Browsing by Author "Kidane, Yared H."
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- Computational approaches for discovery of common immunomodulators in fungal infections: towards broad-spectrum immunotherapeutic interventionsKidane, Yared H.; Lawrence, Christopher B.; Murali, T. M. (2013-10-07)Background Fungi are the second most abundant type of human pathogens. Invasive fungal pathogens are leading causes of life-threatening infections in clinical settings. Toxicity to the host and drug-resistance are two major deleterious issues associated with existing antifungal agents. Increasing a host’s tolerance and/or immunity to fungal pathogens has potential to alleviate these problems. A host’s tolerance may be improved by modulating the immune system such that it responds more rapidly and robustly in all facets, ranging from the recognition of pathogens to their clearance from the host. An understanding of biological processes and genes that are perturbed during attempted fungal exposure, colonization, and/or invasion will help guide the identification of endogenous immunomodulators and/or small molecules that activate host-immune responses such as specialized adjuvants. Results In this study, we present computational techniques and approaches using publicly available transcriptional data sets, to predict immunomodulators that may act against multiple fungal pathogens. Our study analyzed data sets derived from host cells exposed to five fungal pathogens, namely, Alternaria alternata, Aspergillus fumigatus, Candida albicans, Pneumocystis jirovecii, and Stachybotrys chartarum. We observed statistically significant associations between host responses to A. fumigatus and C. albicans. Our analysis identified biological processes that were consistently perturbed by these two pathogens. These processes contained both immune response-inducing genes such as MALT1, SERPINE1, ICAM1, and IL8, and immune response-repressing genes such as DUSP8, DUSP6, and SPRED2. We hypothesize that these genes belong to a pool of common immunomodulators that can potentially be activated or suppressed (agonized or antagonized) in order to render the host more tolerant to infections caused by A. fumigatus and C. albicans. Conclusions Our computational approaches and methodologies described here can now be applied to newly generated or expanded data sets for further elucidation of additional drug targets. Moreover, identified immunomodulators may be used to generate experimentally testable hypotheses that could help in the discovery of broad-spectrum immunotherapeutic interventions. All of our results are available at the following supplementary website: http://bioinformatics.cs.vt.edu/~murali/supplements/2013-kidane-bmc
- The Landscape of Host Transcriptional Response Programs Commonly Perturbed by Bacterial Pathogens:Towards Host-Oriented Broad-Spectrum Drug TargetsKidane, Yared H.; Lawrence, Christopher B.; Murali, T. M. (Public Library of Science, 2013-03-13)Background: The emergence of drug-resistant pathogen strains and new infectious agents pose major challenges to public health. A promising approach to combat these problems is to target the host’s genes or proteins, especially to discover targets that are effective against multiple pathogens, i.e., host-oriented broad-spectrum (HOBS) drug targets. An important first step in the discovery of such drug targets is the identification of host responses that are commonly perturbed by multiple pathogens. Results: In this paper, we present a methodology to identify common host responses elicited by multiple pathogens. First, we identified host responses perturbed by each pathogen using a gene set enrichment analysis of publicly available genome-wide transcriptional datasets. Then, we used biclustering to identify groups of host pathways and biological processes that were perturbed only by a subset of the analyzed pathogens. Finally, we tested the enrichment of each bicluster in human genes that are known drug targets, on the basis of which we elicited putative HOBS targets for specific groups of bacterial pathogens. We identified 84 up-regulated and three down-regulated statistically significant biclusters. Each bicluster contained a group of pathogens that commonly dysregulated a group of biological processes. We validated our approach by checking whether these biclusters correspond to known hallmarks of bacterial infection. Indeed, these biclusters contained biological process such as inflammation, activation of dendritic cells, pro- and anti- apoptotic responses and other innate immune responses. Next, we identified biclusters containing pathogens that infected the same tissue. After a literature-based analysis of the drug targets contained in these biclusters, we suggested new uses of the drugs Anakinra, Etanercept, and Infliximab for gastrointestinal pathogens Yersinia enterocolitica, Helicobacter pylori kx2 strain, and enterohemorrhagic Escherichia coli and the drug Simvastatin for hematopoietic pathogen Ehrlichia chaffeensis. Conclusions: Using a combination of automated analysis of host-response gene expression data and manual study of the literature, we have been able to suggest host-oriented treatments for specific bacterial infections. The analyses and suggestions made in this study may be utilized to generate concrete hypothesis on which gene sets to probe further in the quest for HOBS drug targets for bacterial infections. All our results are available at the following supplementary website: http://bioinformatics.cs.vt.edu/ murali/supplements/2013-kidane-plos-one
- The Landscape of Host Transcriptional Response Programs Commonly Perturbed by Infectious Pathogens: Towards Host-Oriented Broad-Spectrum DrugKidane, Yared H. (Virginia Tech, 2012-03-27)The threat from infectious diseases dates as far back as prehistoric times. Pathogens continue to pose serious challenges to human health. The emergence and spread of diseases such as HIV/AIDS, Severe Acute Respiratory Syndrome (SARS), avian influenza, and the threats of bioterrorism have made infectious diseases major public health concerns. Despite many successes in the discovery of anti-infective medications, the treatment of infectious diseases faces serious challenges, which include (i) the emergence and reemergence of infectious pathogens, (ii) the ability of pathogens to adapt and develop resistance to drugs, and (ii) a shortage in the development and discovery of new anti-infective drugs. Host-Oriented Broad-Spectrum (HOBS) treatments have the promising potential to alleviate these problems. The HOBS treatment paradigm focuses on finding drug targets in human host that are simultaneously effective against a wide variety of infectious agents and toxins. In this dissertation, we present a computational approach to predict HOBS treatments by integrative analysis of three types of data, namely, (a) gene expression data representing host responses upon infection by a pathogen, (b) annotations of genes to pre-defined biological pathways and processes, and (iii) genes that are targets of known drugs. Our methods combine gene set-level enrichment with biclustering. We applied our approach to a compendium of gene expression data sets derived from host cells exposed to bacterial or to fungal pathogens, to functional annotation data from multiple databases, and to drug targets from DrugBank. We present putative host drug targets and drugs with extensive support in the literature for their potential to treat multiple bacterial and fungal infections. These results showcase the potential of our computational approach to predict HOBS drug targets that may be effective against two or more pathogens. Our study takes a clean-slate approach that promises to yield unsuspected or unknown associations between pathogens and biological processes, and thus discern candidate gene/proteins to be further probed as HOBS targets. Furthermore, by focusing on host responses to pathogens as captured by transcriptional data, our proposed approach stimulates host-oriented drug target identification, which has potential to alleviate the problem of drug resistance.
- Modulation of nucleosomal DNA accessibility via charge-altering post-translational modifications in histone coreFenley, Andrew T.; Anandakrishnan, Ramu; Kidane, Yared H.; Onufriev, Alexey V. (2018-03-16)Background Controlled modulation of nucleosomal DNA accessibility via post-translational modifications (PTM) is a critical component to many cellular functions. Charge-altering PTMs in the globular histone core—including acetylation, phosphorylation, crotonylation, propionylation, butyrylation, formylation, and citrullination—can alter the strong electrostatic interactions between the oppositely charged nucleosomal DNA and the histone proteins and thus modulate accessibility of the nucleosomal DNA, affecting processes that depend on access to the genetic information, such as transcription. However, direct experimental investigation of the effects of these PTMs is very difficult. Theoretical models can rationalize existing observations, suggest working hypotheses for future experiments, and provide a unifying framework for connecting PTMs with the observed effects. Results A physics-based framework is proposed that predicts the effect of charge-altering PTMs in the histone core, quantitatively for several types of lysine charge-neutralizing PTMs including acetylation, and qualitatively for all phosphorylations, on the nucleosome stability and subsequent changes in DNA accessibility, making a connection to resulting biological phenotypes. The framework takes into account multiple partially assembled states of the nucleosome at the atomic resolution. The framework is validated against experimentally known nucleosome stability changes due to the acetylation of specific lysines, and their effect on transcription. The predicted effect of charge-altering PTMs on DNA accessibility can vary dramatically, from virtually none to a strong, region-dependent increase in accessibility of the nucleosomal DNA; in some cases, e.g., H4K44, H2AK75, and H2BK57, the effect is significantly stronger than that of the extensively studied acetylation sites such H3K56, H3K115 or H3K122. Proximity to the DNA is suggestive of the strength of the PTM effect, but there are many exceptions. For the vast majority of charge-altering PTMs, the predicted increase in the DNA accessibility should be large enough to result in a measurable modulation of transcription. However, a few possible PTMs, such as acetylation of H4K77, counterintuitively decrease the DNA accessibility, suggestive of the repressed chromatin. A structural explanation for the phenomenon is provided. For the majority of charge-altering PTMs, the effect on DNA accessibility is simply additive (noncooperative), but there are exceptions, e.g., simultaneous acetylation of H4K79 and H3K122, where the combined effect is amplified. The amplification is a direct consequence of the nucleosome–DNA complex having more than two structural states. The effect of individual PTMs is classified based on changes in the accessibility of various regions throughout the nucleosomal DNA. The PTM’s resulting imprint on the DNA accessibility, “PTMprint,” is used to predict effects of many yet unexplored PTMs. For example, acetylation of H4K44 yields a PTMprint similar to the PTMprint of H3K56, and thus acetylation of H4K44 is predicted to lead to a wide range of strong biological effects. Conclusion Charge-altering post-translational modifications in the relatively unexplored globular histone core may provide a precision mechanism for controlling accessibility to the nucleosomal DNA.