scholarly journals Adaptive Evolution of RH5 in Ape Plasmodium species of the Laverania Subgenus

mBio ◽  
2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Lindsey J. Plenderleith ◽  
Weimin Liu ◽  
Oscar A. MacLean ◽  
Yingying Li ◽  
Dorothy E. Loy ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Parasite Species ◽  
Gene Evolution ◽  
Demographic History ◽  
Plasmodium Species ◽  
Host Protein ◽  
Host Cells ◽  
Nucleotide Polymorphisms ◽  
Human Host ◽  
Human Parasite

ABSTRACT Plasmodium falciparum, the major cause of malaria morbidity and mortality in humans, has been shown to have emerged after cross-species transmission of one of six host-specific parasites (subgenus Laverania) infecting wild chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla). Binding of the parasite-encoded ligand RH5 to the host protein basigin is essential for erythrocyte invasion and has been implicated in host specificity. A recent study claimed to have found two amino acid changes in RH5 that “drove the host shift leading to the emergence of P. falciparum as a human pathogen.” However, the ape Laverania data available at that time, which included only a single distantly related chimpanzee parasite sequence, were inadequate to justify any such conclusion. Here, we have investigated Laverania Rh5 gene evolution using sequences from all six ape parasite species. Searching for gene-wide episodic selection across the entire Laverania phylogeny, we found eight codons to be under positive selection, including three that correspond to contact residues known to form hydrogen bonds between P. falciparum RH5 and human basigin. One of these sites (residue 197) has changed subsequent to the transmission from apes to humans that gave rise to P. falciparum, suggesting a possible role in the adaptation of the gorilla parasite to the human host. We also found evidence that the patterns of nucleotide polymorphisms in P. falciparum are not typical of Laverania species and likely reflect the recent demographic history of the human parasite. IMPORTANCE A number of closely related, host-specific malaria parasites infecting wild chimpanzees and gorillas have recently been described. The most important cause of human malaria, Plasmodium falciparum, is now known to have resulted from a cross-species transmission of one of the gorilla parasites. Overcoming species-specific interactions between a parasite ligand, RH5, and its receptor on host cells, basigin, was likely an important step in the origin of the human parasite. We have investigated the evolution of the Rh5 gene and found evidence of adaptive changes during the diversification of the ape parasite species at sites that are known to form bonds with human basigin. One of these changes occurred at the origin of P. falciparum, implicating it as an important adaptation to the human host.

A population genetic perspective on the origin, spread and adaptation of the human malaria agents Plasmodium falciparum and Plasmodium vivax

2021 ◽  
Author(s):  
Virginie Rougeron ◽  
Larson Boundenga ◽  
Céline Arnathau ◽  
Patrick Durand ◽  
François Renaud ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Vivax ◽  
Population Genetic ◽  
Scientific Community ◽  
Parasite Species ◽  
Plasmodium Species ◽  
Protozoan Parasites ◽  
Body Of Knowledge ◽  
Genomic Analyses ◽  
The World

ABSTRACT Malaria is considered one of the most important scourges that humanity has faced during its history, being responsible every year for numerous deaths worldwide. The disease is caused by protozoan parasites, among which two species are responsible of the majority of the burden, Plasmodium falciparum and Plasmodium vivax. For these two parasite species, the questions of their origin (how and when they appeared in humans), of their spread throughout the world, as well as how they have adapted to humans have long been of interest to the scientific community. In this paper we review the existing body of knowledge, including current research dealing with these questions, focusing particularly on genetic and genomic analyses of these parasites and comparison with related Plasmodium species infecting other species of host (such as non-human primates).

scholarly journals A docking-based structural analysis of geldanamycin-derived inhibitor binding to human or Leishmania Hsp90

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Luana Carneiro Palma ◽  
Luiz Felipe Gomes Rebello Ferreira ◽  
Antonio Luis de Oliveira Almeida Petersen ◽  
Beatriz Rocha Simões Dias ◽  
Juliana Perrone Bezerra de Menezes ◽  
...  
Keyword(s):  
Parasite Species ◽  
Heat Shock Protein 90 ◽  
Host Protein ◽  
Host Cells ◽  
Hsp90 Inhibitors ◽  
Clinical Form ◽  
Inhibitor Binding ◽  
Antiparasitic Activity ◽  
The World ◽  
Increased Susceptibility

Abstract Leishmaniasis is a neglected disease that affects millions of individuals around the world. Regardless of clinical form, treatment is based primarily on the use of pentavalent antimonials. However, such treatments are prolonged and present intense side effects, which lead to patient abandonment in many cases. The search for chemotherapeutic alternatives has become a priority. Heat Shock Protein 90 (Hsp90) inhibitors have recently come under investigation due to antiparasitic activity in Plasmodium sp., Trypanosoma sp. and Leishmania sp. Some of these inhibitors, such as geldanamycin and its analogs, 17-AAG and 17-DMAG, bind directly to Hsp90, thereby inhibiting its activity. Previous studies have demonstrated that different parasite species are more susceptible to some of these inhibitors than host cells. We hypothesized that this increased susceptibility may be due to differences in binding of Hsp90 inhibitors to Leishmania protein compared to host protein. Based on the results of the in silico approach used in the present study, we propose that geldanamycin, 17-AAG and 17-DMAG present an increased tendency to bind to the N-terminal domain of Leishmania amazonensis Hsp83 in comparison to human Hsp90. This could be partially explained by differences in intermolecular interactions between each of these inhibitors and Hsp83 or Hsp90. The present findings demonstrate potential for the use of these inhibitors in the context of anti-Leishmania therapy.

scholarly journals Czechoslovakian Wolfdog Genomic Divergence from Its Ancestors Canis lupus, German Shepherd Dog, and Different Sheepdogs of European Origin

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 832
Author(s):  
Nina Moravčíková ◽  
Radovan Kasarda ◽  
Radoslav Židek ◽  
Luboš Vostrý ◽  
Hana Vostrá-Vydrová ◽  
...  
Keyword(s):  
Demographic History ◽  
Genome Structure ◽  
Principal Component ◽  
Genetic Distances ◽  
Nucleotide Polymorphisms ◽  
German Shepherd ◽  
German Shepherd Dog ◽  
Genome Wide ◽  
Scale Population ◽  
History Effect

This study focused on the genomic differences between the Czechoslovakian wolfdog (CWD) and its ancestors, the Grey wolf (GW) and German Shepherd dog. The Saarloos wolfdog and Belgian Shepherd dog were also included to study the level of GW genetics retained in the genome of domesticated breeds. The dataset consisted of 131 animals and 143,593 single nucleotide polymorphisms (SNPs). The effects of demographic history on the overall genome structure were determined by screening the distribution of the homozygous segments. The genetic variance distributed within and between groups was quantified by genetic distances, the FST index, and discriminant analysis of principal components. Fine-scale population stratification due to specific morphological and behavioural traits was assessed by principal component and factorial analyses. In the CWD, a demographic history effect was manifested mainly in a high genome-wide proportion of short homozygous segments corresponding to a historical load of inbreeding derived from founders. The observed proportion of long homozygous segments indicated that the inbreeding events shaped the CWD genome relatively recently compared to other groups. Even if there was a significant increase in genetic similarity among wolf-like breeds, they were genetically separated from each other. Moreover, this study showed that the CWD genome carries private alleles that are not found in either wolves or other dog breeds analysed in this study.

scholarly journals Native Structure-Based Peptides as Potential Protein–Protein Interaction Inhibitors of SARS-CoV-2 Spike Protein and Human ACE2 Receptor

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2157
Author(s):  
Norbert Odolczyk ◽  
Ewa Marzec ◽  
Maria Winiewska-Szajewska ◽  
Jarosław Poznański ◽  
Piotr Zielenkiewicz
Keyword(s):  
Drug Development ◽  
Protein Interactions ◽  
Rna Virus ◽  
Antiviral Drug ◽  
Host Protein ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Short Peptides ◽  
Virus Protein ◽  
Positive Strand Rna

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a positive-strand RNA virus that causes severe respiratory syndrome in humans, which is now referred to as coronavirus disease 2019 (COVID-19). Since December 2019, the new pathogen has rapidly spread globally, with over 65 million cases reported to the beginning of December 2020, including over 1.5 million deaths. Unfortunately, currently, there is no specific and effective treatment for COVID-19. As SARS-CoV-2 relies on its spike proteins (S) to bind to a host cell-surface receptor angiotensin-converting enzyme-2(ACE2), and this interaction is proved to be responsible for entering a virus into host cells, it makes an ideal target for antiviral drug development. In this work, we design three very short peptides based on the ACE2 sequence/structure fragments, which may effectively bind to the receptor-binding domain (RBD) of S protein and may, in turn, disrupt the important virus-host protein–protein interactions, blocking early steps of SARS-CoV-2 infection. Two of our peptides bind to virus protein with affinity in nanomolar range, and as very short peptides have great potential for drug development.

Spatiotemporal distributed lag modelling of multiple Plasmodium species in a malaria elimination setting

2021 ◽  
Vol 30 (1) ◽  
pp. 22-34
Author(s):  
Chawarat Rotejanaprasert ◽  
Duncan Lee ◽  
Nattwut Ekapirat ◽  
Prayuth Sudathip ◽  
Richard J Maude
Keyword(s):  
Data Streams ◽  
Malaria Elimination ◽  
Parasite Species ◽  
Climatic Factors ◽  
Plasmodium Species ◽  
Clinical Malaria ◽  
Spatiotemporal Patterns ◽  
Distributed Lag ◽  
Multiple Data

In much of the Greater Mekong Sub-region, malaria is now confined to patches and small foci of transmission. Malaria transmission is seasonal with the spatiotemporal patterns being associated with variation in environmental and climatic factors. However, the possible effect at different lag periods between meteorological variables and clinical malaria has not been well studied in the region. Thus, in this study we developed distributed lagged modelling accounting for spatiotemporal excessive zero cases in a malaria elimination setting. A multivariate framework was also extended to incorporate multiple data streams and investigate the spatiotemporal patterns from multiple parasite species via their lagged association with climatic variables. A simulation study was conducted to examine robustness of the methodology and a case study is provided of weekly data of clinical malaria cases at sub-district level in Thailand.

scholarly journals Kelch 13-propeller polymorphisms in Plasmodium falciparum from Jazan region, southwest Saudi Arabia

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Ommer Mohammed Dafalla ◽  
Mohammed Alzahrani ◽  
Ahmed Sahli ◽  
Mohammed Abdulla Al Helal ◽  
Mohammad Mohammad Alhazmi ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Saudi Arabia ◽  
Parasite Clearance ◽  
Sub Saharan Africa ◽  
Local Alignment ◽  
Nucleotide Polymorphisms ◽  
Gene Encoding ◽  
Synonymous Mutations ◽  
Search Tool ◽  
Sub Saharan

Abstract Background Artemisinin-based combination therapy (ACT) is recommended at the initial phase for treatment of Plasmodium falciparum, to reduce morbidity and mortality in all countries where malaria is endemic. Polymorphism in portions of P. falciparum gene encoding kelch (K13)-propeller domains is associated with delayed parasite clearance after ACT. Of about 124 different non-synonymous mutations, 46 have been identified in Southeast Asia (SEA), 62 in sub-Saharan Africa (SSA) and 16 in both the regions. This is the first study designed to analyse the prevalence of polymorphism in the P. falciparum k13-propeller domain in the Jazan region of southwest Saudi Arabia, where malaria is endemic. Methods One-hundred and forty P. falciparum samples were collected from Jazan region of southwest Saudi Arabia at three different times: 20 samples in 2011, 40 samples in 2016 and 80 samples in 2020 after the implementation of ACT. Plasmodium falciparum kelch13 (k13) gene DNA was extracted, amplified, sequenced, and analysed using a basic local alignment search tool (BLAST). Results This study obtained 51 non-synonymous (NS) mutations in three time groups, divided as follows: 6 single nucleotide polymorphisms (SNPs) ‘11.8%’ in samples collected in 2011 only, 3 (5.9%) in 2011and 2016, 5 (9.8%) in 2011 and 2020, 5 (9.8%) in 2016 only, 8 (15.7%) in 2016 and 2020, 14 (27.5%) in 2020 and 10 (19.6%) in all the groups. The BLAST revealed that the 2011 isolates were genetically closer to African isolates (53.3%) than Asian ones (46.7%). Interestingly, this proportion changed completely in 2020, to become closer to Asian isolates (81.6%) than to African ones (18.4%). Conclusions Despite the diversity of the identified mutations in the k13-propeller gene, these data did not report widespread artemisinin-resistant polymorphisms in the Jazan region where these samples were collected. Such a process would be expected to increase frequencies of mutations associated with the resistance of ACT.

Associations between varied susceptibilities of PfATP4 inhibitors and genotypes in Ugandan Plasmodium falciparum isolates

2021 ◽  
Author(s):  
Oriana Kreutzfeld ◽  
Stephanie A. Rasmussen ◽  
Aarti A. Ramanathan ◽  
Patrick K. Tumwebaze ◽  
Oswald Byaruhanga ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Single Nucleotide Polymorphisms ◽  
Ex Vivo ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Field Isolates ◽  
Frequent Mutations ◽  
Mixed Field ◽  
P Type

Among novel compounds under recent investigation as potential new antimalarial drugs are three independently developed inhibitors of the Plasmodium falciparum P-type ATPase (PfATP4): KAE609 (cipargamin), PA92, and SJ733. We assessed ex vivo susceptibilities to these compounds of 374 fresh P. falciparum isolates collected in Tororo and Busia districts, Uganda from 2016-2019. Median IC 50 s were 65 nM for SJ733, 9.1 nM for PA92, and 0.5 nM for KAE609. Sequencing of pfatp4 for 218 of these isolates demonstrated many non-synonymous single nucleotide polymorphisms; the most frequent mutations were G1128R (69% of isolates mixed or mutant), Q1081K/R (68%), G223S (25%), N1045K (16%) and D1116G/N/Y (16%). The G223S mutation was associated with decreased susceptibility to SJ733, PA92 and KAE609. The D1116G/N/Y mutations were associated with decreased susceptibility to SJ733, and the presence of mutations at both codons 223 and 1116 was associated with decreased susceptibility to PA92 and SJ733. In all of these cases, absolute differences in susceptibilities of wild type (WT) and mutant parasites were modest. Analysis of clones separated from mixed field isolates consistently identified mutant clones as less susceptible than WT. Analysis of isolates from other sites demonstrated presence of the G223S and D1116G/N/Y mutations across Uganda. Our results indicate that malaria parasites circulating in Uganda have a number of polymorphisms in PfATP4 and that modestly decreased susceptibility to PfATP4 inhibitors is associated with some mutations now present in Ugandan parasites.

Interactions Between Salmonella Typhimurium, Enteropathogenic Escherichia Coli (EPEC), and Host Epithelial Cells

1995 ◽  
Vol 9 (1) ◽  
pp. 31-36 ◽  
Author(s):  
B.B. Finlay
Keyword(s):  
Escherichia Coli ◽  
Epithelial Cells ◽  
Salmonella Typhimurium ◽  
Host Cell ◽  
Inositol Phosphate ◽  
Enteric Pathogens ◽  
Host Protein ◽  
Host Cells ◽  
Enteropathogenic Escherichia Coli ◽  
Sequence Of Events

The interactions that occur between pathogenic micro-organisms and their host cells are complex and intimate. We have used two enteric pathogens, Salmonella typhimurium and enteropathogenic Escherichia coli (EPEC), to examine the interactions that occur between these organisms and epithelial cells. Although these are enteric pathogens, the knowledge and techniques developed from these systems may be applied to the study of dental pathogens. Both S. typhimurium and EPEC disrupt epithelial monolayer integrity, although by different mechanisms. Both pathogens cause loss of microvilli and re-arrangement of the underlying host cytoskeleton. Despite these similarities, both organisms send different signals into the host cell. EPEC signal transduction involves generation of intracellular calcium and inositol phosphate fluxes, and activation of host tyrosine kinases that results in tyrosine phosphorylation of a 90-kDa host protein. Bacterial mutants have been identifed that are deficient in signaling to the host. We propose a sequence of events that occur when EPEC interacts with epithelial cells. Once inside a host cell, S. typhimurium remains within a vacuole. To define some of the parameters of the intracellular environment, we constructed genetic fusions of known genes with lacZ, and used these fusions as reporter probes of the intracellular vacuolar environment. We have also begun to examine the bacterial and host cell factors necessary for S. typhimurium to multiply within epithelial cells. We found that this organism triggers the formation of novel tubular lysosomes, and these structures are linked with intracellular replication.

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