Identification of a novel UDP-sugar pyrophosphorylase with a broad substrate specificity in Trypanosoma cruzi

2010 ◽  
Vol 429 (3) ◽  
pp. 533-543 ◽  
Author(s):  
Ting Yang ◽  
Maor Bar-Peled
Keyword(s):  
Trypanosoma Cruzi ◽  
Alternative Pathway ◽  
Host Cells ◽  
Host Immune System ◽  
Forward Reaction ◽  
Lower Efficiency ◽  
Highly Active ◽  
Trypanosomatid Parasites ◽  
Nucleotide Sugars ◽  
Nucleotide Sugar Biosynthesis

The diverse types of glycoconjugates synthesized by trypanosomatid parasites are unique compared with the host cells. These glycans are required for the parasite survival, invasion or evasion of the host immune system. Synthesis of those glycoconjugates requires a constant supply of nucleotide-sugars (NDP-sugars), yet little is known about how these NDP-sugars are made and supplied. In the present paper, we report a functional gene from Trypanosoma cruzi that encodes a nucleotidyltransferase, which is capable of transforming different types of sugar 1-phosphates and NTP into NDP-sugars. In the forward reaction, the enzyme catalyses the formation of UDP-glucose, UDP-galactose, UDP-xylose and UDP-glucuronic acid, from their respective monosaccharide 1-phosphates in the presence of UTP. The enzyme could also convert glucose 1-phosphate and TTP into TDP-glucose, albeit at lower efficiency. The enzyme requires bivalent ions (Mg2+ or Mn2+) for its activity and is highly active between pH 6.5 and pH 8.0, and at 30–42 °C. The apparent Km values for the forward reaction were 177 μM (glucose 1-phosphate) and 28.4 μM (UTP) respectively. The identification of this unusual parasite enzyme with such broad substrate specificities suggests an alternative pathway that might play an essential role for nucleotide-sugar biosynthesis and for the regulation of the NDP-sugar pool in the parasite.

scholarly journals Complement Activation in Mycoplasma fermentans-Induced Mycoplasma Clearance from Infected Cells: Probing of the Organism with Monoclonal Antibodies against M161Ag

2000 ◽  
Vol 68 (3) ◽  
pp. 1672-1680 ◽  
Author(s):  
Satomi Kikkawa ◽  
Misako Matsumoto ◽  
Tsuguo Sasaki ◽  
Miyuki Nishiguchi ◽  
Kazuhiko Tanaka ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Human Peripheral Blood ◽  
Alternative Pathway ◽  
Human Tumor ◽  
Host Cells ◽  
Low Grade ◽  
Host Immune System ◽  
Human Complement ◽  
Mycoplasma Fermentans ◽  
Infected Cells

ABSTRACT Mycoplasma fermentans, a cell wall-less prokaryote, is capable of infecting humans and has been suggested to serve as a cofactor in AIDS development. Recently, we discovered a novel lipoprotein with a molecular mass of 43 kDa originating from M. fermentans. This protein, named M161Ag, activated human complement via the alternative pathway and efficiently induced the proinflammatory cytokines interleukin 1β (IL-1β), tumor necrosis factor alpha, IL-6, IL-10, and IL-12 in human peripheral blood monocytes. It is likely that M161Ag of M. fermentansaffects the host immune system upon mycoplasma infection. In this study, we developed monoclonal antibodies (MAbs) against M161Ag and examined the direct role of complement in M. fermentans infection using these MAbs as probes.M. fermentans was rapidly cleared from the surfaces of infected cells by human complement, but a low-grade infection persisted in human tumor cell lines. Mycoplasma particles remaining alive in host cells may cause recurrent infection, and liberated M161Ag may serve as a biological response modifier affecting both innate and acquired immunity.

Abstract P407: Role Of Cyclic AMP During The Intracellular Infection Cycle Of Trypanosoma Cruzi

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Daniel E Velez-Ramirez ◽  
Michelle Shimogawa ◽  
Kent Hill
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Host Cells ◽  
Camp Signaling ◽  
Host Immune System ◽  
Infection Cycle ◽  
Tropical Regions ◽  
Host Environment ◽  
Intracellular Infection

Trypanosoma cruzi is the causative agent of Chagas disease, a vector-borne disease. In the 1990s the distribution of the vector, a hematophagous triatomine, and consequently the parasite, was from the southeast tropical regions of Mexico to South America. Now, global warming is causing this distribution to expand to northern territories in Mexico, reaching southern parts of US, in which up to 300,000 people are affected. Furthermore, an increase in chronically-infected immigrants to the US makes Chagas disease a matter of Pan-American public health that it should be addressed by all the America countries. Chagas disease manifests clinically as cardiovascular disease, characterized by hypertrophy of heart, esophagus and colon. Congestive heart failure is the main cause of death (58%) in Chagas patients, whereas cardiac arrhythmias and unexpected deaths add another 36%. A major cause of heart pathology in Chagas disease damage is caused by the host immune system, as it attacks chronically infected tissue. Therefore, pathology of the disease is a direct consequence of the ability of the parasite to invade host cells, so it can establish chronic infection. To achieve this, T. cruzi must sense and adapt to the host environment, but the underlying mechanisms are poorly understood. In particular, parasite signaling pathways used to sense and transduce signals from the host environment are most completely unknown. Our lab studies cAMP signaling in trypanosome parasites and several lines of evidence suggest T. cruzi cAMP signaling is important for host cell invasion, differentiation and persistent infection, which in turn underlies heart tissue pathology of Chagas disease. A transcriptome analysis revealed that mRNA of proteins involved in cAMP metabolism, i.e. adenylate cyclases and phosphodiesterases, are either upregulated or downregulated during the intracellular infection cycle. In fact, the phosphodiesterases have flagellar homologs with known cAMP signaling functions in a related parasite. This suggests that cAMP might fluctuate during as T. cruzi invades, differentiates, and multiplies inside the host cells. We have implemented a cAMP FRET sensor to monitor cAMP levels in trypanosomes to understand the role of cAMP in T. cruzi pathogenesis.

scholarly journals Amastigotes of Trypanosoma cruzi sustain an infective cycle in mammalian cells.

1988 ◽  
Vol 168 (2) ◽  
pp. 649-659 ◽  
Author(s):  
V Ley ◽  
N W Andrews ◽  
E S Robbins ◽  
V Nussenzweig
Keyword(s):  
Trypanosoma Cruzi ◽  
Mammalian Cells ◽  
Protozoan Parasite ◽  
Acute Stage ◽  
Host Cells ◽  
Mammalian Host ◽  
Human Monocytes ◽  
Lower Efficiency ◽  
Cultured Fibroblasts

The two main stages of development of the protozoan parasite Trypanosoma cruzi found in the vertebrate host are the trypomastigote and the amastigote. It has been generally assumed that only trypomastigotes are capable of entering cells and that amastigotes are the intracellular replicative form of the parasite. We show here that after incubation for 4 h with human monocytes in vitro 90% or more of extracellularly derived (24 h) amastigotes of T. cruzi are taken up by the cells. Within 2 h they escape the phagocytic vacuole and enter the cytoplasm, where they divide and after 4-5 d transform into trypomastigotes. Trypomastigotes also invade cultured human monocytes. However, they show a lag of several hours between invasion and the start of DNA duplication, while amastigotes commence replication without an apparent lag. Amastigotes also infect cultured fibroblasts, albeit with lower efficiency. When injected intraperitoneally into mice, amastigotes are as infective as trypomastigotes. Based on these results, and on prior findings that amastigotes are found free in the circulation of mice during the acute stage of the disease (3), it seems likely that the cellular uptake of amastigotes can initiate an alternative subcycle within the life cycle of this parasite in the mammalian host. Also, because trypomastigotes and amastigotes have diverse surface antigens, they may use different strategies to invade host cells.

Basic Biology of Trypanosoma Cruzi

2020 ◽  
Vol 26 ◽  
Author(s):  
Aline Araujo Zuma ◽  
Emile dos Santos Barrias ◽  
Wanderley de Souza
Keyword(s):  
Trypanosoma Cruzi ◽  
Trypanosoma Brucei ◽  
Cell Biology ◽  
Structural Organization ◽  
Developmental Stages ◽  
Endocytic Pathway ◽  
Host Cells ◽  
Cellular Organization ◽  
Basic Biology ◽  
Comparative Information

Abstract:: The present review addresses basic aspects of the biology of the pathogenic protozoa Trypanosoma cruzi and some comparative information with Trypanosoma brucei. Like eukaryotic cells, their cellular organization is similar to that of mammalian hosts. However, these parasites present structural particularities. That is why the following topics are emphasized in this paper: developmental stages of the life cycle in the vertebrate and invertebrate hosts; the cytoskeleton of the protozoa, especially the sub-pellicular microtubules; the flagellum and its attachment to the protozoan body through specialized junctions; the kinetoplast-mitochondrion complex, including its structural organization and DNA replication; the glycosome and its role in the metabolism of the cell; the acidocalcisome, describing its morphology, biochemistry, and functional role; the cytostome and the endocytic pathway; the organization of the endoplasmic reticulum and Golgi complex; the nucleus, describing its structural organization during interphase and division; and the process of interaction of the parasite with host cells. The unique characteristics of these structures also make them interesting chemotherapeutic targets. Therefore, further understanding of cell biology aspects contributes to the development of drugs for chemotherapy.

scholarly journals The novel Dbl homology/BAR domain protein, MsgA, of Talaromyces marneffei regulates yeast morphogenesis during growth inside host cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Harshini Weerasinghe ◽  
Hayley E. Bugeja ◽  
Alex Andrianopoulos
Keyword(s):  
Pathogenic Fungi ◽  
Host Cells ◽  
Microbial Pathogens ◽  
Mammalian Host ◽  
Host Immune System ◽  
Nucleotide Exchange ◽  
Phagocytic Cells ◽  
Macrophage Infection ◽  
Bar Domain ◽  
Talaromyces Marneffei

AbstractMicrobial pathogens have evolved many strategies to evade recognition by the host immune system, including the use of phagocytic cells as a niche within which to proliferate. Dimorphic pathogenic fungi employ an induced morphogenetic transition, switching from multicellular hyphae to unicellular yeast that are more compatible with intracellular growth. A switch to mammalian host body temperature (37 °C) is a key trigger for the dimorphic switch. This study describes a novel gene, msgA, from the dimorphic fungal pathogen Talaromyces marneffei that controls cell morphology in response to host cues rather than temperature. The msgA gene is upregulated during murine macrophage infection, and deletion results in aberrant yeast morphology solely during growth inside macrophages. MsgA contains a Dbl homology domain, and a Bin, Amphiphysin, Rvs (BAR) domain instead of a Plekstrin homology domain typically associated with guanine nucleotide exchange factors (GEFs). The BAR domain is crucial in maintaining yeast morphology and cellular localisation during infection. The data suggests that MsgA does not act as a canonical GEF during macrophage infection and identifies a temperature independent pathway in T. marneffei that controls intracellular yeast morphogenesis.

scholarly journals Amaryllidaceae plants: a potential natural resource for the treatment of Chagas disease

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Nieves Martínez-Peinado ◽  
Nuria Cortes-Serra ◽  
Luciana R. Tallini ◽  
Maria-Jesus Pinazo ◽  
Joaquim Gascon ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Chemical Diversity ◽  
Host Cells ◽  
Cell Toxicity ◽  
Chronic Stage ◽  
Highly Active ◽  
Amastigote Stage ◽  
Medical Need ◽  
Chemical Content ◽  
Unique Chemical

Abstract Background Chagas disease is a neglected zoonosis caused by the parasite Trypanosoma cruzi. It affects over six million people, mostly in Latin America. Drugs available to treat T. cruzi infection have associated toxicity and questionable efficacy at the chronic stage. Hence, the discovery of more effective and safer drugs is an unmet medical need. For this, natural products represent a pool of unique chemical diversity that can serve as excellent templates for the synthesis of active molecules. Methods A collection of 79 extracts of Amaryllidaceae plants were screened against T. cruzi. Active extracts against the parasite were progressed through two cell toxicity assays based on Vero and HepG2 cells to determine their selectivity profile and discard those toxic to host cells. Anti-T. cruzi-specific extracts were further qualified by an anti-amastigote stage assay. Results Two extracts, respectively from Crinum erubescens and Rhodophiala andicola, were identified as highly active and specific against T. cruzi and its mammalian replicative form. Conclusions The results retrieved in this study encourage further exploration of the chemical content of these extracts in search of new anti-T. cruzi drug development starting points. Graphic abstract

scholarly journals Evolutionary Genetics of Mycobacterium tuberculosis and HIV-1: “The Tortoise and the Hare”

2021 ◽  
Vol 9 (1) ◽  
pp. 147
Author(s):  
Ana Santos-Pereira ◽  
Carlos Magalhães ◽  
Pedro M. M. Araújo ◽  
Nuno S. Osório
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Evolutionary Dynamics ◽  
Evolutionary Genetics ◽  
Host Cells ◽  
Whole Genome Sequencing Data ◽  
Host Immune System ◽  
Viral Mutant ◽  
Hiv 1

The already enormous burden caused by Mycobacterium tuberculosis and Human Immunodeficiency Virus type 1 (HIV-1) alone is aggravated by co-infection. Despite obvious differences in the rate of evolution comparing these two human pathogens, genetic diversity plays an important role in the success of both. The extreme evolutionary dynamics of HIV-1 is in the basis of a robust capacity to evade immune responses, to generate drug-resistance and to diversify the population-level reservoir of M group viral subtypes. Compared to HIV-1 and other retroviruses, M. tuberculosis generates minute levels of genetic diversity within the host. However, emerging whole-genome sequencing data show that the M. tuberculosis complex contains at least nine human-adapted phylogenetic lineages. This level of genetic diversity results in differences in M. tuberculosis interactions with the host immune system, virulence and drug resistance propensity. In co-infected individuals, HIV-1 and M. tuberculosis are likely to co-colonize host cells. However, the evolutionary impact of the interaction between the host, the slowly evolving M. tuberculosis bacteria and the HIV-1 viral “mutant cloud” is poorly understood. These evolutionary dynamics, at the cellular niche of monocytes/macrophages, are also discussed and proposed as a relevant future research topic in the context of single-cell sequencing.

scholarly journals A Comparative Genomic Study of Attenuated and Virulent Strains of Babesia bigemina

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 318
Author(s):  
Bernardo Sachman-Ruiz ◽  
Luis Lozano ◽  
José J. Lira ◽  
Grecia Martínez ◽  
Carmen Rojas ◽  
...  
Keyword(s):  
In Vitro Culture ◽  
Virulence Genes ◽  
Laboratory Strain ◽  
Host Cells ◽  
Comparative Genomic ◽  
Local Alignment ◽  
Host Immune System ◽  
Babesia Bigemina ◽  
Genomic Study

Cattle babesiosis is a socio-economically important tick-borne disease caused by Apicomplexa protozoa of the genus Babesia that are obligate intraerythrocytic parasites. The pathogenicity of Babesia parasites for cattle is determined by the interaction with the host immune system and the presence of the parasite’s virulence genes. A Babesia bigemina strain that has been maintained under a microaerophilic stationary phase in in vitro culture conditions for several years in the laboratory lost virulence for the bovine host and the capacity for being transmitted by the tick vector. In this study, we compared the virulome of the in vitro culture attenuated Babesia bigemina strain (S) and the virulent tick transmitted parental Mexican B. bigemina strain (M). Preliminary results obtained by using the Basic Local Alignment Search Tool (BLAST) showed that out of 27 virulence genes described and analyzed in the B. bigemina virulent tick transmitted strain, only five were fully identified in the attenuated laboratory strain. In all cases, the identity and coverture of the identified genes of the wildtype strain were higher than those of the laboratory strain. This finding is putatively associated with the continuous partial loss of virulence genes in the laboratory strain after several passages of the parasite population under optimal in vitro growth conditions. The loss of virulence factors might be reflected in the absence of symptoms of the disease in cattle inoculated with the attenuated strain despite the presence of infection in the bovine host cells.

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