Publications by authors named "Emmanuel Cornillot"

34 Publications

The immune contexture of primary central nervous system diffuse large B cell lymphoma associates with patient survival and specific cell signaling.

Theranostics 2021 22;11(8):3565-3579. Epub 2021 Jan 22.

Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France.

Primary central nervous system diffuse large B-cell lymphoma (PCNSL) is a rare and aggressive entity that resides in an immune-privileged site. The tumor microenvironment (TME) and the disruption of the immune surveillance influence lymphoma pathogenesis and immunotherapy resistance. Despite growing knowledge on heterogeneous therapeutic responses, no comprehensive description of the PCNSL TME is available. We hence investigated the immune subtypes of PCNSL and their association with molecular signaling and survival. Analysis of PCNSL transcriptomes (sequencing, n = 20; microarrays, n = 34). Integrated correlation analysis and signaling pathway topology enabled us to infer intercellular interactions. Immunohistopathology and digital imaging were used to validate bioinformatic results. Transcriptomics revealed three immune subtypes: immune-rich, poor, and intermediate. The immune-rich subtype was associated to better survival and characterized by hyper-activation of STAT3 signaling and inflammatory signaling, , IFNγ and TNF-α, resembling the hot subtype described in primary testicular lymphoma and solid cancer. WNT/β-catenin, HIPPO, and NOTCH signaling were hyper-activated in the immune-poor subtype. HLA down-modulation was clearly associated with a low or intermediate immune infiltration and the absence of T-cell activation. Moreover, HLA class I down-regulation was also correlated with worse survival with implications on immune-intermediate PCNSL that frequently feature reduced HLA expression. A ligand-receptor intercellular network revealed high expression of two immune checkpoints, , CTLA-4/CD86 and TIM-3/LAGLS9. TIM-3 and galectin-9 proteins were clearly upregulated in PCNSL. Altogether, our study reveals that patient stratification according to immune subtypes, HLA status, and immune checkpoint molecule quantification should be considered prior to immune checkpoint inhibitor therapy. Moreover, TIM-3 protein should be considered an axis for future therapeutic development.
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http://dx.doi.org/10.7150/thno.54343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914352PMC
January 2021

The molecular landscape and microenvironment of salivary duct carcinoma reveal new therapeutic opportunities.

Theranostics 2020 15;10(10):4383-4394. Epub 2020 Mar 15.

Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France.

: Salivary duct carcinoma (SDC) is a rare and aggressive salivary gland cancer subtype with poor prognosis. The mutational landscape of SDC has already been the object of several studies, however little is known regarding the functional genomics and the tumor microenvironment despite their importance in oncology. Our investigation aimed at describing both the functional genomics of SDC and the SDC microenvironment, along with their clinical relevance. : RNA-sequencing (24 tumors), proteomics (17 tumors), immunohistochemistry (22 tumors), and multiplexed immunofluorescence (3 tumors) data were obtained from three different patient cohorts and analyzed by digital imaging and bioinformatics. Adjacent non-tumoral tissue from patients in two cohorts were used in transcriptomic and proteomic analyses. : Transcriptomic and proteomic data revealed the importance of Notch, TGF-β, and interferon-γ signaling for all SDCs. We confirmed an overall strong desmoplastic reaction by measuring α-SMA abundance, the level of which was associated with recurrence-free survival (RFS). Two distinct immune phenotypes were observed: immune-poor SDCs (36%) and immune-infiltrated SDCs (64%). Advanced bioinformatics analysis of the transcriptomic data suggested 72 ligand-receptor interactions occurred in the microenvironment and correlated with the immune phenotype. Among these interactions, three immune checkpoints were validated by immunofluorescence, including CTLA-4/DC86 and TIM-3/galectin-9 interactions, previously unidentified in SDC. Immunofluorescence analysis also confirmed an important immunosuppressive role of macrophages and NK cells, also supported by the transcriptomic data. : Together our data significantly increase the understanding of SDC biology and open new perspectives for SDC tumor treatment. Before applying immunotherapy, patient stratification according to the immune infiltrate should be taken into account. Immune-infiltrated SDC could benefit from immune checkpoint-targeting therapy, with novel options such as anti-CTLA-4. Macrophages or NK cells could also be targeted. The dense stroma, i.e., fibroblasts or hyaluronic acid, may also be the focus for immune-poor SDC therapies, e.g. in combination with Notch or TGF-β inhibitors, or molecules targeting SDC mutations.
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http://dx.doi.org/10.7150/thno.42986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150470PMC
April 2021

In Vivo Large-Scale Mapping of Protein Turnover in Human Cerebrospinal Fluid.

Anal Chem 2019 12 2;91(24):15500-15508. Epub 2019 Dec 2.

Université de Montpellier , 34090 Montpellier , France.

The extraction of accurate physiological parameters from clinical samples provides a unique perspective to understand disease etiology and evolution, including under therapy. We introduce a new methodologic framework to map patient proteome dynamics in vivo, either proteome-wide or in large targeted panels. We applied it to ventricular cerebrospinal fluid (CSF) and could determine the turnover parameters of almost 200 proteins, whereas a handful were known previously. We covered a large number of neuron biology- and immune system-related proteins, including many biomarkers and drug targets. This first large data set unraveled a significant relationship between turnover and protein origin that relates to our ability to investigate organ physiology with protein-labeling strategy specifics. Our data constitute the first draft of CSF proteome dynamics as well as a repertoire of peptides for the community to design new analyses. The disclosed methods apply to other fluids or tissues provided sequential sample collection can be performed. We show that the proposed mathematical modeling applies to other analytical methods in the field.
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http://dx.doi.org/10.1021/acs.analchem.9b03328DOI Listing
December 2019

Babesia divergens glycosylphosphatidylinositols modulate blood coagulation and induce Th2-biased cytokine profiles in antigen presenting cells.

Biochimie 2019 Dec 1;167:135-144. Epub 2019 Oct 1.

Institut de Biologie Computationnelle, 34095, Montpellier, France; Institut de Recherche en Cancérologie de Montpellier (IRCM - INSERM U1194), Institut Régional du Cancer de Montpellier (ICM), Université de Montpellier, 34095, Montpellier, France.

Glycosylphosphatidylinositols (GPIs) are glycolipids described as toxins of protozoan parasites due to their inflammatory properties in mammalian hosts characterized by the production of interleukin (IL)-1, IL-12 and tumor necrosis factor (TNF)-α. In the present work, we studied the cytokines produced by antigen presenting cells in response to ten different GPI species extracted from Babesia divergens, responsible for babesiosis. Interestingly, B. divergens GPIs induced the production of anti-inflammatory cytokines (IL-2, IL-5) and of the regulatory cytokine IL-10 by macrophages and dendritic cells. In contrast to all protozoan GPIs studied until now, GPIs from B. divergens did not stimulate the production of TNF-α and IL-12, leading to a unique Th1/Th2 profile. Analysis of the carbohydrate composition of the B. divergens GPIs indicated that the di-mannose structure was different from the evolutionary conserved tri-mannose structure, which might explain the particular cytokine profile they induce. Expression of major histocompatibility complex (MHC) molecules on dendritic cells and apoptosis of mouse peritoneal cells were also analysed. B. divergens GPIs did not change expression of MHC class I, but decreased expression of MHC class II at the cell surface, while GPIs slightly increased the percentages of apoptotic cells. During pathogenesis of babesiosis, the inflammation-coagulation auto-amplification loop can lead to thrombosis and the effect of GPIs on coagulation parameters was investigated. Incubation of B. divergens GPIs with rat plasma ex vivo led to increase of fibrinogen levels and to prolonged activated partial thromboplastin time, suggesting a direct modulation of the extrinsic coagulation pathway by GPIs.
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http://dx.doi.org/10.1016/j.biochi.2019.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079338PMC
December 2019

Case report of the patient source of the Babesia microti R1 reference strain and implications for travelers.

J Travel Med 2018 01;25(1)

Institut de Biologie Computationnelle (IBC), Montpellier, France.

Background: In 2002, a previously healthy 69-year-old man travelled to France from the United States and presented to our hospital with a febrile illness that subsequently was determined to be babesiosis. The blood isolated from this patient served as a source for propagation of the Babesia microti R1 strain with subsequent sequencing and annotation of the parasite genome.

Methods: Upon admission, we obtained a medical history, performed a physical examination, and examined his blood for the presence of a blood borne pathogen by microscopy, PCR and indirect immunofluorescence antibody testing. Once the diagnosis of babesiosis was made, we reviewed the literature to assess the distribution of B. microti-associated babesiosis cases in immunocompetent patients from outside the USA.

Results: The patient recalled a tick bite during the previous month on Cape Cod, Massachusetts. The diagnosis was confirmed by identification of Babesia-infected red blood cells on blood smears, amplification of B. microti DNA in blood by PCR and the presence of B. microti antibody in the serum. This strain was the first isolate of B. microti to be fully sequenced and its annotated genome serves as a reference for molecular and cell biology studies aimed at understanding B. microti pathophysiology and developing diagnostic tests and therapies. A review of babesiosis cases demonstrates a worldwide distribution of B. microti and identifies potential emerging endemic areas where travelers may be at risk of contracting B. microti infection.

Conclusion: This case provides clinical information about the patient infected with the R1 isolate and a review of travel risk, diagnosis and treatment of babesiosis in endemic and non-endemic areas.
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http://dx.doi.org/10.1093/jtm/tax073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927858PMC
January 2018

Functional analysis of Plasmodium falciparum subpopulations associated with artemisinin resistance in Cambodia.

Malar J 2017 Dec 19;16(1):493. Epub 2017 Dec 19.

Institut de Biologie Computationnelle (IBC), 34095, Montpellier, France.

Background: Plasmodium falciparum malaria is one of the most widespread parasitic infections in humans and remains a leading global health concern. Malaria elimination efforts are threatened by the emergence and spread of resistance to artemisinin-based combination therapy, the first-line treatment of malaria. Promising molecular markers and pathways associated with artemisinin drug resistance have been identified, but the underlying molecular mechanisms of resistance remains unknown. The genomic data from early period of emergence of artemisinin resistance (2008-2011) was evaluated, with aim to define k13 associated genetic background in Cambodia, the country identified as epicentre of anti-malarial drug resistance, through characterization of 167 parasite isolates using a panel of 21,257 SNPs.

Results: Eight subpopulations were identified suggesting a process of acquisition of artemisinin resistance consistent with an emergence-selection-diffusion model, supported by the shifting balance theory. Identification of population specific mutations facilitated the characterization of a core set of 57 background genes associated with artemisinin resistance and associated pathways. The analysis indicates that the background of artemisinin resistance was not acquired after drug pressure, rather is the result of fixation followed by selection on the daughter subpopulations derived from the ancestral population.

Conclusions: Functional analysis of artemisinin resistance subpopulations illustrates the strong interplay between ubiquitination and cell division or differentiation in artemisinin resistant parasites. The relationship of these pathways with the P. falciparum resistant subpopulation and presence of drug resistance markers in addition to k13, highlights the major role of admixed parasite population in the diffusion of artemisinin resistant background. The diffusion of resistant genes in the Cambodian admixed population after selection resulted from mating of gametocytes of sensitive and resistant parasite populations.
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http://dx.doi.org/10.1186/s12936-017-2140-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735551PMC
December 2017

Incidence of dengue and chikungunya viruses in mosquitoes and human patients in border provinces of Vietnam.

Parasit Vectors 2017 Nov 9;10(1):556. Epub 2017 Nov 9.

Cirad, Intertryp, UMR 17, TA-A17/G, Campus International de Baillarguet, 34398 Cedex 5, Montpellier, France.

Background: Dengue virus remains a major threat in Vietnam, while chikungunya virus is expected to become one. Surveillance was conducted from 2012 to 2014 in Vietnam to assess the presence of dengue and chikungunya viruses in patients hospitalized with acute fever in five Vietnam provinces neighboring Lao PDR and Cambodia. Surveillance was extended to mosquitoes present in the vicinity of the patients' households.

Results: A total 558 human serum samples were collected along with 1104 adult mosquitoes and 12,041 larvae from 2250 households. Dengue virus was found in 17 (3%) human serum samples and in 9 (0.8%) adult mosquitoes. Chikungunya virus was detected in 2 adult mosquitoes (0.18%) while no chikungunya virus was detected in humans. Differing densities of mosquito populations were found, with the highest in the Long An Province border with Cambodia. Long An Province also displayed the lowest rate of infection, despite a very high Breteau Index, high human population density and presence of the main cross border road system. The highest incidence was found in Dac Nong Province, where the Breteau and Container indices were the second lowest. Dengue virus was detected in five Aedes albopictus, three Aedes aegypti and one Culex vishnui. Chikungunya virus was detected in two Ae. aegypti. All infected mosquitoes belonged to haplotypes described in other parts of the world and a number of novel haplotypes were found among uninfected mosquitoes.

Conclusions: Dengue is considered to be regularly introduced to Vietnam from Cambodia, mostly through human movement. The data reported here provides a complementary picture. Due to intensive international trade, long-distance transportation of mosquito populations may play a role in the regular importation of dengue in Vietnam through Ho Chi Minh City. It is important to decipher the movement of mosquitoes in Vietnam, not only at the Lao PDR and Cambodia borders but also through international trade routes. Mosquito surveillance programs should address and follow mosquito populations instead of mosquito species.
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http://dx.doi.org/10.1186/s13071-017-2422-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680899PMC
November 2017

Human babesiosis: Indication of a molecular mimicry between thrombospondin domains from a novel Babesia microti BmP53 protein and host platelets molecules.

PLoS One 2017 17;12(10):e0185372. Epub 2017 Oct 17.

Institut de Biologie Computationnelle (IBC), LIRMM, CNRS, Université de Montpellier, Montpellier, France.

Human babesiosis is caused by the apicomplexan parasite Babesia microti, which is of major public health concern in the United States and elsewhere, resulting in malaise and fatigue, followed by a fever and hemolytic anemia. In this paper we focus on the characterization of a novel B. microti thrombospondin domain (TSP1)-containing protein (BmP53) from the new annotation of the B. microti genome (locus 'BmR1_04g09041'). This novel protein (BmP53) had a single TSP1 and a transmembrane domain, with a short cytoplasmic tail containing a sub-terminal glutamine residue, but no signal peptide and Von Willebrand factor type A domains (VWA), which are found in classical thrombospondin-related adhesive proteins (TRAP). Co-localization assays of BmP53 and Babesia microti secreted antigen 1 (BmSA1) suggested that BmP53 might be a non-secretory membranous protein. Molecular mimicry between the TSP1 domain from BmP53 and host platelets molecules was indicated through different measures of sequence homology, phylogenetic analysis, 3D structure and shared epitopes. Indeed, hamster isolated platelets cross-reacted with mouse anti-BmP53-TSP1. Molecular mimicry are used to help parasites to escape immune defenses, resulting in immune evasion or autoimmunity. Furthermore, specific host reactivity was also detected against the TSP1-free part of BmP53 in infected hamster sera. In conclusion, the TSP1 domain mimicry might help in studying the mechanisms of parasite-induced thrombocytopenia, with the TSP1-free truncate of the protein representing a potential safe candidate for future vaccine studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185372PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644982PMC
October 2017

Valine/isoleucine variants drive selective pressure in the VP1 sequence of EV-A71 enteroviruses.

BMC Infect Dis 2017 05 8;17(1):333. Epub 2017 May 8.

Cirad, UMR 17, Intertryp, TA-A17/G, Campus International de Baillarguet, 34398, Montpellier Cedex 5, France.

Background: In 2011-2012, Northern Vietnam experienced its first large scale hand foot and mouth disease (HFMD) epidemic. In 2011, a major HFMD epidemic was also reported in South Vietnam with fatal cases. This 2011-2012 outbreak was the first one to occur in North Vietnam providing grounds to study the etiology, origin and dynamic of the disease. We report here the analysis of the VP1 gene of strains isolated throughout North Vietnam during the 2011-2012 outbreak and before.

Methods: The VP1 gene of 106 EV-A71 isolates from North Vietnam and 2 from Central Vietnam were sequenced. Sequence alignments were analyzed at the nucleic acid and protein level. Gene polymorphism was also analyzed. A Factorial Correspondence Analysis was performed to correlate amino acid mutations with clinical parameters.

Results: The sequences were distributed into four phylogenetic clusters. Three clusters corresponded to the subgenogroup C4 and the last one corresponded to the subgenogroup C5. Each cluster displayed different polymorphism characteristics. Proteins were highly conserved but three sites bearing only Isoleucine (I) or Valine (V) were characterized. The isoleucine/valine variability matched the clusters. Spatiotemporal analysis of the I/V variants showed that all variants which emerged in 2011 and then in 2012 were not the same but were all present in the region prior to the 2011-2012 outbreak. Some correlation was found between certain I/V variants and ethnicity and severity.

Conclusions: The 2011-2012 outbreak was not caused by an exogenous strain coming from South Vietnam or elsewhere but by strains already present and circulating at low level in North Vietnam. However, what triggered the outbreak remains unclear. A selective pressure is applied on I/V variants which matches the genetic clusters. I/V variants were shown on other viruses to correlate with pathogenicity. This should be investigated in EV-A71. I/V variants are an easy and efficient way to survey and identify circulating EV-A71 strains.
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http://dx.doi.org/10.1186/s12879-017-2427-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422960PMC
May 2017

Babesia microti from humans and ticks hold a genomic signature of strong population structure in the United States.

BMC Genomics 2016 11 7;17(1):888. Epub 2016 Nov 7.

Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, 06520, USA.

Background: Babesia microti is an emerging tick-borne apicomplexan parasite with increasing geographic range and incidence in the United States. The rapid expansion of B. microti into its current distribution in the northeastern USA has been due to the range expansion of the tick vector, Ixodes scapularis, upon which the causative agent is dependent for transmission to humans.

Results: To reconstruct the history of B. microti in the continental USA and clarify the evolutionary origin of human strains, we used multiplexed hybrid capture of 25 B. microti isolates obtained from I. scapularis and human blood. Despite low genomic variation compared with other Apicomplexa, B. microti was strongly structured into three highly differentiated genetic clusters in the northeastern USA. Bayesian analyses of the apicoplast genomes suggest that the origin of the current diversity of B. microti in northeastern USA dates back 46 thousand years with a signature of recent population expansion in the last 1000 years. Human-derived samples belonged to two rarely intermixing clusters, raising the possibility of highly divergent infectious phenotypes in humans.

Conclusions: Our results validate the multiplexed hybrid capture strategy for characterizing genome-wide diversity and relatedness of B. microti from ticks and humans. We find strong population structure in B. microti samples from the Northeast indicating potential barriers to gene flow.
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http://dx.doi.org/10.1186/s12864-016-3225-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100190PMC
November 2016

Genome-wide diversity and gene expression profiling of Babesia microti isolates identify polymorphic genes that mediate host-pathogen interactions.

Sci Rep 2016 10 18;6:35284. Epub 2016 Oct 18.

Antigen Discovery Inc., Irvine, CA, 92618 USA.

Babesia microti, a tick-transmitted, intraerythrocytic protozoan parasite circulating mainly among small mammals, is the primary cause of human babesiosis. While most cases are transmitted by Ixodes ticks, the disease may also be transmitted through blood transfusion and perinatally. A comprehensive analysis of genome composition, genetic diversity, and gene expression profiling of seven B. microti isolates revealed that genetic variation in isolates from the Northeast United States is almost exclusively associated with genes encoding the surface proteome and secretome of the parasite. Furthermore, we found that polymorphism is restricted to a small number of genes, which are highly expressed during infection. In order to identify pathogen-encoded factors involved in host-parasite interactions, we screened a proteome array comprised of 174 B. microti proteins, including several predicted members of the parasite secretome. Using this immuno-proteomic approach we identified several novel antigens that trigger strong host immune responses during the onset of infection. The genomic and immunological data presented herein provide the first insights into the determinants of B. microti interaction with its mammalian hosts and their relevance for understanding the selective pressures acting on parasite evolution.
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http://dx.doi.org/10.1038/srep35284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082761PMC
October 2016

Genetic Characterization of Plasmodium Putative Pantothenate Kinase Genes Reveals Their Essential Role in Malaria Parasite Transmission to the Mosquito.

Sci Rep 2016 09 20;6:33518. Epub 2016 Sep 20.

Tulane University, Department of Tropical Medicine, New Orleans, LA 70112, USA.

The metabolic machinery for the biosynthesis of Coenzyme A (CoA) from exogenous pantothenic acid (Vitamin B5) has long been considered as an excellent target for the development of selective antimicrobials. Earlier studies in the human malaria parasite Plasmodium falciparum have shown that pantothenate analogs interfere with pantothenate phosphorylation and block asexual blood stage development. Although two eukaryotic-type putative pantothenate kinase genes (PanK1 and PanK2) have been identified in all malaria parasite species, their role in the development of Plasmodium life cycle stages remains unknown. Here we report on the genetic characterization of PanK1 and PanK2 in P. yoelii. We show that P. yoelii parasites lacking either PanK1 or PanK2 undergo normal asexual stages development and sexual stages differentiation, however they are severely deficient in ookinete, oocyst and sporozoite formation inside the mosquito vector. Quantitative transcriptional analyses in wild-type and knockout parasites demonstrate an important role for these genes in the regulation of expression of other CoA biosynthesis genes. Together, our data provide the first genetic evidence for the importance of the early steps of pantothenate utilization in the regulation of CoA biosynthesis and malaria parasite transmission to Anopheles mosquitoes.
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http://dx.doi.org/10.1038/srep33518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028760PMC
September 2016

Plasmodium falciparum parasite population structure and gene flow associated to anti-malarial drugs resistance in Cambodia.

Malar J 2016 06 14;15:319. Epub 2016 Jun 14.

Institut de Biologie Computationnelle (IBC), Montpellier, France.

Background: Western Cambodia is recognized as the epicentre of emergence of Plasmodium falciparum multi-drug resistance. The emergence of artemisinin resistance has been observed in this area since 2008-2009 and molecular signatures associated to artemisinin resistance have been characterized in k13 gene. At present, one of the major threats faced, is the possible spread of Asian artemisinin resistant parasites over the world threatening millions of people and jeopardizing malaria elimination programme efforts. To anticipate the diffusion of artemisinin resistance, the identification of the P. falciparum population structure and the gene flow among the parasite population in Cambodia are essential.

Methods: To this end, a mid-throughput PCR-LDR-FMA approach based on LUMINEX technology was developed to screen for genetic barcode in 533 blood samples collected in 2010-2011 from 16 health centres in malaria endemics areas in Cambodia.

Results: Based on successful typing of 282 samples, subpopulations were characterized along the borders of the country. Each 11-loci barcode provides evidence supporting allele distribution gradient related to subpopulations and gene flow. The 11-loci barcode successfully identifies recently emerging parasite subpopulations in western Cambodia that are associated with the C580Y dominant allele for artemisinin resistance in k13 gene. A subpopulation was identified in northern Cambodia that was associated to artemisinin (R539T resistant allele of k13 gene) and mefloquine resistance.

Conclusions: The gene flow between these subpopulations might have driven the spread of artemisinin resistance over Cambodia.
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http://dx.doi.org/10.1186/s12936-016-1370-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908689PMC
June 2016

A targeted immunomic approach identifies diagnostic antigens in the human pathogen Babesia microti.

Transfusion 2016 08 17;56(8):2085-99. Epub 2016 May 17.

Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, Connecticut.

Background: Babesia microti is a protozoan parasite responsible for the majority of reported cases of human babesiosis and a major risk to the blood supply. Laboratory screening of blood donors may help prevent transfusion-transmitted babesiosis but there is no Food and Drug Administration-approved screening method yet available. Development of a sensitive, specific, and highly automated B. microti antibody assay for diagnosis of acute babesiosis and blood screening could have an important impact on decreasing the health burden of B. microti infection.

Study Design And Methods: Herein, we take advantage of recent advances in B. microti genomic analyses, field surveys of the reservoir host, and human studies in endemic areas to apply a targeted immunomic approach to the discovery of B. microti antigens that serve as signatures of active or past babesiosis infections. Of 19 glycosylphosphatidylinositol (GPI)-anchored protein candidates (BmGPI1-19) identified in the B. microti proteome, 17 were successfully expressed, printed on a microarray chip, and used to screen sera from uninfected and B. microti-infected mice and humans to determine immune responses that are associated with active and past infection.

Results: Antibody responses to various B. microti BmGPI antigens were detected and BmGPI12 was identified as the best biomarker of infection that provided high sensitivity and specificity when used in a microarray antibody assay.

Conclusion: BmGPI12 alone or in combination with other BmGPI proteins is a promising candidate biomarker for detection of B. microti antibodies that might be useful in blood screening to prevent transfusion-transmitted babesiosis.
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http://dx.doi.org/10.1111/trf.13640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644385PMC
August 2016

Surveillance of dengue and chikungunya infection in Dong Thap, Vietnam: A 13-month study.

Asian Pac J Trop Med 2016 Jan 19;9(1):39-43. Epub 2015 Dec 19.

National Institute of Hygiene and Epidemiology, 1 Yersin Street, 10000 Hanoi, Viet Nam. Electronic address:

Objective: To establish a surveillance in Dong Thap, at the border with Cambodia by assessing the presence of DENV serotypes and CHIKV among patients hospitalized at Dong Thap general hospital.

Methods: Cross-sectional descriptive analysis was conducted on a cohort of 131 patients hospitalized with acute fever and symptoms compatible with dengue or chikungunya. The study was conducted from January 2012 to February 2013. The full clinical picture was established as well as serological and molecular detection. Serological analysis was sequentially performed on blood samples collected on admission and an average of seven days after admission. The detection of IgM antibody to DENV was performed by IgM capture ELISA and the detection of DENV and CHIKV RNA was done by reverse-transcription multiplex PCR.

Results: 101 patients out of 131 (77%) were confirmed with dengue. All four dengue serotypes were detected with a predominance of DENV2 and DENV4. No chikungunya infection was detected although reported in neighboring Cambodia. A differential efficiency of serological dengue detection was observed. Efficiency was 29% upon admission and 53% after seven days on the same patients. 30 patients out of 131 (23%) were negative with both DENV and CHIKV.

Conclusions: Dengue is at risk of being underestimated and chikungunya is not systematically detected. Changes in detection and surveillance procedures are therefore discussed to increase efficiency of dengue detection and continue the monitoring the emergence of CHIKV in Dong Thap province and in Vietnam.
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http://dx.doi.org/10.1016/j.apjtm.2015.12.008DOI Listing
January 2016

Subtelomere organization in the genome of the microsporidian Encephalitozoon cuniculi: patterns of repeated sequences and physicochemical signatures.

BMC Genomics 2016 Jan 7;17:34. Epub 2016 Jan 7.

Institut de Recherche en Cancérologie de Montpellier, IRCM - INSERM U1194 & Université de Montpellier & ICM, Institut régional du Cancer Montpellier, Campus Val d'Aurelle, 34298, Montpellier cedex 5, France.

Background: The microsporidian Encephalitozoon cuniculi is an obligate intracellular eukaryotic pathogen with a small nuclear genome (2.9 Mbp) consisting of 11 chromosomes. Although each chromosome end is known to contain a single rDNA unit, the incomplete assembly of subtelomeric regions following sequencing of the genome identified only 3 of the 22 expected rDNA units. While chromosome end assembly remains a difficult process in most eukaryotic genomes, it is of significant importance for pathogens because these regions encode factors important for virulence and host evasion.

Results: Here we report the first complete assembly of E. cuniculi chromosome ends, and describe a novel mosaic structure of segmental duplications (EXT repeats) in these regions. EXT repeats range in size between 3.5 and 23.8 kbp and contain four multigene families encoding membrane associated proteins. Twenty-one recombination sites were identified in the sub-terminal region of E. cuniculi chromosomes. Our analysis suggests that these sites contribute to the diversity of chromosome ends organization through Double Strand Break repair mechanisms. The region containing EXT repeats at chromosome extremities can be differentiated based on gene composition, GC content, recombination sites density and chromosome landscape.

Conclusion: Together this study provides the complete structure of the chromosome ends of E. cuniculi GB-M1, and identifies important factors, which could play a major role in parasite diversity and host-parasite interactions. Comparison with other eukaryotic genomes suggests that terminal regions could be distinguished precisely based on gene content, genetic instability and base composition biais. The diversity of processes assciated with chromosome extremities and their biological consequences, as they are presented in the present study, emphasize the fact that great effort will be necessary in the future to characterize more carefully these regions during whole genome sequencing efforts.
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http://dx.doi.org/10.1186/s12864-015-1920-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704409PMC
January 2016

Role of Aedes aegypti and Aedes albopictus during the 2011 dengue fever epidemics in Hanoi, Vietnam.

Asian Pac J Trop Med 2015 Jul 9;8(7):543-8. Epub 2015 Jul 9.

National Institute of Hygiene and Epidemiology, 1 Yersin Street, 10000 Hanoi, Viet Nam.

Objective: To record the human cases of dengue fever (DF) and investigate the Aedes mosquito species circulating during the Hanoi 2011 DF epidemics.

Methods: 24 different outbreak points were recorded in 8 districts between August and December 2011.

Results: 140 patients were hospitalized following dengue diagnostic with a predominance of males (59.3%) and the 15-34 age class. Only DENV-1 (11.27%) and DENV-2 (88.73%) serotypes were detected in human samples. Mosquito sampling performed in and around patients households revealed the predominance of Aedes aegypti (A. aegypti) (95.15%) versus Aedes albopictus (4.85%).

Conclusions: There is a positive correlation between the population density of A. aegypti and the number of human cases and duration of outbreaks. This was not observed for Aedes albopictus. Three pools of A. aegypti were positive with dengue virus, two with DENV-1 and one with DENV-2.
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http://dx.doi.org/10.1016/j.apjtm.2015.06.009DOI Listing
July 2015

Genetic diversity of human rhinoviruses in Cambodia during a three-year period reveals novel genetic types.

Infect Genet Evol 2015 Oct 29;35:42-9. Epub 2015 Jul 29.

Institut Pasteur in Cambodia, Virology Unit, 5 Monivong Blvd, PO Box 983, Phnom Penh, Cambodia. Electronic address:

Acute respiratory viral infections are a major cause of morbidity during early childhood in developing countries. Human rhinoviruses are the most frequent cause of upper respiratory tract infections in humans, which can range in severity from asymptomatic to clinically severe disease. In this study we collected 4170 nasopharyngeal swabs from patients hospitalised with influenza-like illness in two Cambodian provincial hospitals between 2007 and 2010. Samples were screened for 18 respiratory viruses using 5 multiplex PCRs. A total of 11.2% of samples tested positive for human rhinoviruses (HRV). VP4/2 and VP1 regions were amplified and sequenced to study the distribution of rhinoviruses genotypes and species in Cambodia during this three-year period. Five novel genotypes, 2 species A, 2 species B and 1 species C were identified based on VP1 sequences. Co-infections with other viruses were demonstrated.
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http://dx.doi.org/10.1016/j.meegid.2015.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105975PMC
October 2015

Montpellier Infectious Diseases - Pôle Rabelais (MID) 3rd annual meeting (2014).

Infect Genet Evol 2015 Jun 16;32:161-4. Epub 2015 Mar 16.

Inserm U1058, Université Montpellier & CHRU de Montpellier, Département de Bactériologie-Virologie & Institut de Recherche en Biothérapie, Montpellier, France.

For the third time, teams belonging to the "Montpellier Infectious Diseases" network in the Rabelais BioHealth Cluster held their annual meeting on the 27th and 28th of November in Montpellier, France. While the 2012 meeting was focused on the cooperation between the local force tasks in biomedical and medical chemistry and presented the interdisciplinary research programs designed to fight against virus, bacteria and parasites, the 2014 edition of the meeting was focused on the translational research in infectious diseases and highlighted the bench-to-clinic strategies designed by academic and private research groups in the Montpellier area.
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http://dx.doi.org/10.1016/j.meegid.2015.03.007DOI Listing
June 2015

Orientia tsutsugamushi, agent of scrub typhus, displays a single metapopulation with maintenance of ancestral haplotypes throughout continental South East Asia.

Infect Genet Evol 2015 Apr 8;31:1-8. Epub 2015 Jan 8.

UM2, CPBS, UMR 5236, CNRS-UM1-UM2, 1919 route de Mende, 34293 Montpellier Cedex 5, France; Cirad, UMR 17, Cirad-Ird, TA-A17/G, Campus International de Baillarguet, 34398 Montpellier Cedex 5, France. Electronic address:

Orientia tsutsugamushi is the causative agent of scrub typhus, a major cause of febrile illness in rural area of Asia-Pacific region. A multi-locus sequence typing (MLST) analysis was performed on strains isolated from human patients from 3 countries in Southeast Asia: Cambodia, Vietnam and Thailand. The phylogeny of the 56-kDa protein encoding gene was analyzed on the same strains and showed a structured topology with genetically distinct clusters. MLST analysis did not lead to the same conclusion. DNA polymorphism and phylogeny of individual gene loci indicated a significant level of recombination and genetic diversity whereas the ST distribution indicated the presence of isolated patches. No correlation was found with the geographic origin. This work suggests that weak divergence in core genome and ancestral haplotypes are maintained by permanent recombination in mites while the 56-kDa protein gene is diverging in higher speed due to selection by the mammalian immune system.
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http://dx.doi.org/10.1016/j.meegid.2015.01.005DOI Listing
April 2015

Sequence and annotation of the apicoplast genome of the human pathogen Babesia microti.

PLoS One 2014 3;9(10):e107939. Epub 2014 Oct 3.

Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, Connecticut, United States of America.

The apicomplexan intraerythrocytic parasite Babesia microti is an emerging human pathogen and the primary cause of human babesiosis, a malaria-like illness endemic in the United States. The pathogen is transmitted to humans by the tick vector, Ixodes scapularis, and by transfusion of blood from asymptomatic B. microti-infected donors. Whereas the nuclear and mitochondrial genomes of this parasite have been sequenced, assembled and annotated, its apicoplast genome remained incomplete, mainly due to its low representation and high A+T content. Here we report the complete sequence and annotation of the apicoplast genome of the B. microti R1 isolate. The genome consists of a 28.7 kb circular molecule encoding primarily functions important for maintenance of the apicoplast DNA, transcription, translation and maturation of organellar proteins. Genome analysis and annotation revealed a unique gene structure and organization of the B. microti apicoplast genome and suggest that all metabolic and non-housekeeping functions in this organelle are nuclear-encoded. B. microti apicoplast functions are significantly different from those of the host, suggesting that they might be useful as targets for development of potent and safe therapies for the treatment of human babesiosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0107939PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184790PMC
July 2015

Whole genome mapping and re-organization of the nuclear and mitochondrial genomes of Babesia microti isolates.

PLoS One 2013 4;8(9):e72657. Epub 2013 Sep 4.

Centre d'étude d'agents Pathogènes et Biotechnologies pour la Santé - UMR 5236, Montpellier, France ; Institut de Biologie Computationnelle, Montpellier, France.

Babesia microti is the primary causative agent of human babesiosis, an emerging pathogen that causes a malaria-like illness with possible fatal outcome in immunocompromised patients. The genome sequence of the B. microti R1 strain was reported in 2012 and revealed a distinct evolutionary path for this pathogen relative to that of other apicomplexa. Lacking from the first genome assembly and initial molecular analyses was information about the terminal ends of each chromosome, and both the exact number of chromosomes in the nuclear genome and the organization of the mitochondrial genome remained ambiguous. We have now performed various molecular analyses to characterize the nuclear and mitochondrial genomes of the B. microti R1 and Gray strains and generated high-resolution Whole Genome maps. These analyses show that the genome of B. microti consists of four nuclear chromosomes and a linear mitochondrial genome present in four different structural types. Furthermore, Whole Genome mapping allowed resolution of the chromosomal ends, identification of areas of misassembly in the R1 genome, and genomic differences between the R1 and Gray strains, which occur primarily in the telomeric regions. These studies set the stage for a better understanding of the evolution and diversity of this important human pathogen.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072657PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762879PMC
April 2014

Identification and functional analysis of the primary pantothenate transporter, PfPAT, of the human malaria parasite Plasmodium falciparum.

J Biol Chem 2013 Jul 31;288(28):20558-67. Epub 2013 May 31.

Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

The human malaria parasite Plasmodium falciparum is absolutely dependent on the acquisition of host pantothenate for its development within human erythrocytes. Although the biochemical properties of this transport have been characterized, the molecular identity of the parasite-encoded pantothenate transporter remains unknown. Here we report the identification and functional characterization of the first protozoan pantothenate transporter, PfPAT, from P. falciparum. We show using cell biological, biochemical, and genetic analyses that this transporter is localized to the parasite plasma membrane and plays an essential role in parasite intraerythrocytic development. We have targeted PfPAT to the yeast plasma membrane and showed that the transporter complements the growth defect of the yeast fen2Δ pantothenate transporter-deficient mutant and mediates the entry of the fungicide drug, fenpropimorph. Our studies in P. falciparum revealed that fenpropimorph inhibits the intraerythrocytic development of both chloroquine- and pyrimethamine-resistant P. falciparum strains with potency equal or better than that of currently available pantothenate analogs. The essential function of PfPAT and its ability to deliver both pantothenate and fenpropimorph makes it an attractive target for the development and delivery of new classes of antimalarial drugs.
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http://dx.doi.org/10.1074/jbc.M113.482992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711320PMC
July 2013

Spraguea lophii (Microsporidia) parasite of the teleost fish, Lophius piscatorius from Tunisian coasts: evidence for an extensive chromosome length polymorphism.

Parasitol Int 2013 Feb 9;62(1):66-74. Epub 2012 Oct 9.

Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.

A microsporidian of the genus Spraguea was found parasitizing the nervous tissues of Lophius piscatorius collected from various localities in the Mediterranean coastal areas of Tunisia. The tissue localization, the infection focus aspect and sporal dimorphism are characteristics of Spraguea lophii species. Molecular data based on partial sequence of SSUrRNA encoding gene shows few nucleotide polymorphisms, compared to all described Spraguea isolates. Molecular karyotype obtained on pulsed field gel electrophoresis (1D-PFGE) shows a profile with 14 stained bands in the range of 230-880 kbp and a genome size estimated to 6.700 kbp. The rare cutter endonuclease MluI KARD 2-D-PFGE fingerprint shows an extensive chromosome length polymorphism, but the number of chromosome is unchanged and consists of 15 different molecules. The extensive chromosome length polymorphism is associated to a reduced number of genetic events.
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http://dx.doi.org/10.1016/j.parint.2012.09.007DOI Listing
February 2013

Sequencing of the smallest Apicomplexan genome from the human pathogen Babesia microti.

Nucleic Acids Res 2012 Oct 24;40(18):9102-14. Epub 2012 Jul 24.

Laboratoire de Biologie Cellulaire et Moléculaire (LBCM-EA4558), UFR Pharmacie, Université Montpellier 1, 15, av. Charles Flahault, 34093 Montpellier cedex 5, France.

We have sequenced the genome of the emerging human pathogen Babesia microti and compared it with that of other protozoa. B. microti has the smallest nuclear genome among all Apicomplexan parasites sequenced to date with three chromosomes encoding ∼3500 polypeptides, several of which are species specific. Genome-wide phylogenetic analyses indicate that B. microti is significantly distant from all species of Babesidae and Theileridae and defines a new clade in the phylum Apicomplexa. Furthermore, unlike all other Apicomplexa, its mitochondrial genome is circular. Genome-scale reconstruction of functional networks revealed that B. microti has the minimal metabolic requirement for intraerythrocytic protozoan parasitism. B. microti multigene families differ from those of other protozoa in both the copy number and organization. Two lateral transfer events with significant metabolic implications occurred during the evolution of this parasite. The genomic sequencing of B. microti identified several targets suitable for the development of diagnostic assays and novel therapies for human babesiosis.
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http://dx.doi.org/10.1093/nar/gks700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467087PMC
October 2012

Metagenomic approach studying the taxonomic and functional diversity of the bacterial community in a mesotrophic lake (Lac du Bourget--France).

Environ Microbiol 2009 Sep 25;11(9):2412-24. Epub 2009 Jun 25.

Université Blaise Pascal--Laboratoire Microorganismes: génome et environnement, UMR/CNRS 6023, Aubiere cedex, France.

The main goals of this work were to identify the metabolic pathways of the bacterial community in a lacustrine ecosystem and to establish links between taxonomic composition and the relative abundances of these metabolic pathways. For this purpose, we analysed a 16S rRNA gene library obtained by gene amplification together with a sequence library of both insert ends on c. 7700 fosmids. Whatever the library used, Actinobacteria was the most abundant bacterial group, followed by Proteobacteria and Bacteroidetes. Specific aquatic clades such as acI and acIV (Actinobacteria) or LD12 and GOBB-C201 (Alphaproteobacteria) were found in both libraries. From comparative analysis of metagenomic libraries, the metagenome of this lake was characterized by overrepresentation of genes involved in the degradation of xenobiotics mainly associated with Alphaproteobacteria. Actinobacteria were mainly related to metabolic pathways involved in nucleotide metabolism, cofactors, vitamins, energy, replication and repair. Betaproteobacteria appeared to be characterized by the presence of numerous genes implicated in environmental information processing (membrane transport and signal transduction) whereas glycan and carbohydrate metabolism pathways were overrepresented in Bacteroidetes. These results prompted us to propose hypotheses on the ecological role of these bacterial classes in lacustrine ecosystems.
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http://dx.doi.org/10.1111/j.1462-2920.2009.01969.xDOI Listing
September 2009

InterB multigenic family, a gene repertoire associated with subterminal chromosome regions of Encephalitozoon cuniculi and conserved in several human-infecting microsporidian species.

Curr Genet 2007 Mar;51(3):171-86

Equipe Parasitologie Moléculaire et Cellulaire, Laboratoire de Biologie des Protistes, UMR CNRS 6023, Bâtiment Biologie A, Université Blaise Pascal, 63177 Aubière cedex, France.

Microsporidia are fungi-related obligate intracellular parasites that infect numerous animals, including man. Encephalitozoon cuniculi harbours a very small genome (2.9 Mbp) with about 2,000 coding sequences (CDSs). Most repeated CDSs are of unknown function and are distributed in subterminal regions that mark the transitions between subtelomeric rDNA units and chromosome cores. A potential multigenic family (interB) encoding proteins within a size range of 579-641 aa was investigated by PCR and RT-PCR. Thirty members were finally assigned to the E. cuniculi interB family and a predominant interB transcript was found to originate from a newly identified gene on chromosome III. Microsporidian species from eight different genera infecting insects, fishes or mammals, were tested for a possible intra-phylum conservation of interB genes. Only representatives of the Encephalitozoon, Vittaforma and Brachiola genera, differing in host range but all able to invade humans, were positive. Molecular karyotyping of Brachiola algerae showed a complex set of chromosome bands, providing a haploid genome size estimate of 15-20 Mbp. In spite of this large difference in genome complexity, B. algerae and E. cuniculi shared some similar interB gene copies and a common location of interB genes in near-rDNA subterminal regions.
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http://dx.doi.org/10.1007/s00294-006-0114-xDOI Listing
March 2007

Description of a xenoma-inducing microsporidian, Microgemma tincae n. sp., parasite of the teleost fish Symphodus tinca from Tunisian coasts.

Dis Aquat Organ 2005 Jul;65(3):217-26

Parasitologie Moléculaire et Cellulaire, UMR 6023 CNRS--Université Blaise Pascal, Campus Universitaire des Cézeaux, Bâtiment Biologie A, 63177 Aubière cedex, France.

A xenoma-inducing microsporidian species was found to infect the liver of the teleost fish, peacock wrasse Symphodus (Crenilabrus) tinca. Minimal estimates of the prevalence of the parasite in fishes caught along Tunisian coasts were as high as 43 % for Bizerte samples (over 2 yr) and 72% for Monastir samples (over 3 yr). Developmental stages were dispersed within a xenoma structure that was bounded only by the plasma membrane of the hypertrophic host cell. Ultrastructural features support allocation to the genus Microgemma Ralphs and Matthews, 1986. Meronts were multinucleate plasmodia and were surrounded by rough endoplasmic reticulum (RER) of the host cell. Merogonic plasmodia developed into sporogonic plasmodia, with loss of the RER interface. Sporogony was polysporoblastic. Ovocylindrical spores (3.6 x 1.2 microm) harbored a lamellar polaroplast and a polar tube that was coiled 9 times. Spore features and host specificity led us to propose a new species, Microgemma tincae. The conversion of M. tincae xenomas into well-visible cyst structures or granulomas reflected an efficient host response involving the infiltration of phagocytic cells, degradation of various parasite stages and formation of a thick fibrous wall. The small subunit rDNA gene of M. tincae was partially sequenced. Phylogenetic analysis confirms the placement within the family Tetramicriidae represented by the genera Tetramicra and Microgemma.
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http://dx.doi.org/10.3354/dao065217DOI Listing
July 2005

Chromosomal composition of the genome in the monomorphic diplokaryotic microsporidium Paranosema grylli: analysis by two-dimensional pulsed-field gel electrophoresis.

Folia Parasitol (Praha) 2005 May;52(1-2):145-57

Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064 St. Petersburg, Russia.

The molecular karyotype of Paranosema grylli Sokolova, Seleznev, Dolgikh et Issi, 1994, a monomorphic diplokaryotic microsporidium, comprises numerous bright and faint bands of nonstoichiometric staining intensity. Restriction analysis of chromosomal DNAs by "karyotype and restriction display" 2-D PFGE has demonstrated that the complexity of molecular karyotype of P. grylli is related to the pronounced length polymorphism of-homologous chromosomes. The background of this phenomenon is discussed in the context of ploidy state, reproductive strategy and population structure in this microsporidium. We propose that the remarkable size variation between homologous chromosomes in P. grylli may be a consequence of ectopic recombination at the chromosome extremities.
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http://dx.doi.org/10.14411/fp.2005.019DOI Listing
May 2005