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Genetic Analysis, Pathogenic Process Deciphering, Drug Development in Parasitic Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 51270

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Dr. Christophe Chevillard

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TAGC/INSERM U1090, Aix Marseille Université AMU, Parc Scientifique de Luminy Case 928, 163 Avenue de Luminy, CEDEX 09, 13288 Marseille, France
Interests: cardiac & cardiovascular systems; parasitology; genomics; schistosomiasis; human susceptibility to infection
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Special Issue Information

Dear Colleagues,

Infectious diseases still affect the health of many people today. The morbidity and mortality rates associated with these diseases are considerable. However, it is now recognized that these infections particularly affect some individuals while sparing others. Significant progresses have been made in recent years for each of these diseases. These important changes essentially concern:

Patient management (new methods for diagnosis based on molecular biology tests);
Genetic analysis (case controls studies, whole genome analysis, linkage analysis exome sequencing, variant enrichment analysis);
Identification of susceptible loci, which is an important step in the knowledge of these diseases but is essential to characterize the functional impact of these variants with methods such as those linked to crispr/cas9 technology;
Deciphering the pathogenic processes (single -omic and multiple -omic approaches and high-throughput sequencing strategies). Indeed, -omic approaches provide a full set of data which are useful in exploring the pathogenic process. However, the analysis of an -omic approach does not provide a complete overview of biological systems. Recently, many tools have been developed to study all these -omics together. The data from the different -omics will be grouped into groups of data with similar behavior, and then an auto-encoder will be used to keep only the groups that allow phenotype prediction of the individuals;
Identification and characterization of biomarkers that can be used for diagnosis as well as prognosis tests (biomarker set development based on OMIC results, machine learning etc.);
Development of new drugs, exhaustive studies on the efficacy of old and/or new drugs or drug cocktails.

The submission of original research articles or up-to-date review articles, and commentaries related to these (non-exhaustive) topics is encouraged.

Dr. Christophe Chevillard
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

American or African trypanosomiasis
-omic
multi-omic
pathogenic process
biomarkers
drugs

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Published Papers (9 papers)

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Research

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21 pages, 5081 KiB

Open AccessArticle

Early Transcriptional Liver Signatures in Experimental Visceral Leishmaniasis

by Génesis Palacios, Raquel Diaz-Solano, Basilio Valladares, Roberto Dorta-Guerra and Emma Carmelo

Int. J. Mol. Sci. 2021, 22(13), 7161; https://doi.org/10.3390/ijms22137161 - 2 Jul 2021

Cited by 4 | Viewed by 2892

Abstract

Transcriptional analysis of complex biological scenarios has been used extensively, even though sometimes the results of such analysis may prove imprecise or difficult to interpret due to an overwhelming amount of information. In this study, a large-scale real-time qPCR experiment was coupled to multivariate statistical analysis in order to describe the main immunological events underlying the early L. infantum infection in livers of BALB/c mice. High-throughput qPCR was used to evaluate the expression of 223 genes related to immunological response and metabolism 1, 3, 5, and 10 days post infection. This integrative analysis showed strikingly different gene signatures at 1 and 10 days post infection, revealing the progression of infection in the experimental model based on the upregulation of particular immunological response patterns and mediators. The gene signature 1 day post infection was not only characterized by the upregulation of mediators involved in interferon signaling and cell chemotaxis, but also the upregulation of some inhibitory markers. In contrast, at 10 days post infection, the upregulation of many inflammatory and Th1 markers characterized a more defined gene signature with the upregulation of mediators in the IL-12 signaling pathway. Our results reveal a significant connection between the expression of innate immune response and metabolic and inhibitory markers in early L. infantum infection of the liver. Full article

(This article belongs to the Special Issue Genetic Analysis, Pathogenic Process Deciphering, Drug Development in Parasitic Diseases)

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28 pages, 5145 KiB

Open AccessArticle

Genetic Predisposition to the Mortality in Septic Shock Patients: From GWAS to the Identification of a Regulatory Variant Modulating the Activity of a CISH Enhancer

by Florian Rosier, Audrey Brisebarre, Claire Dupuis, Sabrina Baaklini, Denis Puthier, Christine Brun, Lydie C. Pradel, Pascal Rihet and Didier Payen

Int. J. Mol. Sci. 2021, 22(11), 5852; https://doi.org/10.3390/ijms22115852 - 29 May 2021

Cited by 14 | Viewed by 4348

Abstract

The high mortality rate in septic shock patients is likely due to environmental and genetic factors, which influence the host response to infection. Two genome-wide association studies (GWAS) on 832 septic shock patients were performed. We used integrative bioinformatic approaches to annotate and prioritize the sepsis-associated single nucleotide polymorphisms (SNPs). An association of 139 SNPs with death based on a false discovery rate of 5% was detected. The most significant SNPs were within the CISH gene involved in cytokine regulation. Among the 139 SNPs associated with death and the 1311 SNPs in strong linkage disequilibrium with them, we investigated 1439 SNPs within non-coding regions to identify regulatory variants. The highest integrative weighted score (IW-score) was obtained for rs143356980, indicating that this SNP is a robust regulatory candidate. The rs143356980 region is located in a non-coding region close to the CISH gene. A CRISPR-Cas9-mediated deletion of this region and specific luciferase assays in K562 cells showed that rs143356980 modulates the enhancer activity in K562 cells. These analyses allowed us to identify several genes associated with death in patients with septic shock. They suggest that genetic variations in key genes, such as CISH, perturb relevant pathways, increasing the risk of death in sepsis patients. Full article

(This article belongs to the Special Issue Genetic Analysis, Pathogenic Process Deciphering, Drug Development in Parasitic Diseases)

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13 pages, 2447 KiB

Open AccessArticle

Pharmacogenomic Profile and Adverse Drug Reactions in a Prospective Therapeutic Cohort of Chagas Disease Patients Treated with Benznidazole

by Lucas A. M. Franco, Carlos H. V. Moreira, Lewis F. Buss, Lea C. Oliveira, Roberta C. R. Martins, Erika R. Manuli, José A. L. Lindoso, Michael P. Busch, Alexandre C. Pereira and Ester C. Sabino

Int. J. Mol. Sci. 2021, 22(4), 1960; https://doi.org/10.3390/ijms22041960 - 16 Feb 2021

Cited by 5 | Viewed by 2198

Abstract

Chagas disease remains a major social and public health problem in Latin America. Benznidazole (BZN) is the main drug with activity against Trypanosoma cruzi. Due to the high number of adverse drug reactions (ADRs), BZN is underprescribed. The goal of this study was to evaluate the genetic and transcriptional basis of BZN adverse reactions. Methods: A prospective cohort with 102 Chagas disease patients who underwent BZN treatment was established to identify ADRs and understand their genetic basis. The patients were classified into two groups: those with at least one ADR (n = 73), and those without ADRs (n = 29). Genomic analyses were performed comparing single nucleotide polymorphisms between groups. Transcriptome data were obtained comparing groups before and after treatment, and signaling pathways related to the main ADRs were evaluated. Results: A total of 73 subjects (71.5%) experienced ADRs. Dermatological symptoms were most frequent (45.1%). One region of chromosome 16, at the gene LOC102724084 (rs1518601, rs11861761, and rs34091595), was associated with ADRs (p = 5.652 × 10⁻⁸). Transcriptomic data revealed three significantly enriched signaling pathways related to BZN ADRs. Conclusions: These data suggest that part of adverse BZN reactions might be genetically determined and may facilitate patient risk stratification prior to starting BZN treatment. Full article

(This article belongs to the Special Issue Genetic Analysis, Pathogenic Process Deciphering, Drug Development in Parasitic Diseases)

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16 pages, 2878 KiB

Open AccessArticle

Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds

by Nieves Martinez-Peinado, Clara Martori, Nuria Cortes-Serra, Julian Sherman, Ana Rodriguez, Joaquim Gascon, Jordi Alberola, Maria-Jesus Pinazo, Alheli Rodriguez-Cortes and Julio Alonso-Padilla

Int. J. Mol. Sci. 2021, 22(2), 688; https://doi.org/10.3390/ijms22020688 - 12 Jan 2021

Cited by 16 | Viewed by 2924

Abstract

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have variable efficacy and frequent adverse effects, especially during the long regimens required for treating the chronic stage of the disease. T. cruzi modulates the host cell-metabolism to accommodate the cell cytosol into a favorable growth environment and acquire nutrients for its multiplication. In this study we evaluated the specific anti-T. cruzi activity of nine bio-energetic modulator compounds. Notably, we identified that 17-DMAG, which targets the ATP-binding site of heat shock protein 90 (Hsp90), has a very high (sub-micromolar range) selective inhibition of the parasite growth. This inhibitory effect was also highly potent (IC₅₀ = 0.27 μmol L⁻¹) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind T. cruzi Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic T. cruzi infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages. Full article

(This article belongs to the Special Issue Genetic Analysis, Pathogenic Process Deciphering, Drug Development in Parasitic Diseases)

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23 pages, 1081 KiB

Open AccessArticle

Computational Identification of Master Regulators Influencing Trypanotolerance in Cattle

by Abirami Rajavel, Armin Otto Schmitt and Mehmet Gültas

Int. J. Mol. Sci. 2021, 22(2), 562; https://doi.org/10.3390/ijms22020562 - 8 Jan 2021

Cited by 2 | Viewed by 3282

Abstract

African Animal Trypanosomiasis (AAT) is transmitted by the tsetse fly which carries pathogenic trypanosomes in its saliva, thus causing debilitating infection to livestock health. As the disease advances, a multistage progression process is observed based on the progressive clinical signs displayed in the host’s body. Investigation of genes expressed with regular monotonic patterns (known as Monotonically Expressed Genes (MEGs)) and of their master regulators can provide important clue for the understanding of the molecular mechanisms underlying the AAT disease. For this purpose, we analysed MEGs for three tissues (liver, spleen and lymph node) of two cattle breeds, namely trypanosusceptible Boran and trypanotolerant N’Dama. Our analysis revealed cattle breed-specific master regulators which are highly related to distinguish the genetic programs in both cattle breeds. Especially the master regulators MYC and DBP found in this study, seem to influence the immune responses strongly, thereby susceptibility and trypanotolerance of Boran and N’Dama respectively. Furthermore, our pathway analysis also bolsters the crucial roles of these master regulators. Taken together, our findings provide novel insights into breed-specific master regulators which orchestrate the regulatory cascades influencing the level of trypanotolerance in cattle breeds and thus could be promising drug targets for future therapeutic interventions. Full article

(This article belongs to the Special Issue Genetic Analysis, Pathogenic Process Deciphering, Drug Development in Parasitic Diseases)

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16 pages, 2229 KiB

Open AccessArticle

Trypanosoma cruzi Modulates PIWI-Interacting RNA Expression in Primary Human Cardiac Myocytes during the Early Phase of Infection

by Kayla J. Rayford, Ayorinde Cooley, Ashutosh Arun, Girish Rachakonda, Yulia Kleschenko, Fernando Villalta, Siddharth Pratap, Maria F. Lima and Pius N. Nde

Int. J. Mol. Sci. 2020, 21(24), 9439; https://doi.org/10.3390/ijms21249439 - 11 Dec 2020

Cited by 9 | Viewed by 2817

Abstract

Trypanosoma cruzi dysregulates the gene expression profile of primary human cardiomyocytes (PHCM) during the early phase of infection through a mechanism which remains to be elucidated. The role that small non-coding RNAs (sncRNA) including PIWI-interacting RNA (piRNA) play in regulating gene expression during the early phase of infection is unknown. To understand how T. cruzi dysregulate gene expression in the heart, we challenged PHCM with T. cruzi trypomastigotes and analyzed sncRNA, especially piRNA, by RNA-sequencing. The parasite induced significant differential expression of host piRNAs, which can target and regulate the genes which are important during the early infection phase. An average of 21,595,866 (88.40%) of clean reads mapped to the human reference genome. The parasite induced 217 unique piRNAs that were significantly differentially expressed (q ≥ 0.8). Of these differentially expressed piRNAs, 6 were known and 211 were novel piRNAs. In silico analysis showed that some of the dysregulated known and novel piRNAs could target and potentially regulate the expression of genes including NFATC2, FOS and TGF-β1, reported to play important roles during T. cruzi infection. Further evaluation of the specific functions of the piRNAs in the regulation of gene expression during the early phase of infection will enhance our understanding of the molecular mechanism of T. cruzi pathogenesis. Our novel findings constitute the first report that T. cruzi can induce differential expression of piRNAs in PHCM, advancing our knowledge about the involvement of piRNAs in an infectious disease model, which can be exploited for biomarker and therapeutic development. Full article

(This article belongs to the Special Issue Genetic Analysis, Pathogenic Process Deciphering, Drug Development in Parasitic Diseases)

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Review

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29 pages, 3196 KiB

Open AccessReview

Mitochondria as a Cellular Hub in Infection and Inflammation

by Pauline Andrieux, Christophe Chevillard, Edecio Cunha-Neto and João Paulo Silva Nunes

Int. J. Mol. Sci. 2021, 22(21), 11338; https://doi.org/10.3390/ijms222111338 - 20 Oct 2021

Cited by 151 | Viewed by 22560

Abstract

Mitochondria are the energy center of the cell. They are found in the cell cytoplasm as dynamic networks where they adapt energy production based on the cell’s needs. They are also at the center of the proinflammatory response and have essential roles in the response against pathogenic infections. Mitochondria are a major site for production of Reactive Oxygen Species (ROS; or free radicals), which are essential to fight infection. However, excessive and uncontrolled production can become deleterious to the cell, leading to mitochondrial and tissue damage. Pathogens exploit the role of mitochondria during infection by affecting the oxidative phosphorylation mechanism (OXPHOS), mitochondrial network and disrupting the communication between the nucleus and the mitochondria. The role of mitochondria in these biological processes makes these organelle good targets for the development of therapeutic strategies. In this review, we presented a summary of the endosymbiotic origin of mitochondria and their involvement in the pathogen response, as well as the potential promising mitochondrial targets for the fight against infectious diseases and chronic inflammatory diseases. Full article

(This article belongs to the Special Issue Genetic Analysis, Pathogenic Process Deciphering, Drug Development in Parasitic Diseases)

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24 pages, 2164 KiB

Open AccessReview

Oxidative Stress as a Possible Target in the Treatment of Toxoplasmosis: Perspectives and Ambiguities

by Karolina Szewczyk-Golec, Marta Pawłowska, Roland Wesołowski, Marcin Wróblewski and Celestyna Mila-Kierzenkowska

Int. J. Mol. Sci. 2021, 22(11), 5705; https://doi.org/10.3390/ijms22115705 - 27 May 2021

Cited by 36 | Viewed by 5215

Abstract

Toxoplasma gondii is an apicomplexan parasite causing toxoplasmosis, a common disease, which is most typically asymptomatic. However, toxoplasmosis can be severe and even fatal in immunocompromised patients and fetuses. Available treatment options are limited, so there is a strong impetus to develop novel therapeutics. This review focuses on the role of oxidative stress in the pathophysiology and treatment of T. gondii infection. Chemical compounds that modify redox status can reduce the parasite viability and thus be potential anti-Toxoplasma drugs. On the other hand, oxidative stress caused by the activation of the inflammatory response may have some deleterious consequences in host cells. In this respect, the potential use of natural antioxidants is worth considering, including melatonin and some vitamins, as possible novel anti-Toxoplasma therapeutics. Results of in vitro and animal studies are promising. However, supplementation with some antioxidants was found to promote the increase in parasitemia, and the disease was then characterized by a milder course. Undoubtedly, research in this area may have a significant impact on the future prospects of toxoplasmosis therapy. Full article

(This article belongs to the Special Issue Genetic Analysis, Pathogenic Process Deciphering, Drug Development in Parasitic Diseases)

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22 pages, 1285 KiB

Open AccessReview

piRNAs as Modulators of Disease Pathogenesis

by Kayla J. Rayford, Ayorinde Cooley, Jelonia T. Rumph, Ashutosh Arun, Girish Rachakonda, Fernando Villalta, Maria F. Lima, Siddharth Pratap, Smita Misra and Pius N. Nde

Int. J. Mol. Sci. 2021, 22(5), 2373; https://doi.org/10.3390/ijms22052373 - 27 Feb 2021

Cited by 34 | Viewed by 4086

Abstract

Advances in understanding disease pathogenesis correlates to modifications in gene expression within different tissues and organ systems. In depth knowledge about the dysregulation of gene expression profiles is fundamental to fully uncover mechanisms in disease development and changes in host homeostasis. The body of knowledge surrounding mammalian regulatory elements, specifically regulators of chromatin structure, transcriptional and translational activation, has considerably surged within the past decade. A set of key regulators whose function still needs to be fully elucidated are small non-coding RNAs (sncRNAs). Due to their broad range of unfolding functions in the regulation of gene expression during transcription and translation, sncRNAs are becoming vital to many cellular processes. Within the past decade, a novel class of sncRNAs called PIWI-interacting RNAs (piRNAs) have been implicated in various diseases, and understanding their complete function is of vital importance. Historically, piRNAs have been shown to be indispensable in germline integrity and stem cell development. Accumulating research evidence continue to reveal the many arms of piRNA function. Although piRNA function and biogenesis has been extensively studied in Drosophila, it is thought that they play similar roles in vertebrate species, including humans. Compounding evidence suggests that piRNAs encompass a wider functional range than small interfering RNAs (siRNAs) and microRNAs (miRNAs), which have been studied more in terms of cellular homeostasis and disease. This review aims to summarize contemporary knowledge regarding biogenesis, and homeostatic function of piRNAs and their emerging roles in the development of pathologies related to cardiomyopathies, cancer, and infectious diseases. Full article

(This article belongs to the Special Issue Genetic Analysis, Pathogenic Process Deciphering, Drug Development in Parasitic Diseases)

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