Immune Response and Microbiota Profiles during Coinfection with Plasmodium vivax and Soil-Transmitted Helminths

ABSTRACT The role of the gut microbiota during coinfection with soil-transmitted helminths (STH) and Plasmodium spp. is poorly understood. We examined peripheral blood and fecal samples from 130 individuals who were either infected with Plasmodium vivax only, coinfected with P. vivax and STH, infected with STH alone, or not infected with either P. vivax or STH. In addition to a complete blood count (CBC) with differential, transcriptional profiling of peripheral blood samples was performed by transcriptome sequencing (RNA-Seq), fecal microbial communities were determined by 16S rRNA gene sequencing, and circulating cytokine levels were measured by bead-based immunoassays. Differences in blood cell counts, including an increased percentage of neutrophils, associated with a transcriptional signature of neutrophil activation, were driven primarily by P. vivax infection. P. vivax infection was also associated with increased levels of interleukin 6 (IL-6), IL-8, and IL-10; these cytokine levels were not affected by STH coinfection. Surprisingly, P. vivax infection was more strongly associated with differences in the microbiota than STH infection. Children infected with only P. vivax exhibited elevated Bacteroides and reduced Prevotella and Clostridiaceae levels, but these differences were not observed in individuals coinfected with STH. We also observed that P. vivax parasitemia was higher in the STH-infected population. When we used machine learning to identify the most important predictors of the P. vivax parasite burden (among P. vivax-infected individuals), bacterial taxa were the strongest predictors of parasitemia. In contrast, circulating transforming growth factor β (TGF-β) was the strongest predictor of the Trichuris trichiura egg burden. This study provides unexpected evidence that the gut microbiota may have a stronger link with P. vivax than with STH infection. IMPORTANCE Plasmodium (malaria) and helminth parasite coinfections are frequent, and both infections can be affected by the host gut microbiota. However, the relationship between coinfection and the gut microbiota is unclear. By performing comprehensive analyses on blood/stool samples from 130 individuals in Colombia, we found that the gut microbiota may have a stronger relationship with the number of P. vivax (malaria) parasites than with the number of helminth parasites infecting a host. Microbiota analysis identified more predictors of the P. vivax parasite burden, whereas analysis of blood samples identified predictors of the helminth parasite burden. These results were unexpected, because we expected each parasite to be associated with greater differences in its biological niche (blood for P. vivax and the intestine for helminths). Instead, we find that bacterial taxa were the strongest predictors of P. vivax parasitemia levels, while circulating TGF-β levels were the strongest predictor of helminth parasite burdens.

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The immune response and microbiota profiles during co-infection with P. vivax and soil-transmitted helminths

10.1101/2020.01.30.925032 ◽

2020 ◽

Author(s):

Alice V. Easton ◽

Mayra Raciny-Aleman ◽

Victor Liu ◽

Erica Ruan ◽

Maria Fernanda Yasnot ◽

...

Keyword(s):

Low Income ◽

Peripheral Blood ◽

Complete Blood Count ◽

Transcriptional Profiling ◽

Parasite Burden ◽

Low Income Countries ◽

Soil Transmitted Helminths ◽

Transcriptional Signature ◽

Cell Counts ◽

Cytokine Levels

AbstractCo-infection with soil-transmitted helminths (STH) and Plasmodium spp. parasites is a common occurrence in tropical low-income countries, but the consequences of this interaction remain poorly understood. Here, we performed a multi-omic analysis on peripheral blood and fecal samples from 130 individuals in Tierralta, Córdoba, Colombia who were infected with P. vivax alone (n = 33), co-infected with P. vivax and STH (n = 27), infected with STH alone (n = 39) or were infected with neither P. vivax nor STH (n = 31). In addition to Complete Blood Count (CBC) with differential, transcriptional profiling of peripheral blood samples was performed by RNA-Seq, fecal microbial communities were determined by 16S ribosomal RNA gene sequencing and circulating cytokine levels were measured by bead-based immunoassays. Differences in blood cell counts were driven primarily by P. vivax infection, including an increased percentage of neutrophils that was associated with a transcriptional signature of neutrophil activation in the blood. P. vivax infection was also associated with increased levels of IL-6, IL-8 and IL-10, and these cytokine levels were not affected by STH co-infection. Surprisingly, P. vivax infection was more strongly associated with changes in the microbiome than STH infection. Children infected with P. vivax exhibited elevated Bacteroides and reduced Prevotella and Clostridiaceae, but these differences were not observed in individuals co-infected with STH. We also observed that P. vivax parasitemia was higher in the STH-infected population. When we used machine learning to identify the most important predictors of P. vivax parasite burden from all measured variables, bacterial taxa were the strongest predictors of parasitemia levels. In contrast, circulating TGF-β was the strongest predictor of T. trichiura egg burden. This study provides unexpected evidence that the gut microbiota may have a stronger link with P. vivax than with STH infection.

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Sirolimus-eluting stents in the canine cerebral vasculature: a prospective, randomized, blinded assessment of safety and vessel response

Journal of Neurosurgery ◽

10.3171/jns.2004.100.4.0688 ◽

2004 ◽

Vol 100 (4) ◽

pp. 688-694 ◽

Cited By ~ 29

Author(s):

Elad I. Levy ◽

Ricardo A. Hanel ◽

Jay U. Howington ◽

Balazs Nemes ◽

Alan S. Boulos ◽

...

Keyword(s):

Peripheral Blood ◽

Bare Metal Stents ◽

Metal Stents ◽

Bare Metal ◽

Cerebral Vasculature ◽

Blood Samples ◽

Content Type ◽

Stent Stenosis ◽

Fine Print

Object. Use of the sirolimus-eluting stent has led to a reduction of in-stent stenosis following treatment of coronary atherosclerosis, whereas treatment of intracranial atherosclerosis with bare-metal stents results in excessive restenosis rates of approximately 40%. Neurotoxicity effects and vessel injury are unknown in the cerebral vasculature. To assess the safety profile and vascular effects of sirolimus-coated stents, the authors conducted a prospective comparative study in which drug-eluting and bare-metal stents were implanted in the canine basilar artery (BA). Methods. Sixteen mongrel dogs were randomized (eight animals per group) to receive either bare-metal 1.5 × 8—mm (six-cell) stents or sirolimus-eluting stents of the same dimensions. Interventionists, histopathologists, and histopathology technicians who participated in the study were blinded to the stent characteristics. Stents were implanted in the canine BA. Serial peripheral blood samples were obtained during the 1st week after implantation to determine the time-dependent serum concentration of sirolimus. Follow-up angiographic studies were performed 30 days after stent implantation to assess the effects of stent placement on the BA and brainstem perforating vessels. Explantation of the stent and BA was performed immediately after angiography by using a pressurized formalin fixation procedure. Histological and computer-assisted morphometric analyses of specimens obtained in each animal were performed. Sirolimus could not be detected in peripheral blood samples obtained later than 24 hours posttreatment. On follow-up angiography, all perforating vessels observed on initial angiograms remained patent, and no evidence of parent vessel damage or pseudoaneurysm formation was observed. Explanted vessels and brainstem sections did not demonstrate evidence of histological neurotoxicity, such as gliosis or infarction. No significant differences were found in the time to endothelialization of bare-metal and sirolimus-coated stents. Smooth-muscle cell (SMC) proliferation, the putative agent for restenosis, was lower in animals receiving sirolimus-coated stents (p = 0.003). Additionally, intimal fibrin density was increased in the dogs treated with sirolimus-coated stents (p < 0.0001). Histological evidence of an inflammatory response demonstrated a trend toward a reduced response in the sirolimus group (mean 0.58) compared with the bare-metal group (mean 0.83, p = 0.33). Conclusions. No neurotoxic effects were observed in the intracranial vessel walls or brainstem tissue in which sirolimus-coated stents were implanted. Compared with bare-metal stents, the sirolimus-coated devices did not impair endothelialization and, furthermore, tended to reduce the proliferation of SMCs. These findings indicate that sirolimus-coated devices may inhibit in-stent stenosis. Further studies with longer-term follow up are required to assess the restenosis rates of sirolimus-coated stents implanted in the intracranial vasculature.

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Th1/Th2 Cytokine Profile in Patients Coinfected with HIV and Leishmania in Brazil

Clinical and Vaccine Immunology ◽

10.1128/cvi.00076-11 ◽

2011 ◽

Vol 18 (10) ◽

pp. 1765-1769 ◽

Cited By ~ 7

Author(s):

Maria Zilma Andrade Rodrigues ◽

Maria Fernanda Rios Grassi ◽

Sanjay Mehta ◽

Xing-Quan Zhang ◽

Luana Leandro Gois ◽

...

Keyword(s):

Immune Responses ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Peripheral Blood Mononuclear ◽

Content Type ◽

Th2 Cytokine ◽

Cytokine Levels ◽

Blood Mononuclear Cells ◽

Ifn Γ

ABSTRACTTo evaluate the effects of HIV on immune responses in cutaneous leishmaniasis (CL), we quantified cytokine levels from plasma and stimulated peripheral blood mononuclear cells (PBMCs) from individuals infected with HIV and/or CL. Gamma interferon (IFN-γ) and interleukin 13 (IL-13) levels and the ratio of IFN-γ to IL-10 produced in response to stimulation with solubleLeishmaniaantigens were significantly lower in HIV-Leishmania-coinfected patients than in CL-monoinfected patients.

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Rapid Prediction of Peripheral Blood CD34 Counts Using a Multiple Regression Model Derived from Automated Hematology Analyzer Cell Population Data

Blood ◽

10.1182/blood.v126.23.3099.3099 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3099-3099 ◽

Cited By ~ 1

Author(s):

Thomas Porturas ◽

Mary Sell ◽

Leah Irwin ◽

Una O'Doherty ◽

Carlos Hipolito Villa

Keyword(s):

Flow Cytometry ◽

Stem Cell ◽

Multiple Regression ◽

Peripheral Blood ◽

Population Data ◽

Blood Samples ◽

Peripheral Blood Cd34 ◽

Cell Counts ◽

Flow Cytometric ◽

Hematology Analyzer

Abstract Background: Although peripheral blood CD34+ stem cell counts by flow cytometry correlate well with yields, the time, complexity, and cost associated with flow cytometry limits its utility. Rapid, cost-effective, surrogate predictors (with <1hr turnaround) would allow for same-visit analyses and alteration of collection and mobilization strategies, particularly for the optimal use of time-sensitive and costly agents such as plerixafor. We previously demonstrated that morphologic parameters of neutrophil-like cells measured by hematology analyzers correlated with CD34 counts. We aimed to improve these models by using multiple regression analyses on data from a common hematology analyzer. Methods: Patients undergoing stem cell apheresis were evaluated over a 6 month period. The day prior to initiation of apheresis, and on the morning of initial collection, peripheral blood samples were drawn into EDTA collection tubes and flow cytometric CD34 measurement and/or CBCs were performed on the Beckman Coulter DxH 800 hematology analyzer per standard protocol. CD34 cells were counted by flow cytometric ISHAGE protocols. Data from the DxH (48 variables per specimen) were exported into a data matrix with the corresponding flow cytometric data. Multiple regression analysis was performed using a step-wise method with log(peripheral CD34) as the dependent variable (SPSS, IBM). Data were randomly selected into a training-set of 70% of cases and a test-set of 30% of cases for validation. The derived model was further tested against peripheral blood data from the morning of collection to predict harvest yields. Further analyses were performed using Prism (GraphPad). Results: Tandem peripheral blood CD34 counts and CBC cell-population data were obtained from 69 blood samples in 64 patients. The population included patients with multiple myeloma (45), non-Hodgkin lymphoma (12), Hodgkin lymphoma (5), and amyloidosis (2). 41% of patients were female. In the test data set examining collection yields, 37 patients were mobilized with GCSF (+/- chemotherapy) alone, while 17 had plerixafor added to the regimen. 33 of these patients had same-day CBC data available for model prediction. The median processed volume was 15 L (range 5.9 to 19.7). The model to predict peripheral CD34 counts incorporated 3 variables from the hematology analyzer data (SD-V-EGC, SD-C-EGC, and NE#). Interestingly, the model included two variables descriptive of the morphology of early granulocytic cells. The model demonstrated an R value of 0.829 (adjusted R2 = 0.670, figure 1a). In testing the morning-of-collection model-predicted peripheral CD34, we found the model performed similarly to flow cytometry in predicting 1st collection yields. Furthermore, the CD34 prediction using the model (Figure 1 b) resulted in similar correlation with first-collection yields in patients treated with plerixafor versus patients not treated with plerixafor, in contrast to day-prior CD34 counts by flow-cytometry (Figure 1c). Two outliers for CD34 cell yield based on model predicted peripheral CD34 were identified. In one patient, the processed volume was very low (6.8 L, <5% percentile), while the second had a low mononuclear cell collection efficiency (35%) compared to the mean in this population (58.7%±23.3%). Threshold values for the model accurately identified patients appropriate for collection initiation (or plerixafor administration). Conclusion: Using data from a common, automated CBC analyzer, we developed a rapid, less-costly, and simple model to predict CD34 cell counts and 1st harvest yields. Because the measurement results can be obtained within the same clinic visit, and can be repeated with each CBC, the model is particularly useful to guide optimal use of plerixafor. We also envision that the model is useful for quality assurance of collection by identifying patients in whom cell yields were sub-optimal with respect to predicted CD34 cell counts. Additional studies to test the model in a larger population are ongoing. We propose that this model (and similarly derived models) can be implemented in clinical planning algorithms to improve the efficiency and cost of stem cell collection by apheresis. Acknowledgments: We would like to acknowledge and the nurses and staff of the apheresis unit and the stem cell and flow cytometry laboratories at the Hospital of the University of Pennsylvania for their contributions. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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NKG2C+CD57+ Natural Killer Cells May Play an Important Role in Maintaining Virus-Specific Immune Reconstitution Post-Allogeneic HSCT

Blood ◽

10.1182/blood-2018-99-110779 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3327-3327

Author(s):

Debora Queiros ◽

Susanne Luther-Wolf ◽

Eva M Weissinger ◽

Arnold Ganser

Keyword(s):

T Cells ◽

Healthy Volunteers ◽

Nk Cells ◽

Natural Killer ◽

Peripheral Blood ◽

Immune Reconstitution ◽

Blood Samples ◽

Allogeneic Hsct ◽

Cell Counts ◽

Cmv Reactivation

Abstract Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for malignant hematological diseases in adults. Due to the delayed immune reconstitution after HSCT, human cytomegalovirus (CMV) can reactivate, leading to prolonged hospitalization and increased morbidity and even mortality. Natural Killer (NK) cells have recently been described to undergo persistent reconfiguration in response to CMV-reactivation. Here we analyzed the presence and expansion of CMV-specific NK cells in patients after allogeneic HSCT. Methods: A multicolor flow cytometry panel for monitoring the CMV-specific NK cell (NKG2C+CD57+) reconstitution and expression of activating receptors was established. Reconstitution of CMV-specific NK cells was assessed in peripheral blood samples from 67 CMV-seropositive patients. The samples were collected and analyzed between day 0 and 100 post-HSCT at intervals of 7-10 days. Monitoring of CMV-reactivation by CMV-pp65 expression and reconstitution of CMV-specific T cells (CMV-CTLs) was done routinely in our laboratory, using 7 commercially available, certified CMV-tetramers, allowing for comparison of CMV-CTL and NKG2C+CD57+ NK cells. For further immunological tests, PBMCs from CMV-seropositive healthy volunteers were isolated by density gradient centrifugation. NK cells were negatively selected by magnetic bead separation. Additional purification of NKG2C+CD57+ NK cellswas achieved by cell sorting. Selected NK cells were expanded by co-culture with irradiated allogeneic PBMCs as feeder cells and the medium was supplemented with PHA and IL-2. Expanded CD57+NKG2C+ NK cells were KIR-typed. Results: Our patient cohort consisted of 67 patients after allogeneic HSCT with a median age of 59 years (range: 20-75). Forty-two patients (62.7%) were transplanted for acute leukemia, 54 (80.6%) received reduced intensity conditioning (RIC) and 62 (92.5%) received anti-thymocyte-antibodies globulin (ATG). GvHD-prophylaxis was cyclosporine A (CsA) in combination with mycophenolate motefil (MMF) for 82.1% of the patients and 77.6% were transplanted from matched donors. Thirty-three (49.2%) patients reactivated CMV (median age: 59.5 years, range 28-75; median day of reactivation: 38 days post-HSCT, range: 19-54). A significant increase in the absolute cell counts of NKG2C+CD57+ NK cells was observed after CMV reactivation, when compared to patients who did not reactivate CMV (p<0.0001). Interestingly, we observed a decreased expression of the CD8-molecule on NK cells during CMV-reactivation. CD8-expression on NK cells was previously described to be associated with a more cytotoxic phenotype of NK cells, this decrease may be a consequence of apoptosis following lytic activity. Monitoring for an additional activation marker, NKG2D, showed a significant increased expression after CMV reactivation (p=0.006), demonstrating not only the activating regulation of NK cells, but also, the co-stimulatory effects on T cell proliferation and cytokine production. Remarkably, when comparing NKG2C+CD57+ NK cells with CMV-specific T cells (Figure 1), both cell populations show similar kinetics of expansion, with an increase in the absolute cell counts during and after CMV-reactivation. NKG2C+CD57+ preliminary expansion-studies were performed using peripheral blood samples from CMV-seropositive healthy volunteers. After two weeks in culture, an expansion of up to 3100-fold was achieved. Further studies to assess the proliferative capacity of NKG2C+CD57+ subpopulation and its functional properties post-HSCT, are ongoing. In addition, an extensive panel of cytokines and chemokines excreted by the NKG2C+CD57+cells will be studied in order to evaluate their recruitment ability of other cell-types. Conclusion: Taken together, our results indicate that NK cells undergo a dynamic modulation and expansion of this population occurs in response to CMV-reactivation. Additionally, NKG2C+CD57+ NK cells may substitute for missing CMV-specific T cells shortly after HSCT and may play an important role in sustaining the immune reconstitution after CMV-reactivation. This study shows that NKG2C+CD57+ NK cells can be selected and expanded in vitro, holding promise for adoptive transfer in patients with recurrent CMV-reactivations. Disclosures Ganser: Novartis: Membership on an entity's Board of Directors or advisory committees.

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Th17 cells: A prognostic marker for MS rebound after natalizumab cessation?

Multiple Sclerosis Journal ◽

10.1177/1352458516640609 ◽

2016 ◽

Vol 23 (1) ◽

pp. 114-118 ◽

Cited By ~ 13

Author(s):

Jürgen Haas ◽

Katharina Schneider ◽

Alexander Schwarz ◽

Mirjam Korporal-Kuhnke ◽

Simon Faller ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Activity ◽

Prognostic Marker ◽

Peripheral Blood ◽

Th17 Cell ◽

Th17 Cells ◽

T Helper ◽

T Helper 17 ◽

Blood Samples ◽

Cytokine Levels

Background: Multiple sclerosis (MS) patients are at risk of renewed disease activity after discontinuing natalizumab (NAT) treatment. Objective: Assessing the implication of T helper 17 (Th17) cells in MS reactivation after NAT cessation. Methods: We monitored frequencies of Th17 cells and interleukin (IL)-17 cytokine levels in blood samples of 57 MS patients, without, during, and after NAT exposure. Results: Frequencies of both Th17 cells and, in part, also IL-17 levels, in peripheral blood increased under prolonged NAT therapy, returned to baseline after NAT withdrawal and became almost undetectable in blood samples of individuals who experienced relapses during the wash-out phase. Conclusion: Assessing the Th17-cell/IL-17 axis might help to predict rebound MS activity after NAT withdrawal.

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A Plasmodium vivax Plasmid DNA- and Adenovirus-Vectored Malaria Vaccine Encoding Blood-Stage Antigens AMA1 and MSP142 in a Prime/Boost Heterologous Immunization Regimen Partially Protects Aotus Monkeys against Blood-Stage Challenge

Clinical and Vaccine Immunology ◽

10.1128/cvi.00539-16 ◽

2017 ◽

Vol 24 (4) ◽

Cited By ~ 4

Author(s):

Nicanor Obaldia ◽

Michael G. Stockelman ◽

William Otero ◽

Jennifer A. Cockrill ◽

Harini Ganeshan ◽

...

Keyword(s):

Plasmodium Vivax ◽

Plasmid Dna ◽

Recombinant Dna ◽

Protective Efficacy ◽

Significant Proportion ◽

Parasite Burden ◽

Merozoite Surface Protein ◽

Blood Stage ◽

Vaccine Platform ◽

Content Type

ABSTRACT Malaria is caused by parasites of the genus Plasmodium, which are transmitted to humans by the bites of Anopheles mosquitoes. After the elimination of Plasmodium falciparum, it is predicted that Plasmodium vivax will remain an important cause of morbidity and mortality outside Africa, stressing the importance of developing a vaccine against P. vivax malaria. In this study, we assessed the immunogenicity and protective efficacy of two P. vivax antigens, apical membrane antigen 1 (AMA1) and the 42-kDa C-terminal fragment of merozoite surface protein 1 (MSP142) in a plasmid recombinant DNA prime/adenoviral (Ad) vector boost regimen in Aotus monkeys. Groups of 4 to 5 monkeys were immunized with plasmid DNA alone, Ad alone, prime/boost regimens with each antigen, prime/boost regimens with both antigens, and empty vector controls and then subjected to blood-stage challenge. The heterologous immunization regimen with the antigen pair was more protective than either antigen alone or both antigens delivered with a single vaccine platform, on the basis of their ability to induce the longest prepatent period and the longest time to the peak level of parasitemia, the lowest peak and mean levels of parasitemia, the smallest area under the parasitemia curve, and the highest self-cure rate. Overall, prechallenge MSP142 antibody titers strongly correlated with a decreased parasite burden. Nevertheless, a significant proportion of immunized animals developed anemia. In conclusion, the P. vivax plasmid DNA/Ad serotype 5 vaccine encoding blood-stage parasite antigens AMA1 and MSP142 in a heterologous prime/boost immunization regimen provided significant protection against blood-stage challenge in Aotus monkeys, indicating the suitability of these antigens and this regimen for further development.

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Intestinal Microbiota of Mice Influences Resistance to Staphylococcus aureus Pneumonia

Infection and Immunity ◽

10.1128/iai.00037-15 ◽

2015 ◽

Vol 83 (10) ◽

pp. 4003-4014 ◽

Cited By ~ 86

Author(s):

Stefanie Gauguet ◽

Samantha D'Ortona ◽

Kathryn Ahnger-Pier ◽

Biyan Duan ◽

Neeraj K. Surana ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Gut Microbiota ◽

Intestinal Microbiota ◽

Cell Types ◽

Lavage Fluid ◽

Staphylococcal Infection ◽

Infection Model ◽

Content Type ◽

Interleukin 22 ◽

Cell Counts

Th17 immunity in the gastrointestinal tract is regulated by the intestinal microbiota composition, particularly the presence of segmented filamentous bacteria (sfb), but the role of the intestinal microbiota in pulmonary host defense is not well explored. We tested whether altering the gut microbiota by acquiring sfb influences the susceptibility to staphylococcal pneumonia via induction of type 17 immunity. Groups of C57BL/6 mice which differed in their intestinal colonization with sfb were challenged with methicillin-resistantStaphylococcus aureusin an acute lung infection model. Bacterial burdens, bronchoalveolar lavage fluid (BALF) cell counts, cell types, and cytokine levels were compared between mice from different vendors, mice from both vendors after cohousing, mice given sfb orally prior to infection, and mice with and without exogenous interleukin-22 (IL-22) or anti-IL-22 antibodies. Mice lacking sfb developed more severeS. aureuspneumonia than mice colonized with sfb, as indicated by higher bacterial burdens in the lungs, lung inflammation, and mortality. This difference was reduced when sfb-negative mice acquired sfb in their gut microbiota through cohousing with sfb-positive mice or when given sfb orally. Levels of type 17 immune effectors in the lung were higher after infection in sfb-positive mice and increased in sfb-negative mice after acquisition of sfb, as demonstrated by higher levels of IL-22 and larger numbers of IL-22+TCRβ+cells and neutrophils in BALF. Exogenous IL-22 protected mice fromS. aureuspneumonia. The murine gut microbiota, particularly the presence of sfb, promotes pulmonary type 17 immunity and resistance toS. aureuspneumonia, and IL-22 protects against severe pulmonary staphylococcal infection.

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Bone Marrow Is a Major Parasite Reservoir inPlasmodium vivaxInfection

mBio ◽

10.1128/mbio.00625-18 ◽

2018 ◽

Vol 9 (3) ◽

pp. e00625-18 ◽

Cited By ~ 50

Author(s):

Nicanor Obaldia ◽

Elamaran Meibalan ◽

Juliana M. Sa ◽

Siyuan Ma ◽

Martha A. Clark ◽

...

Keyword(s):

Bone Marrow ◽

Plasmodium Vivax ◽

Peripheral Blood ◽

Specific Gene ◽

Content Type ◽

Antibody Assays ◽

Basic Biology ◽

Sexual Stages ◽

Human Infections ◽

Health Burdens

ABSTRACTPlasmodium vivaxcauses heavy burdens of disease across malarious regions worldwide. MatureP. vivaxasexual and transmissive gametocyte stages occur in the blood circulation, and it is often assumed that accumulation/sequestration in tissues is not an important phase in their development. Here, we present a systematic study ofP. vivaxstage distributions in infected tissues of nonhuman primate (NHP) malaria models as well as in blood from human infections. In a comparative analysis of the transcriptomes ofP. vivaxandPlasmodium falciparumblood-stage parasites, we found a conserved cascade of stage-specific gene expression despite the greatly different gametocyte maturity times of these two species. Using this knowledge, we validated a set of conserved asexual- and gametocyte-stage markers both by quantitative real-time PCR and by antibody assays of peripheral blood samples from infected patients and NHP (Aotussp.). Histological analyses ofP. vivaxparasites in organs of 13 infected NHP (AotusandSaimirispecies) demonstrated a major fraction of immature gametocytes in the parenchyma of the bone marrow, while asexual schizont forms were enriched to a somewhat lesser extent in this region of the bone marrow as well as in sinusoids of the liver. These findings suggest that the bone marrow is an important reservoir for gametocyte development and proliferation of malaria parasites.IMPORTANCEPlasmodium vivaxmalaria continues to cause major public health burdens worldwide. Yet, significant knowledge gaps in the basic biology and epidemiology ofP. vivaxmalaria remain, largely due to limited available tools for research and diagnostics. Here, we present a systematic examination of tissue sequestration duringP. vivaxinfection. Studies of nonhuman primates and malaria patients revealed enrichment of developing sexual stages (gametocytes) and mature replicative stages (schizonts) in the bone marrow and liver, relative to those present in peripheral blood. Identification of the bone marrow as a majorP. vivaxtissue reservoir has important implications for parasite diagnosis and treatment.

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Purification Methodology for Viable and Infective Plasmodium vivax Gametocytes That Is Compatible with Transmission-Blocking Assays

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01136-15 ◽

2015 ◽

Vol 59 (10) ◽

pp. 6638-6641 ◽

Cited By ~ 3

Author(s):

Omaira Vera ◽

Paula Brelas de Brito ◽

Letusa Albrecht ◽

Keillen Monick Martins-Campos ◽

Paulo F. P. Pimenta ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Plasmodium Vivax ◽

Control Strategies ◽

Current Control ◽

Significant Progress ◽

Blood Samples ◽

Transmission Blocking ◽

Content Type ◽

Early Appearance ◽

Unique Biology

ABSTRACTSignificant progress toward the control of malaria has been achieved, especially regardingPlasmodium falciparuminfections. However, the unique biology ofPlasmodium vivaxhampers current control strategies. The early appearance ofP. vivaxgametocytes in the peripheral blood and the impossibility of culturing this parasite are major drawbacks. Using blood samples from 40P. vivax-infected patients, we describe here a methodology to purify viable gametocytes and further infect anophelines. This method opens new avenues to validate transmission-blocking strategies.

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