A Molecular Interaction Map of Klebsiella pneumoniae and Its Human Host Reveals Potential Mechanisms of Host Cell Subversion

Abstract

Klebsiella pneumoniae is a leading cause of pneumonia and septicemia across the world. The rapid emergence of multidrug-resistant K. pneumoniae strains necessitates the discovery of effective drugs against this notorious pathogen. However, there is a dearth of knowledge on the mechanisms by which this deadly pathogen subverts host cellular machinery. To fill this knowledge gap, our study attempts to identify the potential mechanisms of host cell subversion by building a K. pneumoniae–human interactome based on rigorous computational methodology. The putative host targets inferred from the predicted interactome were found to be functionally enriched in the host’s immune surveillance system and allied functions like apoptosis, hypoxia, etc. A multifunctionality-based scoring system revealed P53 as the most multifunctional protein among host targets accompanied by HIF1A and STAT1. Moreover, mining of host protein–protein interaction (PPI) network revealed that host targets interact among themselves to form a network (TTPPI), where P53 and CDC5L occupy a central position. The TTPPI is composed of several inter complex interactions which indicate that K. pneumoniae might disrupt functional coordination between these protein complexes through targeting of P53 and CDC5L. Furthermore, we identified four pivotal K. pneumoniae-targeted transcription factors (TTFs) that are part of TTPPI and are involved in generating host’s transcriptional response to K. pneumoniae-mediated sepsis. In a nutshell, our study identifies some of the pivotal molecular targets of K. pneumoniae which primarily correlate to the physiological response of host during K. pneumoniae-mediated sepsis.

Genome-Wide RNAi Screening Identifies Novel Pathways/Genes Involved in Oxidative Stress and Repurposable Drugs to Preserve Cystic Fibrosis Airway Epithelial Cell Integrity

“…In fact, CDC5L is a cell cycle regulatory element involved in the catalytic steps of mRNA splicing and DNA damage repair [ 44 ]. A recent study has shown that a bacterial stressor, the deadly pathogen Klebsiella pneumoniae , subverts host cellular machinery by targeting p53 and CDC5L as pivotal molecular targets with a profound role in disease pathogenesis [ 64 ]. Moreover, CDC5L has been postulated as a reliable biomarker in COPD, a major predisposing factor of which is oxidative stress [ 65 ].…”

Interactions and Implications of Klebsiella pneumoniae with Human Immune Responses and Metabolic Pathways: A Comprehensive Review

“… 38 This interplay bears significant implications for both the host’s immune response dynamics and the pathogen’s viability within the host environment. 39 However, The specific mechanisms underlying this interaction, particularly its impact on the overall outcome of K. pneumoniae infections, warrant further comprehensive investigation.…”

Decoding the host–pathogen interspecies molecular crosstalk during oral candidiasis in humans: an in silico analysis

“…Thus, to predict through the best possible way, we chose HPIDB 3.0 (Ammari et al, 2016) that aids the annotation, prediction, and visualization of host-pathogen interactions (HPIs) by retrieving all experimentally established pathogen-host PPI data (Ammari et al, 2016). Moreover, this technique was widely used in various research articles to envision the host-pathogen interaction, e.g., Leptospira interrogans and Homo sapiens (Kumar et al, 2019), Burkholderia pseudomallei and Homo sapiens (Loaiza et al, 2020), and Klebsiella pneumoniae and Homo sapiens (Saha and Kundu, 2021). We initially entered the sequences of C. albicans in FASTA format in the HPIDB 3.0.…”

“…Other combinations provided either profuse or trivial interactions which were not suitable for our downstream analysis. Furthermore, we noticed that these screening criteria had also been utilized as the best reciprocal blast hit criteria for deducing human-Klebsiella pneumoniae interaction (Saha and Kundu, 2021). Subsequently, considering these stringent criteria, we retrieved 822 interactions, consisting of 412 C. albicans and 353 human nodes.…”