasally with aerosolized Yersinia pestis strain CO92. Various tissues and blood samples were collected in short intervals from 6 h till 42 h post‐exposure. Transcriptomic profiles of blood indicated early perturbation as the number of differentially expressed genes increased until 24 h post‐exposure. As suggested by functional analyses, Y. pestis had potentially paralyzed the host defense much earlier than bacteria was detected in the blood. Early activation of the apoptotic networks possibly facilitated the pathogen to overwhelm host defense mechanisms, circumventing the activated pro‐inflammatory response and ubiquitin‐ and microtubule‐mediated defense. Pathogens target the host ubiquitin system in order to manipulate immunity. For instance, Yersinia species have been reported to trigger deubiquitylation by inhibiting NF‐κB activity. Microtubule dynamics are known to be another marked target for early pathogenic intervention. The host‐ubiquitin and host‐microtubule relationships were studied herein for better understanding of Yersinia pathogenicity and how the host succumbs, despite increasing early defense machinery. Lungs and adjacent lymph nodes, such as submandibular and mediastinal lymph nodes, are the port‐of‐entry for the intranasal exposure of Y. pestis. These tissues indicated signs of infection much earlier than the onset of serological infection. The expressions of ubiquitin were probed in these tissues along with the microtubule‐associated tau protein. Longitudinal analysis of tissue‐specific transcriptomic profiles associated with these two protein networks was integrated. Tissue‐specific tau‐ubiquitin protein expression patterns potentially manifested the temporal character of the host defense. For instance, a weak early response to Y. pestis assault was followed by a steady increase of ubiquitin load in the lungs. A completely opposite trend was found in tau expression which showed a gradual reduction with time. An orthogonal pattern was observed in the submandibular lymph node, where ubiquitin decreased and tau increased with time. Integration of these proteomic patterns with the gene‐protein co‐enriched networks indicated potential regulators were mediating the pathogen proliferation and host defense manipulation.The present longitudinal tissue‐specific study can explain the key molecular underpinnings associated with the pathogenesis of pneumonic plague. The significance of this result is underlined by the fact that most of these molecular perturbations occurred at the asymptomatic state, even before blood showed signs of bacterial infection. Hence, potential early markers of Y. pestis pathogenesis could be mined from this analysis.Support or Funding InformationThis work was supported by Defense Threat Reduction Agency, Funding #: TMTI0029_09_WR_T