| 1. |
- Asghar, Muhammad, et al.
(författare)
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Cellular aging dynamics after acute malaria infection : A 12-month longitudinal study
- 2018
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Ingår i: Aging Cell. - : Wiley. - 1474-9718 .- 1474-9726. ; 17:1, s. 12702-12702
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Tidskriftsartikel (refereegranskat)abstract
- Accelerated cellular aging and reduced lifespan have recently been shown in birds chronically infected with malaria parasites. Whether malaria infection also affects cellular aging in humans has not been reported. Here, we assessed the effect of a single acute Plasmodium falciparum malaria infection on cellular aging dynamics in travelers prospectively followed over one year in Sweden. DNA and RNA were extracted from venous blood collected at the time of admission and repeatedly up to one year. Telomere length was measured using real-time quantitative PCR, while telomerase activity and CDKN2A expression were measured by reverse transcriptase (RT)-qPCR. Our results show that acute malaria infection affects cellular aging as reflected by elevated levels of CDKN2A expression, lower telomerase activity, and substantial telomere shortening during the first three months postinfection. After that CDKN2A expression declined, telomerase activity increased and telomere length was gradually restored over one year, reflecting that cellular aging was reversed. These findings demonstrate that malaria infection affects cellular aging and the underlying cellular mechanism by which pathogens can affect host cellular aging and longevity need to be elucidated. Our results urge the need to investigate whether repeated malaria infections have more pronounced and long-lasting effects on cellular aging and lifespan (similarly to what was observed in birds) in populations living in malaria endemic areas.
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| 2. |
- Homann, Manijeh Vafa, et al.
(författare)
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Detection of Malaria Parasites After Treatment in Travelers : A 12-months Longitudinal Study and Statistical Modelling Analysis
- 2017
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 25, s. 66-72
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Tidskriftsartikel (refereegranskat)abstract
- The rapid clearance of malaria parasite DNA from circulation has widely been accepted as a fact without being systemically investigated. We assessed the persistence of parasite DNA in travelers treated for Plasmodium falciparum malaria in a malaria-free area. Venous blood was collected at the time of admission and prospectively up to one year. DNA and RNA were extracted and analyzed using species-specific and gametocyte-specific real-time PCR as well as merozoite surface protein 2 (msp2)-PCR. In 31 successfully treated individuals, asexual parasites were seen by microscopy until two days after treatment, whereas parasite DNA was detected by msp2- and species-specific PCR up to days 31 and 42, respectively. Statistical modelling predicted 26% (+/- 0.05 SE) species-specific PCR positivity until day 40 and estimated 48 days for all samples to become PCR negative. Gametocytes were detected by microscopy and PCR latest two days after treatment. C-T values correlated well with microscopy-defined parasite densities before but not after treatment started. These results reveal that PCR positivity can persist several weeks after treatment without evidence of viable sexual or asexual parasites, indicating that PCR may overestimate parasite prevalence after treatment.
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| 3. |
- Jahnmatz, Peter, et al.
(författare)
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Memory B-Cell Responses Against Merozoite Antigens After Acute Plasmodium falciparum Malaria, Assessed Over One Year Using a Novel Multiplexed FluoroSpot Assay
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Memory B cells (MBCs) are believed to be important for the maintenance of immunity to malaria, and these cells need to be explored in the context of different parasite antigens and their breadth and kinetics after natural infections. However, frequencies of antigen-specific MBCs are low in peripheral blood, limiting the number of antigens that can be studied, especially when small blood volumes are available. Here, we developed a multiplexed reversed B-cell FluoroSpot assay capable of simultaneously detecting MBCs specific for the four Plasmodium falciparum blood-stage antigens, MSP-1(19), MSP-2, MSP-3 and AMA-1. We used the assay to study the kinetics of the MBC response after an acute episode of malaria and up to one year following treatment in travelers returning to Sweden from sub-Saharan Africa. We show that the FluoroSpot assay can detect MBCs to all four merozoite antigens in the same well, and that the breadth and kinetics varied between individuals. We further found that individuals experiencing a primary infection could mount and maintain parasite-specific MBCs to a similar extent as previously exposed adults, already after a single infection. We conclude that the multiplexed B-cell FluoroSpot is a powerful tool for assessing antigen-specific MBC responses to several antigens simultaneously, and that the kinetics of MBC responses against merozoite surface antigens differ over the course of one year. These findings contribute to the understanding of acquisition and maintenance of immune responses to malaria.
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| 4. |
- Müller-Sienerth, Nicole, et al.
(författare)
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A panel of recombinant proteins from human-infective Plasmodium species for serological surveillance
- 2020
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Ingår i: Malaria Journal. - : BMC. - 1475-2875. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background: Malaria remains a global health problem and accurate surveillance of Plasmodium parasites that are responsible for this disease is required to guide the most effective distribution of control measures. Serological surveillance will be particularly important in areas of low or periodic transmission because patient antibody responses can provide a measure of historical exposure. While methods for detecting host antibody responses to Plasmodium falciparum and Plasmodium vivax are well established, development of serological assays for Plasmodium knowlesi, Plasmodium ovale and Plasmodium malariae have been inhibited by a lack of immunodiagnostic candidates due to the limited availability of genomic information.Methods: Using the recently completed genome sequences from P. malariae, P. ovale and P. knowlesi, a set of 33 candidate cell surface and secreted blood-stage antigens was selected and expressed in a recombinant form using a mammalian expression system. These proteins were added to an existing panel of antigens from P. falciparum and P. vivax and the immunoreactivity of IgG, IgM and IgA immunoglobulins from individuals diagnosed with infections to each of the five different Plasmodium species was evaluated by ELISA. Logistic regression modelling was used to quantify the ability of the responses to determine prior exposure to the different Plasmodium species.Results: Using sera from European travellers with diagnosed Plasmodium infections, antigens showing species-specific immunoreactivity were identified to select a panel of 22 proteins from five Plasmodium species for serological profiling. The immunoreactivity to the antigens in the panel of sera taken from travellers and individuals living in malaria-endemic regions with diagnosed infections showed moderate power to predict infections by each species, including P. ovale, P. malariae and P. knowlesi. Using a larger set of patient samples and logistic regression modelling it was shown that exposure to P. knowlesi could be accurately detected (AUC=91%) using an antigen panel consisting of the P. knowlesi orthologues of MSP10, P12 and P38.Conclusions: Using the recent availability of genome sequences to all human-infective Plasmodium spp. parasites and a method of expressing Plasmodium proteins in a secreted functional form, an antigen panel has been compiled that will be useful to determine exposure to these parasites.
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| 5. |
- Mutemi, Doreen D., et al.
(författare)
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Antibody-Dependent Respiratory Burst against Plasmodium falciparum Merozoites in Individuals Living in an Area with Declining Malaria Transmission
- 2024
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Ingår i: Vaccines. - : MDPI. - 2076-393X. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- Malaria transmission intensity affects the development of naturally acquired immunity to malaria. An absolute correlate measure of protection against malaria is lacking. However, antibody-mediated functions against Plasmodium falciparum correlate with protection against malaria. In children, antibody-mediated functions against P. falciparum decline with reduced exposure. It is unclear whether adults maintain antibody-mediated functions as malaria transmission declines. This study assessed antibody-dependent respiratory burst (ADRB) in individuals from an area with declining malaria transmission. In an age-matched analysis, we compare ADRB activity during high versus low malaria transmission periods. Age significantly predicted higher ADRB activity in the high (p < 0.001) and low (p < 0.001) malaria transmission periods. ADRB activity was higher during the high compared to the low malaria transmission period in older children and adults. Only older adults during the high malaria transmission period had their median ADRB activity above the ADRB cut-off. Ongoing P. falciparum infection influenced ADRB activity during the low (p = 0.01) but not the high (p = 0.29) malaria transmission period. These findings propose that naturally acquired immunity to P. falciparum is affected in children and adults as malaria transmission declines, implying that vaccines will be necessary to induce and maintain protection against malaria.
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| 6. |
- Parigi, Sara M., et al.
(författare)
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Flt3 ligand expands bona fide innate lymphoid cell precursors in vivo
- 2018
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- A common helper-like innate lymphoid precursor (CHILP) restricted to the innate lymphoid cells (ILC) lineage has been recently characterized. While specific requirements of transcription factors for CHILPs development has been partially described, their ability to sense cytokines and react to peripheral inflammation remains unaddressed. Here, we found that systemic increase in Flt3L levels correlated with the expansion of Lineage (Lin)(neg)alpha 4 beta 7(+) precursors in the adult murine bone marrow. Expanded Lin(neg)alpha 4 beta 7(+) precursors were bona fide CHILPs as seen by their ability to differentiate into all helper ILCs subsets but cNK in vivo. Interestingly, Flt3L-expanded CHILPs transferred into lymphopenic mice preferentially reconstituted the small intestine. While we did not observe changes in serum Flt3L during DSS-induced colitis in mice or plasma from inflammatory bowel disease (IBD) patients, elevated Flt3L levels were detected in acute malaria patients. Interestingly, while CHILP numbers were stable during the course of DSS-induced colitis, they expanded following increased serum Flt3L levels in malaria-infected mice, hence suggesting a role of the Flt3L-ILC axis in malaria. Collectively, our results indicate that Flt3L expands CHILPs in the bone marrow, which might be associated with specific inflammatory conditions.
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| 7. |
- Sundling, Christopher, et al.
(författare)
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B cell profiling in malaria reveals expansion and remodeling of CD11c+ B cell subsets
- 2019
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Ingår i: JCI Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 4:9
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Tidskriftsartikel (refereegranskat)abstract
- Humoral immunity is important in limiting clinical disease in malaria, yet the longitudinal B cell response to infection remains unclear. We performed a 1-year prospective study in patients treated for acute Plasmodium fakiporum malaria for the first time or with previous exposure to the disease. Using an unbiased exploratory approach with mass cytometry, followed by targeted flow cytometry, we found that approximately 80% of mature B cells that proliferated in response to acute infection expressed CD11c. Only approximately 40% of CD11c+ B cells displayed an atypical B cell phenotype, with the remaining cells primarily made up of activated and resting memory B cells. The CD11c+ B cells expanded rapidly following infection, with previous exposure to malaria resulting in a significantly larger increase compared with individuals with primary infection. This was attributed to an expansion of switched CD11c+ B cells that was absent in primary infected individuals. The rate of contraction of the CD11c+ B cell compartment was independent of previous exposure to malaria and displayed a slow decay, with a half-life of approximately 300 days. Collectively, these results identify CD11c as a marker of B cells responding to malaria and further highlight differences in primary and secondary B cell responses during infection.
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| 8. |
- Yman, Victor, et al.
(författare)
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Antibody acquisition models : A new tool for serological surveillance of malaria transmission intensity
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Serology has become an increasingly important tool for the surveillance of a wide range of infectious diseases. It has been particularly useful to monitor malaria transmission in elimination settings where existing metrics such as parasite prevalence and incidence of clinical cases are less sensitive. Seroconversion rates, based on antibody prevalence to Plasmodium falciparum asexual blood-stage antigens, provide estimates of transmission intensity that correlate with entomological inoculation rates but lack precision in settings where seroprevalence is still high. Here we present a new and widely applicable method, based on cross-sectional data on individual antibody levels. We evaluate its use as a sero-surveillance tool in a Tanzanian setting with declining malaria prevalence. We find that the newly developed mathematical models produce more precise estimates of transmission patterns, are robust in high transmission settings and when sample sizes are small, and provide a powerful tool for serological evaluation of malaria transmission intensity.
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| 9. |
- Yman, Victor
(författare)
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Antibody responses to Plasmodium falciparum as markers of exposure and tools to monitor malaria transmission
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Plasmodium falciparum malaria has the highest death toll of all human parasitic diseases and nearly half of the global population is living at risk of infection. Reducing the malaria burden with the goal of achieving elimination will require sustained commitment for control and better monitoring tools that can guide efforts to limit transmission. An effective malaria vaccine could significantly accelerate progress towards elimination but incomplete understanding of malaria immunity hampers vaccine development. Antibodies are key components of immunity to malaria and can also serve as sensitive markers of exposure. Data on the dynamics and specificity of the antibody response in natural P. falciparum infection could improve our understanding of the acquisition and maintenance of immunity, and be used to develop better serological tools for transmission surveillance. In study I, we examined the temporal trends in malaria transmission over a period of 25 years in a closely monitored population in a rural area in Tanzania. We detected a gradual reduction in parasite prevalence starting prior to large-scale interventions and found that evaluation of spleen rate and haemoglobin levels were complementary to microscopy and molecular methods for estimates of malaria burden in this area of initially very high transmission. In study II, we developed new models for serological surveillance of malaria transmission based on cross-sectional data on age-specific antibody levels and evaluated their performance by further examining the transmission trends observed in study I. We demonstrated that these models are robust and improve precision in serological transmission estimates based on cross-sectional antibody data. In study III, we conducted a longitudinal follow-up of travellers treated for malaria in Sweden. We provided quantitative estimates of the dynamics and the longevity of malaria-specific antibodies and antibody secreting cells in absence of reexposure. In study IV, we examined the antibody responses to 111 P. falciparum antigens in the longitudinally followed travellers and identified novel candidate serological markers of recent exposure that warrant further evaluation. Together these studies contribute to our overall understanding of the acquisition and maintenance of the antimalarial antibody response. The results help to improve current methods for serological malaria transmission surveillance and provide new information on antibody responses to P. falciparum that should be explored as markers of exposure.
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| 10. |
- Yman, Victor, et al.
(författare)
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Persistent transmission of Plasmodium malariae and Plasmodium ovale species in an area of declining Plasmodium falciparum transmission in eastern Tanzania
- 2019
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Ingår i: PLoS Neglected Tropical Diseases. - : PUBLIC LIBRARY SCIENCE. - 1935-2727 .- 1935-2735. ; 13:5
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Tidskriftsartikel (refereegranskat)abstract
- A reduction in the global burden of malaria over the past two decades has encouraged efforts for regional malaria elimination. Despite the need to target all Plasmodium species, current focus is mainly directed towards Plasmodium falciparum, and to a lesser extent P. vivax. There is a substantial lack of data on both global and local transmission patterns of the neglected malaria parasites P. malariae and P. ovale spp. We used a species-specific real-time PCR assay targeting the Plasmodium 18s rRNA gene to evaluate temporal trends in the prevalence of all human malaria parasites over a 22-year period in a rural village in Tanzania.We tested 2897 blood samples collected in five cross-sectional surveys conducted between 1994 and 2016. Infections with P. falciparum, P. malariae, and P. ovale spp. were detected throughout the study period, while P. vivax was not detected. Between 1994 and 2010, we found a more than 90% reduction in the odds of infection with all detected species. The odds of P. falciparum infection was further reduced in 2016, while the odds of P. malariae and P. ovale spp. infection increased 2- and 6-fold, respectively, compared to 2010. In 2016, non-falciparum species occurred more often as mono-infections. The results demonstrate the persistent transmission of P. ovale spp., and to a lesser extent P. malariae despite a continued decline in P. falciparum transmission. This illustrates that the transmission patterns of the non-falciparum species do not necessarily follow those of P. falciparum, stressing the need for attention towards non-falciparum malaria in Africa. Malaria elimination will require a better understanding of the epidemiology of P. malariae and P. ovale spp. and improved tools for monitoring the transmission of all Plasmodium species, with a particular focus towards identifying asymptomatic carriers of infection and designing appropriate interventions to enhance malaria control. Author summary The reduction in the global burden of malaria has encouraged efforts for elimination. Attempts to control and monitor transmission have mainly focused on the predominant malaria parasites Plasmodium falciparum and P. vivax. However, eliminating malaria requires the elimination of all human malaria parasites and limited interest has been directed towards estimating the disease burden attributable to the neglected malaria parasites P. ovale spp. and P. malariae. The authors used molecular methods to analyse 2897 blood samples collected in five cross-sectional surveys over a period of 22 years, and described the transmission patterns of all human malaria parasites in a Tanzanian village. They demonstrate a persistent transmission of P. malariae and P. ovale spp. despite a substantial reduction in transmission of P. falciparum, highlighting the need for more attention towards non-falciparum malaria. The authors discuss the implications of these findings in the context of current efforts for regional malaria elimination.
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