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1.
Current Strategies for Elimination of HIV-1 Latent Reservoirs Using Chemical Compounds Targeting Host and Viral Factors.
Jean, MJ, Fiches, G, Hayashi, T, Zhu, J
AIDS research and human retroviruses. 2019;(1):1-24
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Abstract
Since the implementation of combination antiretroviral therapy (cART), rates of HIV type 1 (HIV-1) mortality, morbidity, and newly acquired infections have decreased dramatically. In fact, HIV-1-infected individuals under effective suppressive cART approach normal life span and quality of life. However, long-term therapy is required because the virus establish a reversible state of latency in memory CD4+ T cells. Two principle strategies, namely "shock and kill" approach and "block and lock" approach, are currently being investigated for the eradication of these HIV-1 latent reservoirs. Actually, both of these contrasting approaches are based on the use of small-molecule compounds to achieve the cure for HIV-1. In this review, we discuss the recent progress that has been made in designing and developing small-molecule compounds for both strategies.
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Mal de Río Cuarto virus infection causes hormone imbalance and sugar accumulation in wheat leaves.
de Haro, LA, Arellano, SM, Novák, O, Feil, R, Dumón, AD, Mattio, MF, Tarkowská, D, Llauger, G, Strnad, M, Lunn, JE, et al
BMC plant biology. 2019;(1):112
Abstract
BACKGROUND Mal de Río Cuarto virus (MRCV) infects several monocotyledonous species including maize and wheat. Infected plants show shortened internodes, partial sterility, increased tillering and reduced root length. To better understand the molecular basis of the plant-virus interactions leading to these symptoms, we combined RNA sequencing with metabolite and hormone measurements. RESULTS More than 3000 differentially accumulated transcripts (DATs) were detected in MRCV-infected wheat plants at 21 days post inoculation compared to mock-inoculated plants. Infected plants exhibited decreased levels of TaSWEET13 transcripts, which are involved in sucrose phloem loading. Soluble sugars, starch, trehalose 6-phosphate (Tre6P), and organic and amino acids were all higher in MRCV-infected plants. In addition, several transcripts related to plant hormone metabolism, transport and signalling were increased upon MRCV infection. Transcripts coding for GA20ox, D14, MAX2 and SMAX1-like proteins involved in gibberellin biosynthesis and strigolactone signalling, were reduced. Transcripts involved in jasmonic acid, ethylene and brassinosteroid biosynthesis, perception and signalling and in auxin transport were also altered. Hormone measurements showed that jasmonic acid, brassinosteroids, abscisic acid and indole-3-acetic acid were significantly higher in infected leaves. CONCLUSIONS Our results indicate that MRCV causes a profound hormonal imbalance that, together with alterations in sugar partitioning, could account for the symptoms observed in MRCV-infected plants.
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Environmental structure drives resistance to phages and antibiotics during phage therapy and to invading lysogens during colonisation.
Sousa, JAM, Rocha, EPC
Scientific reports. 2019;(1):3149
Abstract
Microbial communities are shaped by bacteriophages through predation and lysogeny. A better understanding of the interactions between these processes across different types of environments is key to elucidate how phages mediate microbial competition and to design efficient phage therapies. We introduce an individual-based model (eVIVALDI) to investigate the role of environmental structure in the elimination of a population with a combined treatment of antibiotics and virulent phages, and in the invasion of a population of phage-sensitive bacteria by lysogens. We show that structured environments facilitate the emergence of double resistance, to antibiotics and phages, due to limited diffusion of phage particles and increased nutrient availability from dead cells. They also hinder phage amplification, thus decreasing the generation of phage genetic diversity and increasing the unpredictability of phage-bacteria arms-races. We used a machine learning approach to determine the variables most important for the invasion of sensitive populations by lysogens. They revealed that phage-associated traits and environmental structure are the key drivers of the process. Structured environments hinder invasions, and accounting for their existence improves the fit of the model to published in vivo experimental data. Our results underline environmental structure as key to understand in vivo phage-bacteria interactions.
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Transposable Elements Adaptive Role in Genome Plasticity, Pathogenicity and Evolution in Fungal Phytopathogens.
Mat Razali, N, Cheah, BH, Nadarajah, K
International journal of molecular sciences. 2019;(14)
Abstract
Transposable elements (TEs) are agents of genetic variability in phytopathogens as they are a source of adaptive evolution through genome diversification. Although many studies have uncovered information on TEs, the exact mechanism behind TE-induced changes within the genome remains poorly understood. Furthermore, convergent trends towards bigger genomes, emergence of novel genes and gain or loss of genes implicate a TE-regulated genome plasticity of fungal phytopathogens. TEs are able to alter gene expression by revamping the cis-regulatory elements or recruiting epigenetic control. Recent findings show that TEs recruit epigenetic control on the expression of effector genes as part of the coordinated infection strategy. In addition to genome plasticity and diversity, fungal pathogenicity is an area of economic concern. A survey of TE distribution suggests that their proximity to pathogenicity genes TEs may act as sites for emergence of novel pathogenicity factors via nucleotide changes and expansion or reduction of the gene family. Through a systematic survey of literature, we were able to conclude that the role of TEs in fungi is wide: ranging from genome plasticity, pathogenicity to adaptive behavior in evolution. This review also identifies the gaps in knowledge that requires further elucidation for a better understanding of TEs' contribution to genome architecture and versatility.
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Determination of an Interaction Network between an Extracellular Bacterial Pathogen and the Human Host.
Griesenauer, B, Tran, TM, Fortney, KR, Janowicz, DM, Johnson, P, Gao, H, Barnes, S, Wilson, LS, Liu, Y, Spinola, SM
mBio. 2019;(3)
Abstract
A major gap in understanding infectious diseases is the lack of information about molecular interaction networks between pathogens and the human host. Haemophilus ducreyi causes the genital ulcer disease chancroid in adults and is a leading cause of cutaneous ulcers in children in the tropics. We developed a model in which human volunteers are infected on the upper arm with H. ducreyi until they develop pustules. To define the H. ducreyi and human interactome, we determined bacterial and host transcriptomic and host metabolomic changes in pustules. We found that in vivoH. ducreyi transcripts were distinct from those in the inocula, as were host transcripts in pustule and wounded control sites. Many of the upregulated H. ducreyi genes were found to be involved in ascorbic acid and anaerobic metabolism and inorganic ion/nutrient transport. The top 20 significantly expressed human pathways showed that all were involved in immune responses. We generated a bipartite network for interactions between host and bacterial gene transcription; multiple positively correlated networks contained H. ducreyi genes involved in anaerobic metabolism and host genes involved with the immune response. Metabolomic studies showed that pustule and wounded samples had different metabolite compositions; the top ion pathway involved ascorbate and aldarate metabolism, which correlated with the H. ducreyi transcriptional response and upregulation of host genes involved in ascorbic acid recycling. These data show that an interactome exists between H. ducreyi and the human host and suggest that H. ducreyi exploits the metabolic niche created by the host immune response.IMPORTANCE Dual RNA sequencing (RNA-seq) offers the promise of determining an interactome at a transcriptional level between a bacterium and the host but has yet to be done on any bacterial infection in human tissue. We performed dual RNA-seq and metabolomics analyses on wounded and infected sites following experimental infection of the arm with H. ducreyi Our results suggest that H. ducreyi survives in an abscess by utilizing l-ascorbate as an alternative carbon source, possibly taking advantage of host ascorbic acid recycling, and that H. ducreyi also adapts by upregulating genes involved in anaerobic metabolism and inorganic ion and nutrient transport. To our knowledge, this is the first description of an interaction network between a bacterium and the human host at a site of infection.
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6.
Modulation of Host Cell Metabolism by Chlamydia trachomatis.
Rother, M, Teixeira da Costa, AR, Zietlow, R, Meyer, TF, Rudel, T
Microbiology spectrum. 2019;(3)
Abstract
Propagation of the intracellular bacterial pathogen Chlamydia trachomatis is strictly bound to its host cells. The bacterium has evolved by minimizing its genome size at the cost of being completely dependent on its host. Many of the vital nutrients are synthesized only by the host, and this has complex implications. Recent advances in loss-of-function analyses and the metabolomics of human infected versus noninfected cells have provided comprehensive insight into the molecular changes that host cells undergo during the stage of infection. Strikingly, infected cells acquire a stage of high metabolic activity, featuring distinct aspects of the Warburg effect, a condition originally assigned to cancer cells. This condition is characterized by aerobic glycolysis and an accumulation of certain metabolites, altogether promoting the synthesis of crucial cellular building blocks, such as nucleotides required for DNA and RNA synthesis. The altered metabolic program enables tumor cells to rapidly proliferate as well as C. trachomatis-infected cells to feed their occupants and still survive. This program is largely orchestrated by a central control board, the tumor suppressor protein p53. Its downregulation in C. trachomatis-infected cells or mutation in cancer cells not only alters the metabolic state of cells but also conveys the prevention of programmed cell death involving mitochondrial pathways. While this points toward common features in the metabolic reprogramming of infected and rapidly proliferating cells, it also forwards novel treatment options against chronic intracellular infections involving well-characterized host cell targets and established drugs.
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7.
Fruit ripening: the role of hormones, cell wall modifications, and their relationship with pathogens.
Forlani, S, Masiero, S, Mizzotti, C
Journal of experimental botany. 2019;(11):2993-3006
Abstract
Fruits result from complex biological processes that begin soon after fertilization. Among these processes are cell division and expansion, accumulation of secondary metabolites, and an increase in carbohydrate biosynthesis. Later fruit ripening is accomplished by chlorophyll degradation and cell wall lysis. Fruit maturation is an essential step to optimize seed dispersal, and is controlled by a complex network of transcription factors and genetic regulators that are strongly influenced by phytohormones. Abscisic acid (ABA) and ethylene are the major regulators of ripening and senescence in both dry and fleshy fruits, as demonstrated by numerous ripening-defective mutants, effects of exogenous hormone application, and transcriptome analyses. While ethylene is the best characterized player in the final step of a fruit's life, ABA also has a key regulatory role, promoting ethylene production and acting as a stress-related hormone in response to drought and pathogen attack. In this review, we focus on the role of ABA and ethylene in relation to the interconnected biotic and abiotic phenomena that affect ripening and senescence. We integrate and discuss the most recent data available regarding these biological processes, which are crucial for post-harvest fruit conservation and for food safety.
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8.
Genome Wide Association Study of Karnal Bunt Resistance in a Wheat Germplasm Collection from Afghanistan.
Gupta, V, He, X, Kumar, N, Fuentes-Davila, G, Sharma, RK, Dreisigacker, S, Juliana, P, Ataei, N, Singh, PK
International journal of molecular sciences. 2019;(13)
Abstract
Karnal bunt disease of wheat, caused by the fungus Neovossia indica, is one of the most important challenges to the grain industry as it affects the grain quality and also restricts the international movement of infected grain. It is a seed-, soil- and airborne disease with limited effect of chemical control. Currently, this disease is contained through the deployment of host resistance but further improvement is limited as only a few genotypes have been found to carry partial resistance. To identify genomic regions responsible for resistance in a set of 339 wheat accessions, genome-wide association study (GWAS) was undertaken using the DArTSeq® technology, in which 18 genomic regions for Karnal bunt resistance were identified, explaining 5-20% of the phenotypic variation. The identified quantitative trait loci (QTL) on chromosome 2BL showed consistently significant effects across all four experiments, whereas another QTL on 5BL was significant in three experiments. Additional QTLs were mapped on chromosomes 1DL, 2DL, 4AL, 5AS, 6BL, 6BS, 7BS and 7DL that have not been mapped previously, and on chromosomes 4B, 5AL, 5BL and 6BS, which have been reported in previous studies. Germplasm with less than 1% Karnal bunt infection have been identified and can be used for resistance breeding. The SNP markers linked to the genomic regions conferring resistance to Karnal bunt could be used to improve Karnal bunt resistance through marker-assisted selection.
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Bifidobacterial Dialogue With Its Human Host and Consequent Modulation of the Immune System.
Alessandri, G, Ossiprandi, MC, MacSharry, J, van Sinderen, D, Ventura, M
Frontiers in immunology. 2019;:2348
Abstract
Since bifidobacteria are among the pioneering colonizers of the human infant gut, their interaction with their host is believed to start soon following birth. Several members of the Bifidobacterium genus are purported to exert various health-promoting effects at local and systemic levels, e.g., limiting pathogen colonization/invasion, influencing gut homeostasis, and influencing the immune system through changes in innate and/or adaptive immune responses. This has promoted extensive research efforts to shed light on the precise mechanisms by which bifidobacteria are able to stimulate and interact with the host immune system. These studies uncovered a variety of secreted or surface-associated molecules that act as essential mediators for the establishment of a bifidobacteria-host immune system dialogue, and that allow interactions with mucosa-associated immune cells. Additionally, the by-products generated from bifidobacterial carbohydrate metabolism act as vectors that directly and indirectly trigger the host immune response, the latter by stimulating growth of other commensal microorganisms such as propionate- or butyrate-producing bacteria. This review is aimed to provide a comprehensive overview on the wide variety of strategies employed by bifidobacteria to engage with the host immune system.
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Changes in Host Response to Mycobacterium tuberculosis Infection Associated With Type 2 Diabetes: Beyond Hyperglycemia.
Segura-Cerda, CA, López-Romero, W, Flores-Valdez, MA
Frontiers in cellular and infection microbiology. 2019;:342
Abstract
Tuberculosis (TB) remains as the first cause of death among infectious diseases worldwide. Global incidence of tuberculosis is in part coincident with incidence of type 2 diabetes (T2D). Incidence of T2D is recognized as a high-risk factor that may contribute to tuberculosis dissemination. However, mechanisms which favor infection under T2D are just starting to emerge. Here, we first discuss the evidences that are available to support a metabolic connection between TB and T2D. Then, we analyze the evidences of metabolic changes which occur during T2D gathered thus far for its influence on susceptibility to M. tuberculosis infection and TB progression, such as hyperglycemia, increase of 1AC levels, increase of triglycerides levels, reduction of HDL-cholesterol levels, increased concentration of lipoproteins, and modification of the activity of some hormones related to the control of metabolic homeostasis. Finally, we recognize possible advantages of metabolic management of immunity to develop new strategies for treatment, diagnosis, and prevention of tuberculosis.