| 21. |
- Ismail, Hodan Ahmed, et al.
(författare)
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Subclass responses and their half-lives for antibodies against EBA175 and PfRh2 in naturally acquired immunity against Plasmodium falciparum malaria
- 2014
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Plasmodium falciparum EBA175 and PfRh2 belong to two main families involved in parasite invasion, and both are potential vaccine candidates. Current knowledge is limited regarding which target antigens and subclasses of antibodies are actually important for protection, and how naturally acquired immunity is achieved. Methods: Repeated blood samples were collected from individuals in Nigeria over a period of almost one year. ELISA was used to analyse subclasses of IgG responses. Results: For both EBA175 (region III-V) and (a fragment of) PfRh2, the dominant antibody responses consisted of IgG1 and IgG3 followed by IgG2, while for PfRh2 there was also a relatively prominent response for IgG4. High levels of IgG1, IgG2 and IgG3 for EBA175 and total IgG for PfRh2 correlated significantly with a lower parasitaemia during the study period. Children with HbAS had higher levels of some subclasses compared to children with HbAA, while in adults the pattern was the opposite. The half-lives of IgG2 and IgG4 against EBA175 were clearly shorter than those for IgG1 and IgG3. Conclusion: EBA175 and PfRh2 are potential targets for protective antibodies since both correlated with lower parasitaemia. The shorter half-lives for IgG2 and IgG4 might explain why these subclasses are often considered less important in protection against malaria. Triggering the right subclass responses could be of critical importance in a successful vaccine. Further studies are needed to evaluate the role of haemoglobin polymorphisms and their malaria protective effects in this process.
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| 22. |
- Joannin, Nicolas, et al.
(författare)
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RSpred, a set of Hidden Markov Models to detect and classify the RIFIN and STEVOR proteins of Plasmodium falciparum
- 2011
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Ingår i: BMC Genomics. - : BioMed Central. - 1471-2164. ; 12:119
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Tidskriftsartikel (refereegranskat)abstract
- Background: Many parasites use multicopy protein families to avoid their hosts immune system through a strategy called antigenic variation. RIFIN and STEVOR proteins are variable surface antigens uniquely found in the malaria parasites Plasmodium falciparum and P. reichenowi. Although these two protein families are different, they have more similarity to each other than to any other proteins described to date. As a result, they have been grouped together in one Pfam domain. However, a recent study has described the sub-division of the RIFIN protein family into several functionally distinct groups. These sub-groups require phylogenetic analysis to sort out, which is not practical for large-scale projects, such as the sequencing of patient isolates and meta-genomic analysis. Results: We have manually curated the rif and stevor gene repertoires of two Plasmodium falciparum genomes, isolates DD2 and HB3. We have identified 25% of mis-annotated and similar to 30 missing rif and stevor genes. Using these data sets, as well as sequences from the well curated reference genome (isolate 3D7) and field isolate data from Uniprot, we have developed a tool named RSpred. The tool, based on a set of hidden Markov models and an evaluation program, automatically identifies STEVOR and RIFIN sequences as well as the sub-groups: A-RIFIN, B-RIFIN, B1-RIFIN and B2-RIFIN. In addition to these groups, we distinguish a small subset of STEVOR proteins that we named STEVOR-like, as they either differ remarkably from typical STEVOR proteins or are too fragmented to reach a high enough score. When compared to Pfam and TIGRFAMs, RSpred proves to be a more robust and more sensitive method. We have applied RSpred to the proteomes of several P. falciparum strains, P. reichenowi, P. vivax, P. knowlesi and the rodent malaria species. All groups were found in the P. falciparum strains, and also in the P. reichenowi parasite, whereas none were predicted in the other species. Conclusions: We have generated a tool for the sorting of RIFIN and STEVOR proteins, large antigenic variant protein groups, into homogeneous sub-families. Assigning functions to such protein families requires their subdivision into meaningful groups such as we have shown for the RIFIN protein family. RSpred removes the need for complicated and time consuming phylogenetic analysis methods. It will benefit both research groups sequencing whole genomes as well as others working with field isolates. RSpred is freely accessible via http://www.ifm.liu.se/bioinfo/.
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| 23. |
- Joannin, Nicolas, et al.
(författare)
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Sub-grouping and sub-functionalization of the RIFIN multi-copy protein family.
- 2008
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 9, s. 19-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Parasitic protozoans possess many multicopy gene families which have central roles in parasite survival and virulence. The number and variability of members of these gene families often make it difficult to predict possible functions of the encoded proteins. The families of extra-cellular proteins that are exposed to a host immune response have been driven via immune selection to become antigenically variant, and thereby avoid immune recognition while maintaining protein function to establish a chronic infection. RESULTS: We have combined phylogenetic and function shift analyses to study the evolution of the RIFIN proteins, which are antigenically variant and are encoded by the largest multicopy gene family in Plasmodium falciparum. We show that this family can be subdivided into two major groups that we named A- and B-RIFIN proteins. This suggested sub-grouping is supported by a recently published study that showed that, despite the presence of the Plasmodium export (PEXEL) motif in all RIFIN variants, proteins from each group have different cellular localizations during the intraerythrocytic life cycle of the parasite. In the present study we show that function shift analysis, a novel technique to predict functional divergence between sub-groups of a protein family, indicates that RIFINs have undergone neo- or sub-functionalization. CONCLUSION: These results question the general trend of clustering large antigenically variant protein groups into homogenous families. Assigning functions to protein families requires their subdivision into meaningful groups such as we have shown for the RIFIN protein family. Using phylogenetic and function shift analysis methods, we identify new directions for the investigation of this broad and complex group of proteins.
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| 24. |
- Kaddumukasa, Mark, et al.
(författare)
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Parasite Specific Antibody Increase Induced by an Episode of Acute P. falciparum Uncomplicated Malaria.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- There is no approved vaccine for malaria, and precisely how human antibody responses to malaria parasite components and potential vaccine molecules are developed and maintained remains poorly defined. In this study, antibody anamnestic or memory response elicited by a single episode of P. falciparum infection was investigated.
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| 25. |
- Lugaajju, Allan, et al.
(författare)
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Development of Plasmodium falciparum specific naïve, atypical, memory and plasma B cells during infancy and in adults in an endemic area
- 2017
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: B-cells are essential in immunity against malaria, but which sub-sets of B-cells specifically recognize Plasmodium falciparum and when they appear is still largely unknown. Results: Using the flow cytometry technique for detection of P. falciparum specific (Pf+) B-cells, this study for the first time measured the development of Pf+ B cell (CD19+) phenotypes in Ugandan babies from birth up to nine months, and in their mothers. The babies showed increases in Pf+ IgG memory B-cells (MBCs), atypical MBCs, and plasma cells/blasts over time, but the proportion of these cells were still lower than in the mothers who displayed stable levels (5, 18, and 3%, respectively). Pf+ non-IgG+ MBCs and naïve B-cells binding to P. falciparum antigens were higher in the babies compared to the mothers (12 and 50%). In ELISA there was an increase in IgG and IgM antibodies over time in babies, and stable levels in mothers. At baby delivery, multigravidae mothers had a higher proportion of Pf+ IgG MBCs and less Pf+ naïve B-cells than primigravidae mothers. Conclusions: In newborns, naïve B-cells are a major player in recognizing P. falciparum. In adults, the high proportion of Pf+ atypical MBCs suggests a major role for these cells. Both in infants and adults, non-IgG+ MBCs were higher than IgG MBCs, indicating that these cells deserve more focus in future.
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| 26. |
- Lugaajju, Allan, et al.
(författare)
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Novel flow cytometry technique for detection of Plasmodium falciparum specific B-cells in humans: increased levels of specific B-cells in ongoing infection.
- 2015
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Malaria caused by Plasmodium falciparum is still a major health threat in endemic areas especially for children below 5 years of age. While it is recognized that antibody immunity plays an important role in controlling the disease, knowledge of the mechanisms of sustenance and natural boosting of immunity is very limited. Before, it has not been possible to investigate malaria specific B-cells directly in flow cytometry, making it difficult to know how much of a B cell response is due to malaria, or how much is due to other immunological stimulators.
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| 27. |
- Mok, Bobo W., et al.
(författare)
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Default Pathway of var2csa Switching and Translational Repression in Plasmodium falciparum
- 2008
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 3:4, s. e1982-
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Tidskriftsartikel (refereegranskat)abstract
- Antigenic variation is a subtle process of fundamental importance to the survival of a microbial pathogen. In Plasmodium falciparum malaria, PfEMP1 is the major variable antigen and adhesin expressed at the surface of the infected erythrocyte, which is encoded for by members of a family of 60 var-genes. Peri-nuclear repositioning and epigenetic mechanisms control their mono-allelic expression. The switching of PfEMP1 depends in part on variable transition rates and short-lived immune responses to shared minor epitopes. Here we show var-genes to switch to a common gene that is highly transcribed, but sparsely translated into PfEMP1 and not expressed at the erythrocyte surface. Highly clonal and adhesive P. falciparum, which expressed distinct var-genes and the corresponding PfEMP1s at onset, were propagated without enrichment or panning. The parasites successively and spontaneously switched to transcribe a shared var-gene (var2csa) matched by the loss of PfEMP1 surface expression and host cell-binding. The var2csa gene repositioned in the peri-nuclear area upon activation, away from the telomeric clusters and heterochromatin to transcribe spliced, full-length RNA. Despite abundant transcripts, the level of intracellular PfEMP1 was low suggesting post-transcriptional mechanisms to partake in protein expression. In vivo, off-switching and translational repression may constitute one pathway, among others, coordinating PfEMP1 expression.
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| 28. |
- Ngara, Mtakai, et al.
(författare)
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Exploring parasite heterogeneity using single-cell RNA-seq reveals a gene signature among sexual stage Plasmodium falciparum parasites
- 2018
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 371:1, s. 130-138
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Tidskriftsartikel (refereegranskat)abstract
- The malaria parasite has a complex lifecycle, including several events of differentiation and stage progression, while actively evading immunity in both its mosquito and human hosts. Important parasite gene expression and regulation during these events remain hidden in rare populations of cells. Here, we combine a capillary-based platform for cell isolation with single-cell RNA-sequencing to transcriptionally profile 165 single infected red blood cells (iRBCs) during the intra-erythrocytic developmental cycle (IDC). Unbiased analyses of single-cell data grouped the cells into eight transcriptional states during IDC. Interestingly, we uncovered a gene signature from the single iRBC analyses that can successfully discriminate between developing asexual and sexual stage parasites at cellular resolution, and we verify five, previously undefined, gametocyte stage specific genes. Moreover, we show the capacity of detecting expressed genes from the variable gene families in single parasites, despite the sparse nature of data. In total, the single parasite transcriptomics holds promise for molecular dissection of rare parasite phenotypes throughout the malaria lifecycle.
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| 29. |
- Nordenfelt, Patrik, et al.
(författare)
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Health-related quality of life in relation to disease activity in adults with hereditary angioedema in Sweden
- 2017
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Ingår i: Allergy and Asthma Proceedings. - : OceanSide Publications. - 1088-5412 .- 1539-6304. ; 38:6, s. 447-455
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Tidskriftsartikel (refereegranskat)abstract
- Background: Health-related quality of life (HR-QoL) is impaired in patients with hereditary angioedema (HAE) but has not yet been satisfactorily described.Objective: To study HR-QoL in patients with HAE by combining different HR-QoL instruments with disease activity assessment. Methods: All adults in the Swedish HAE registry were invited to take part in this questionnaire study, which used the generic HR-QoL instruments, EuroQol 5 Dimensions 5 Level (EQ-5D-5L) and the RAND Corporation Short Form 36 (RAND-36), the disease-specific Angioedema Quality of Life instrument (AE-QoL), the recently introduced Angioedema Activity Score (AAS) form, and questionnaires on sick leave and prophylactic medication.Results: Sixty-four of 133 adults (26 men, 38 women) between 18 and 91 years old responded. The most affected HR-QoL dimensions in the EQ-5D-5L were pain/discomfort and anxiety/depression; in the RAND-36, energy/fatigue, general health, pain; and, in the AE-QoL, fears/shame and fatigue/mood. Women had lower HR-QoL in the RAND-36 for general health and energy/fatigue (p < 0.05). Patients who reported any AAS of >0 had significantly impaired HR-QoL. There were significant associations (p < 0.05) between the AAS and EQ-5D-5L, between the AAS and all dimensions of the RAND-36 except physical function, and between the AAS and AE-QoL in all dimensions. Nine of 36 patients who reported sick leave during the previous 4 weeks had significantly impaired HR-QoL in all the instruments (p < 0.05). There was no significant difference in HR-QoL in the patients with and the patients without prophylactic medication, except for the nutrition dimension of the AE-QoL (p < 0.05).Conclusion: Comprehensive information is obtained by combining different HR-QoL instruments. Pain, anxiety/depression, and fatigue/mood are important aspects of HAE but the AE-QoL disregards pain. HR-QoL was not significantly affected by prophylaxis. Increased disease activity was associated with impaired HR-QoL, which justifies more active disease management.
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| 30. |
- Nordenfelt, Patrik
(författare)
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Hereditary Angioedema in Sweden : a National Project
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Hereditary angioedema (HAE) due to C1-inhibitor deficiency, type I and II, is a rare disease with an estimated prevalence of 1/50,000. Angioedema in the larynx can be life threatening and angioedema in the abdomen and skin can give severe and disabling pain. Data on patients with HAE in Sweden were scarce before our study.Aim: To study the prevalence of HAE, and to investigate clinical manifestations, treatments, and Health-Related Quality of Life (HR-QoL) in adults and children in Sweden.Method: In studies, I and II, all patients received a written questionnaire followed by a phone interview with questions about clinical manifestations, medication, sick leave and QoL. In study III the patients completed EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaires for both the attack-free state (EQ5D today), and the last HAE attack (EQ5D attack). Questions were also asked about sick-leave. In study IV all adults received questionnaires with EQ-5D-5L and RAND-36, Angioedema Quality of Life instrument (AE-QoL), and Angioedema Activity Score (AAS) form, and questionnaires on sick leave and prophylactic medication.Results: We identified 146 patients, 110 adults and 36 children with HAE, type I (n=136) or II (n=10), giving a minimal HAE prevalence of 1.54/100,000. For adults, the median age at onset of symptoms was 12 years and median age at diagnosis was 22 years. Median age at onset of symptoms for children was 4 years and at diagnosis 3 years. During the previous year, 47% of adults experienced at least 12 attacks, 21% 4-11 attacks, 11% 1-3 attacks, while 22% were asymptomatic. For children, the corresponding figures were about the same. The median number of attacks in those having attacks was 14 in adults and 6 in children last year. Adult females reported on average 19 attacks the previous year versus nine for males. Irrespective of location nine out of 10 reported pain. Trigger factors were experienced in 95 % of adults and 74 % of children. Plasma-derived C1-inhibitor concentrate (pdC1INH) had a very good effect on acute attacks. Long-term prophylaxis with androgens and pdC1INH reduced the annual attack frequency by more than 50 %. Of the children’s parents, 73% had been on parental leave to care for the child due to HAE symptoms. Health and QoL were generally rated as good. In study III 103 of 139 responded and reported an EQ5D today score that was significantly higher than the EQ5D attack score. Attack frequency had a negative effect on EQ5D today. Children had significantly higher EQ-5D-5L than adults. Forty four percent had been absent from work or school during the latest attack. In study IV 64 of 133 adults responded. The most affected HR-QoL dimensions in EQ-5D-5L were pain/discomfort and anxiety/depression, in RAND-36 energy/fatigue, general health, health transition, pain, and in AE-QoL fears/shame and fatigue/mood. Females had significantly lower HR-QoL in RAND-36 for general health and energy/fatigue. There was an association between AAS and EQ-5D-5L/RAND-36 (except physical function) /AEQoL. There was no significant difference in HR-QoL in patients with and without prophylactic medication.Conclusion: The minimal prevalence of HAE type I and II in Sweden is 1.54/100,000. Median age at onset was 12 years. Adult females had twice as many attacks as males, adults had also twice as many attacks as children. For acute treatment, pdC1INH had a very good effect. For long term prophylaxis, androgens and pdC1INH had good effect. The most affected HR-QoL dimensions in EQ-5D-5L were pain/discomfort and anxiety/ depression, in RAND-36 energy/fatigue, general health, health transition and pain, and in AE-QoL fears/shame and fatigue/mood. Children reported better HR-QoL than adults. AE-QoL is more disease-specific in HAE than the generic instruments EQ-5D-5L and RAND-36. However, the latter highlights the pain aspect, whereas AE-QoL does not. Patients with high disease activity should thus be considered for more intensive treatment to improve their HR-QoL.
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