scholarly journals Antigenic variation in Giardia lamblia and the host's immune response

1997 ◽  
Vol 352 (1359) ◽  
pp. 1369-1375 ◽  
Author(s):  
Theodore E. Nash
Keyword(s):  
Giardia Lamblia ◽  
Antigenic Variation ◽  
Protozoan Parasite ◽  
Scid Mice ◽  
Surface Proteins ◽  
Mouse Strains ◽  
Post Inoculation ◽  
Immune Pressure ◽  
Selection Of

Giardia lamblia , a protozoan parasite of the small intestine of humans and other animals, undergoes surface antigenic variation. The antigens involved belong to a family of variant–specific surface proteins (VSPs), which are unique, cysteine–rich zinc finger proteins. The patterns of infection in humans and animals fail to show the expected cyclical waves of increasing and decreasing numbers of parasites expressing unique VSPs. Nevertheless, changes in VSP expression occur within the population in vivo owing to selection of VSPs by both immune and non–immune mechanisms. After inoculation of a single G. lamblia clone (able to persist in in the absence of immune pressure) expressing one VSP (greater than 90 per cent) into mice or humans, the original VSP continues to be expressed until 2 weeks post inoculation (p.i.), when many other VSPs gradually replace it. Selection by immune–mediated processes is suggested because switching occurs at the same time that humoral responses are first detected. In most mouse strains, switching also occurs at about two weeks. Almost all trophozoites are eliminated at three weeks (p.i.), but a barely detectable infection persists over months. In neonatal mice, apparent self–cure is delayed until the sixth or seventh week. Antigenic switching does not occur in adult or neonatal SCID mice, but does occur in neonatal nude mice, thus implicating B–cell–mediated mechanisms in immune switching. Not all VSPs are expressed to the same degree in vivo . Some VSPs appear to be preferentially selected whereas others are eliminated on a non–immune basis. In infections in which immunity does not play a role, such as in SCID mice, and during the first week of infection in immunocompetent mice or gerbils, persisting VSPs are preferentially expressed and maintained whereas non–persisting VSPs are replaced within the first week of infection. The purpose of antigenic variation may be presentation of a wide assortment of VSPs to hosts, increasing the chance of a successful initial infection or reinfection. Immune selection of variants comes into play following biological selection.

scholarly journals Comparative proteomics of three Giardia lamblia strains: investigation of antigenic variation in the post-genomic era

Parasitology ◽  
2020 ◽  
Vol 147 (9) ◽  
pp. 1008-1018 ◽  
Author(s):  
Joachim Müller ◽  
Sophie Braga ◽  
Anne-Christine Uldry ◽  
Manfred Heller ◽  
Norbert Müller
Keyword(s):  
Giardia Lamblia ◽  
Antigenic Variation ◽  
Restriction Analysis ◽  
Surface Proteins ◽  
Differentially Expressed ◽  
Laboratory Research ◽  
Persistent Diarrhoea ◽  
Reading Frame ◽  
Expression Levels ◽  
Predominant Variant

AbstractGiardia lamblia is a causative agent of persistent diarrhoea widespread in regions with low hygienic standards. Laboratory research is based on cloned lines issuing from various patient isolates typed in the late 1980s and 90s using restriction analysis and serology. In the present study, we compared the well-characterized strain WBC6 with another clone of the parent WB isolate termed WBA1 and with a clone from another isolate, GS/M-83-H7, using shotgun mass spectrometry proteomics. We identified 398 proteins differentially expressed between the GS and both WB isolates and 97 proteins differentially expressed between the two WB isolates. We investigated the expression levels of the predominant variant-specific surface proteins (VSPs) in each clone and matched the previously described major VSPs of each strain to the corresponding open reading frame sequences identified by whole-genome sequencing efforts. Furthermore, since the original WB isolate comes from a patient treated with metronidazole, we compared the susceptibilities of the strains to nitro compounds, as well the expression levels of enzymes involved in nitro reduction and on the corresponding enzyme activities and found distinct differences between the three strains.

scholarly journals Influenza Hemagglutinin and Neuraminidase: Yin–Yang Proteins Coevolving to Thwart Immunity

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 346 ◽  
Author(s):  
Ivan Kosik ◽  
Jonathan W. Yewdell
Keyword(s):  
Influenza A ◽  
Antigenic Variation ◽  
Innate Immune ◽  
Viral Fitness ◽  
Adaptive Immune ◽  
Influenza Hemagglutinin ◽  
Immune Pressure ◽  
Virion Release ◽  
Infectious Cycle

Influenza A virions possess two surface glycoproteins—the hemagglutinin (HA) and neuraminidase (NA)—which exert opposite functions. HA attaches virions to cells by binding to terminal sialic acid residues on glycoproteins/glycolipids to initiate the infectious cycle, while NA cleaves terminal sialic acids, releasing virions to complete the infectious cycle. Antibodies specific for HA or NA can protect experimental animals from IAV pathogenesis and drive antigenic variation in their target epitopes that impairs vaccine effectiveness in humans. Here, we review progress in understanding HA/NA co-evolution as each acquires epistatic mutations to restore viral fitness to mutants selected in the other protein by host innate or adaptive immune pressure. We also discuss recent exciting findings that antibodies to HA can function in vivo by blocking NA enzyme activity to prevent nascent virion release and enhance Fc receptor-based activation of innate immune cells.

scholarly journals A Lesson in Survival, by Giardia lamblia

2010 ◽  
Vol 10 ◽  
pp. 2019-2031 ◽  
Author(s):  
Andrea A. S. Rópolo ◽  
Maria C. Touz
Keyword(s):  
Giardia Lamblia ◽  
Drug Targets ◽  
Antigenic Variation ◽  
Protozoan Parasite ◽  
Arginine Deiminase ◽  
Multiple Roles ◽  
Variation Potential ◽  
Acquired Immune Responses ◽  
The One ◽  
Potential Drug Targets

In the relationships between host and parasites, there is a cross-talk that involves diverse mechanisms developed by two different genetic systems during years of evolution. On the one hand, immunocompetent hosts have developed effective innate and acquired immune responses that are used to restrict or avoid parasitism. On the other hand, parasites evade the immune response, expressing different antigens on their surface or by using other specific mechanisms, such as nutrient depletion. In this review, we analyze the survival mechanisms used by the protozoan parasiteGiardia lambliaduring infection. In particular, we examine the multiple roles played by the enzyme arginine deiminase during colonization of the gut, also involving the parasite's mechanism of antigenic variation. Potential drug targets for the treatment of giardiasis are also discussed.

scholarly journals Effect of Bifidobacterium Probiotic in the Treatment of Giardiasis Infection in Mice

2019 ◽  
Vol 16 (4) ◽  
pp. 0849
Author(s):  
Israa Mohammad Abd AL-Khaliq
Keyword(s):  
Single Dose ◽  
Giardia Lamblia ◽  
Control Group ◽  
Post Inoculation ◽  
Daily Application ◽  
Probiotic Activity ◽  
Giardia Cysts

Metronidazole therapy is recommended in the treatment of giardiasis,athough some clinical reports mention the resistance to this drug from many pathogens. Many studies were applied to show the effect of probiotic to prevent or to heal diseases of gastrointestine, but only few is known about probiotic activity against infections of protozoa. This study aims to evaluate the efficiency of Bifidobacterium against infection with Giardia lamblia   in experimental mice. It was found that daily application of viable Bifidobacterium cells with a single dose (0.1ml∕mice∕day) significantly reduced the shedding of Giardia lamblia parasite cysts in feces, and infection completely disappeared at the day (15th) post inoculation with this probiotic.  Also, it was noticed that Giardia cysts were reduced in the group treated with metronidazole, and infection cured at day (17th) from treatment, while the control group showed shedding cysts of this parasite. Histopathologically, the effect of Bifidobacterium in vivo by gut cells modulation prevents the colonization of Giardia, leading to reduce the infection with this parasite.

scholarly journals FcγRII (CD32) modulates antibody clearance in NOD SCID mice leading to impaired antibody-mediated tumor cell deletion

2020 ◽  
Vol 8 (1) ◽  
pp. e000619
Author(s):  
Robert J Oldham ◽  
C Ian Mockridge ◽  
Sonya James ◽  
Patrick J Duriez ◽  
H T Claude Chan ◽  
...  
Keyword(s):  
Interleukin 2 ◽  
Scid Mice ◽  
Surface Proteins ◽  
Antitumor Efficacy ◽  
Mouse Strains ◽  
Antibody Isotype ◽  
Preclinical Development ◽  
Nsg Mice ◽  
Rapid Clearance

BackgroundImmune compromised mice are increasingly used for the preclinical development of monoclonal antibodies (mAb). Most common are non-obese diabetic (NOD) severe combined immunodeficient (SCID) and their derivatives such as NOD SCID interleukin-2 γ-/- (NSG), which are attractive hosts for patient-derived xenografts. Despite their widespread use, the relative biological performance of mAb in these strains has not been extensively studied.MethodsClinically relevant mAb of various isotypes were administered to tumor and non-tumor-bearing SCID and NOD SCID mice and the mAb clearance monitored by ELISA. Expression analysis of surface proteins in both strains was carried out by flow cytometry and immunofluorescence microscopy. Further analysis was performed in vitro by surface plasmon resonance to assess mAb affinity for Fcγ receptors (FcγR) at pH 6 and pH 7.4. NOD SCID mice genetically deficient in different FcγR were used to delineate their involvement.ResultsHere, we show that strains on the NOD SCID background have significantly faster antibody clearance than other strains leading to reduced antitumor efficacy of clinically relevant mAb. This rapid clearance is dependent on antibody isotype, the presence of Fc glycosylation (at N297) and expression of FcγRII. Comparable effects were not seen in the parental NOD or SCID strains, demonstrating the presence of a compound defect requiring both genotypes. The absence of endogenous IgG was the key parameter transferred from the SCID as reconstituting NOD SCID or NSG mice with exogenous IgG overcame the rapid clearance and recovered antitumor efficacy. In contrast, the NOD strain was associated with reduced expression of the neonatal Fc Receptor (FcRn). We propose a novel mechanism for the rapid clearance of certain mAb isotypes in NOD SCID mouse strains, based on their interaction with FcγRII in the context of reduced FcRn.ConclusionsThis study highlights the importance of understanding the limitation of the mouse strain being used for preclinical evaluation, and demonstrates that NOD SCID strains of mice should be reconstituted with IgG prior to studies of mAb efficacy.

scholarly journals Establishment of Cloned Anaplasma phagocytophilum and Analysis of p44 Gene Conversion within an Infected Horse and Infected SCID Mice

2005 ◽  
Vol 73 (8) ◽  
pp. 5106-5114 ◽  
Author(s):  
Quan Lin ◽  
Yasuko Rikihisa
Keyword(s):  
Anaplasma Phagocytophilum ◽  
Antigenic Variation ◽  
Severe Combined Immunodeficiency ◽  
Hypervariable Region ◽  
Scid Mice ◽  
Infection Period ◽  
Immune Pressure ◽  
Precise Analysis ◽  
Cloning Method ◽  
Novel Method

ABSTRACT Diverse p44 alleles at the p44 expression locus (p44Es) encoding surface-exposed major membrane proteins, P44s, of Anaplasma phagocytophilum were hypothesized to be garnered by recombination to enact antigenic variation. However, this hypothesis has not been proven so far, due to inability to clone this obligate intragranulocytic rickettsia. To define the p44E recombination, we developed a novel method to clone A. phagocytophilum. This isogenic cloned population containing a defined p44E was used to infect a naive horse and severe combined immunodeficiency (SCID) mice. During a 58-day infection period in the blood of the horse, p44E conversion was evident in a total of 11 new p44Es, 48% (115/242) of the sequenced p44E population. During a 50-day infection period in the blood of SCID mice, p44E conversion was manifested in a total of 13 new p44Es, 42% (192/460) of the p44E population. Thus, similar levels of p44E convertants were detected in either the presence or absence of an acquired immune system, suggesting that T- and B-cell immune pressure was not essential for recombination and/or selection of the p44E variants. Analysis of sequentially changed p44Es revealed that the entire central hypervariable region of donor p44 pseudogenes or of donor full-length p44s replaced the same region of the resident p44E as a cassette. Putative recombination points were detected within p44 conserved regions flanking the central hypervariable region by the TOPALi analysis. Our results unambiguously demonstrated p44E recombination. The cloning method developed would facilitate precise analysis of the recombination process and the extent of diversity which the recombination creates in the antigenic repertoire.

scholarly journals Experimental Infections of Neonatal Mice with Cysts of Giardia lamblia Clone GS/M-83-H7 Are Associated with an Antigenic Reset of the Parasite

2004 ◽  
Vol 72 (8) ◽  
pp. 4763-4771 ◽  
Author(s):  
N. von Allmen ◽  
M. Bienz ◽  
A. Hemphill ◽  
N. Müller
Keyword(s):  
Giardia Lamblia ◽  
Antigenic Variation ◽  
Early Stage ◽  
Surface Protein ◽  
Protozoan Parasite ◽  
Simultaneous Increase ◽  
Transcriptional Level ◽  
Mrna Levels ◽  
Experimental Infections ◽  
Major Surface

ABSTRACT Transmission of the protozoan parasite Giardia lamblia from one to another host individuum occurs through peroral ingestion of cysts which, following excystation in the small intestine, release two trophozoites each. Many studies have focused on the major surface antigen, VSP (for variant surface protein), which is responsible for the antigenic variability of the parasite. By using trophozoites of G. lamblia clone GS/M-83-H7 (expressing VSP H7) and the neonatal mouse model for experimental infections, we quantitatively assessed the process of antigenic variation of the parasite on the transcriptional level. In the present study, variant-specific regions identified on different GS/M-83-H7 vsp sequences served as targets for quantitative reverse transcription-PCR to monitor alterations in vsp mRNA levels during infection. Respective results demonstrated that antigenic switching of both the duodenal trophozoite and the cecal cyst populations was associated with a massive reduction in vsp H7 mRNA levels but not with a simultaneous increase in transcripts of any of the subvariant vsp genes analyzed. Most importantly, we also explored giardial variant-type formation and vsp mRNA levels after infection of mice with cysts. This infection mode led to an antigenic reset of the parasite in that a VSP H7-negative inoculum “converted” into a population of intestinal trophozoites that essentially consisted of the original VSP H7 type. This antigenic reset appears to be associated with excystation rather than with a selective process which favors expansion of a residual population of VSP H7 types within the antigenically diversified cyst inoculum. Based on these findings, the VSP H7 type has to be regarded as a predominant variant of G. lamblia clone GS/M-83-H7 which (re-)emerges during early-stage infection and may contribute to an optimal establishment of the parasite within the intestine of the experimental murine host.

A Model System for Proliferation and Characterisation of Stem Cells in Childhood T-ALL.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1370-1370
Author(s):  
Charlotte V. Cox ◽  
Roger S. Evely ◽  
Allison Blair
Keyword(s):  
Myeloid Cell ◽  
Scid Mice ◽  
Model Systems ◽  
Preclinical Model ◽  
Post Inoculation ◽  
Number Of Children ◽  
Cell Engraftment

Abstract T cell acute lymphoblastic leukaemias (T-ALL) are highly aggressive malignancies representing 10–15% of paediatric and 25% adult ALLs. T-ALL was considered to arise as a consequence of clonal expansion of early thymocytes. However, progress towards increasing our understanding of the biology of this disease has been hampered by lack of appropriate culture systems to study primary cells and use of murine model systems that often do not accurately reflect human disease. Traditional xenograft models of leukaemia have involved implantation of malignant cells or immortalised leukaemic cell lines with either intraperitoneal or subcutaneous localisation of leukaemia. These models do not mimic the normal pathophysiology of the disease and may therefore provide misleading data. Since evaluation of new agents in paediatric malignancies is limited by the small number of children eligible for clinical trails, there is a need for a predictive preclinical model of paediatric ALL. We have previously used a long-term suspension culture system to evaluate proliferation of T-ALL cells in vitro and demonstrated these cells had a CD34+/CD4−, CD7− phenotype. T-ALL cells with this phenotype were also capable of engrafting NOD/SCID mice, suggesting the disease may arise in a more primitive cell. In this study we have attempted to further characterise T-ALL cells with long-term proliferative ability in vivo and to investigate the kinetics of engraftment. Unsorted cells and cells sorted for the expression of CD133 and CD7 from 5 T-ALL patients were inoculated into sublethally irradiated NOD/SCID mice. Peripheral blood samples were taken at weekly intervals from the lateral tail vein from two weeks post inoculation onwards. BM samples were analysed from 4 weeks post inoculation and all animals were sacrificed no later than 10 weeks post inoculation. Human CD45+ cells were first detected at day 17-post inoculation (1.54–3.8% CD45+). By week 4, this had increased to 4.4–21% CD45+ in PB samples, while levels in BM aspirates were significantly higher at this stage (24–47% CD45+). This pattern of tissue dissemination closely mimics that observed in the patients. The levels of CD45+ cells continued to rise with time and had exceeded 85% in the BM of animals injected with cells from 3 patients by week 7-post inoculation. FISH and flow cytometric analyses showed the engrafted cells had a similar karyotype and phenotype to the patient at diagnosis and there was no evidence of myeloid cell engraftment. Cells harvested from these animals have been used in secondary, tertiary and quaternary transplants with no loss of NOD/SCID repopulating potential and similar engraftment kinetics. Quinary transplants are currently underway. In the sorted cell populations, only the CD133+/CD7− subfraction was capable of engrafting, 0.5–54% CD45+, with as few as 1.4x103–5x103 cells. There was no engraftment with the other subfractions despite injecting 10 to 1000-fold more cells. These engrafted cells expressed high levels of CD34, CD2, CD4 and CD7 and very low levels of CD133. This phenotype was similar to that of the patients at diagnosis, implying they had differentiated in vivo. These data add to the evidence that T-ALL may arise in a cell with a more primitive phenotype, rather than committed thymocytes. These cells may be the most relevant targets for emerging therapeutic strategies and we describe a robust, reproducible in vivo leukaemia model which could be used to investigate the efficacy of novel agents for the treatment of paediatric T-ALL.

scholarly journals TprK Sequence Diversity Accumulates during Infection of Rabbits with Treponema pallidum subsp. pallidum Nichols Strain

2006 ◽  
Vol 74 (3) ◽  
pp. 1896-1906 ◽  
Author(s):  
Rebecca E. LaFond ◽  
Arturo Centurion-Lara ◽  
Charmie Godornes ◽  
Wesley C. Van Voorhis ◽  
Sheila A. Lukehart
Keyword(s):  
Antigenic Variation ◽  
Treponema Pallidum ◽  
Adaptive Immune Response ◽  
Serial Passage ◽  
Sequence Diversity ◽  
Adaptive Immune ◽  
Immune Pressure ◽  
V Region ◽  
Slow Passage

ABSTRACT The tprK gene in Treponema pallidum undergoes antigenic variation. In all T. pallidum isolates examined to date, except the Nichols type strain, heterogeneous tprK sequences have been identified. This heterogeneity is localized to seven variable (V) regions, and tprK sequence diversity accumulates with serial passage in naïve rabbits. The T. pallidum Nichols genome described a single tprK sequence, and after decades of independent passage, only minor tprK sequence diversity is seen among the Nichols strains from different laboratories. We hypothesized that T. pallidum Nichols is capable of only limited tprK diversification. To address this hypothesis, we passaged the T. pallidum Nichols strain in naïve rabbits at the peak of infection (rapid passage) or after the adaptive immune response had cleared most organisms in vivo (slow passage). After 22 rapid passages (9- to 10-day intervals), no tprK V region sequence changes were observed. In contrast, after two slow passages (30- to 35-day intervals), three V regions had sequences that were completely different from that of the original inoculum. New sequences were observed in all seven V regions by the fifth slow passage. In contrast to the rapid-passaged Nichols strain, rapid-passaged Chicago C, a clonal strain isolated from the highly diverse parent Chicago strain, developed significant tprK diversification. These findings suggest that tprK variation can occur, but at a lower rate, in Nichols and that immune pressure may be required for accumulation of bacteria with diverse tprK sequences. Adaptation to growth in rabbits may explain the limited repertoire of V region sequences seen in the Nichols strain.

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