IL-17Aは赤痢アメーバの腸管感染においてIFN-γ/IL-4比の減少と持続感染に寄与する

Amebiasis is an infectious disease caused by Entamoeba histolytica, an anaerobic protozoan parasite, and is a major public health problem worldwide, particularly in areas with inadequate sanitation and poor hygiene. Th1 responses, represented by interferon gamma (IFN-γ), play a protective role by clearing the amebae from the gut, whereas Th2 responses are responsible for chronic infection. Th17 responses preconditioned by vaccination or by modulating the intestinal microbiome protect mice from the settlement of E. histolytica. However, the role of interleukin-17A (IL-17A), which is upregulated during the natural course of intestinal amebiasis, has not been clarified. The aim of this study was to investigate the role of IL-17A during intestinal amebiasis in a mouse model. IL-17A knockout and wild-type CBA/J mice were challenged intracecally with 2 × 106 E. histolytica trophozoites, and their infection, pathology, and immune responses were monitored. Neither the initial settlement of E. histolytica nor the inflammation of the cecum was affected by the absence of IL-17A for week 1, but the infection rate and parasite burden declined in a late stage of infection, accompanied by an increased IFN-γ/IL-4 ratio. Therefore, IL-17A contributes to the persistence of E. histolytica and modulates the immune response, including the IFN-γ/IL-4 ratio, which may be responsible for the reduction of the parasite burden in the IL-17A knockout mice during the chronic phase of intestinal amebiasis.長崎大学学位論文 学位記番号:博(医歯薬)甲第1005号 学位授与年月日:平成29年12月6日Author: Sharmina Deloer, Risa Nakamura, Mihoko Kikuchi, Taeko Moriyasu, Yombo Dan Justin Kalenda, Eman Sayed Mohammed, Masachika Senba, Yoichiro Iwakura, Hiroki Yoshida, Shinjiro HamanoCitation: Parasitology International, 66(6), pp.817-823; 2017Nagasaki University (長崎大学)課程博

マンソン住血吸虫感染の血清診断に応用可能なタンデムリピート抗原に関する研究

The diagnosis of schistosome infection, followed by effective treatment and/or mass drug administration, is crucial to reduce the disease burden. Suitable diagnostic tests and field-applicable tools are required to sustain schistosomiasis control programs. We therefore assessed the potential of tandem repeat (TR) proteins for sero-diagnosis of Schistosoma mansoni infection using an experimental mouse model.TR genes in the genome of S. mansoni were searched in silico and 7 candidates, named SmTR1, 3, 8, 9, 10, 11 and 15, were selected. Total RNA was extracted from S. mansoni adult worms and eggs. Target TR genes were amplified, cloned, and the proteins were expressed in Escherichia coli competent cells. Female BALB/c mice were infected with 100 S. mansoni cercariae and sera were collected each week post-infection for 18. weeks. The levels of IgG antibodies to SmTR antigens were compared to those to soluble egg antigen (SEA) and to soluble worm antigen preparation (SWAP). Sera of infected mice reacted to all the antigens whereas those of naive mice did not. IgG responses to SmTR1, 3, 9 and 10 were detected at the early stage of infection. Interestingly, antibodies reacting to SmTR3, 9, 10 and 15 dramatically decreased 4. weeks after treatment with praziquantel, while those against SEA and SWAP remained elevated.Our study suggests that TR proteins, especially SmTR10, may be suitable antigens for sero-diagnosis of infection by S. mansoni and are potential markers for monitoring and surveillance of schistosomiasis, including re-infection after treatment with praziquantel.長崎大学学位論文 学位記番号:博(医歯薬)甲第803号 学位授与年月日:平成27年9月18日Author: Yombo Dan Justin Kalenda, Kentaro Kato, Yasuyuki Goto, Yoshito Fujii, Shinjiro HamanoCitation: Parasitology International, 64(6), pp.503-512; 2015Nagasaki University (長崎大学)課程博

Spatial distribution and risk factors of Schistosoma haematobium and hookworm infections among schoolchildren in Kwale, Kenya

Background: Large-scale schistosomiasis control programs are implemented in regions with diverse social and economic environments. A key epidemiological feature of schistosomiasis is its small-scale heterogeneity. Locally profiling disease dynamics including risk factors associated with its transmission is essential for designing appropriate control programs. To determine spatial distribution of schistosomiasis and its drivers, we examined schoolchildren in Kwale, Kenya. Methodology/Principal findings: We conducted a cross-sectional study of 368 schoolchildren from six primary schools. Soil-transmitted helminths and Schistosoma mansoni eggs in stool were evaluated by the Kato-Katz method. We measured the intensity of Schistosoma haematobium infection by urine filtration. The geometrical mean intensity of S. haematobium was 3.1 eggs/10 ml urine (school range, 1.4?9.2). The hookworm geometric mean intensity was 3.2 eggs/g feces (school range, 0?17.4). Heterogeneity in the intensity of S. haematobium and hookworm infections was evident in the study area. To identify factors associated with the intensity of helminth infections, we utilized negative binomial generalized linear mixed models. The intensity of S. haematobium infection was associated with religion and socioeconomic status (SES), while that of hookworm infection was related to SES, sex, distance to river and history of anthelmintic treatment. Conclusions/Significance: Both S. haematobium and hookworm infections showed micro-geographical heterogeneities in this Kwale community. To confirm and explain our observation of high S. haematobium risk among Muslims, further extensive investigations are necessary. The observed small scale clustering of the S. haematobium and hookworm infections might imply less uniform strategies even at finer scale for efficient utilization of limited resources

Proprotein Convertase Subtilisin/Kexin 9 level is independently associated with 10-year cardiovascular risk in blood donors in Kinshasa: A cross-sectional study based on Framingham predictive equation

Context and objective: Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) plays an important role in lipid homeostasis. The present study aimed  to determine whether PCSK9 is a potential cardiovascular risk (CVR) factor among apparently healthy people. Methods:  A cross-sectional  study was conducted between August 2016 and July 2020 in the City of Kinshasa, Democratic Republic of the Congo. Volunteer and regular blood  donors from the Catholic medical network (Bureau Diocésain des OEuvres Médicales [BDOM]/Kinshasa) were enrolled in this study. Serum PCSK9  and lipid levels were measured by ELISA and enzymatic colorimetric method, respectively. Framingham’s predictive equation was used for predicting  cardiac events. Pearson's correlation coefficients (r) were calculated to assess the association between the different lipid fractions and  PCSK-9. The search for the determinants of 10 year-risk of a high cardiovascular event was carried out using the cultivariate binary logistic  regression model. Results: Of 296 subjects included in the present study, 264 (89.1 %) had low and 32 (10.8 %) high CVR. Age ≥ 50 years (aOR 5), low HDL-c (aOR 5),  high LDL-c (aOR 6), hypertriglyceridemia (aOR 4), and belonging to the 3rd tertile of PCSK9 ((aOR 4.4) emerged as independent determinants of high  CVR. Conclusion: High plasma levels of PCSK9 are associated with high CVR in apparently healthy people. Prospective studies in the general population  to confirm this Framingham cardiovascular prediction are needed.    French title: Le taux de Proprotein Convertase Subtilisin/Kexin 9 est indépendamment associé au risque cardiovasculaire à 10 ans chez les donneurs de sang à Kinshasa : Etude transversale basée sur Contexte et objectif: La Proprotéine Convertase Subtilisine Kexin type 9 (PCSK9) est importante dans l'homéostasie des lipides. Cette étude visait à  établir le rôle potentiel de PCSK9 comme facteur de risque cardiovasculaire (RCV). Méthodes. L’enquête transversale couvrant la période d’août 2016 à juillet 2020 a été conduite dans la ville de Kinshasa (RD Congo), sur des donneurs de sang volontaires et réguliers au sein du réseau médical catholique (BDOM). La technique Elisa a permis l’analyse de PCSK9 sérique et le taux des lipides était dosé par la méthode enzymatique colorimétrique. L'équation de prédiction des événements CV a recourru à la méthode Framingham. La corrélation entre le taux des lipides sériques et le PCSK-9 a été faite à l’aide de corrélation linéraire de Pearson. La régression logistique binaire multivariée a déterminé le niveau du risque futur  des événements CV. Résultats: 264/296 sujets (89,1 %) avaient un RCV faible, 32 (10,8 %) un RCV élevé. Les principaux déterminants du RCV étaient :  âge ≥ 50 ans (ORa 5), taux bas de HDL-c (ORa 4), taux élevé de LDL-c (ORa 6) et/ou de triglycéride (ORa 4) et l'appartenance au 3ème tertile de PCSK9 (ORa 4). Conclusion: Le taux plasmatique élevé de PCSK9 constitue un facteur de risque un RCV élevé dans cette population en bonne santé apparente. L’extension de l’étude dans la   pulation générale est nécessaire pour la validation de ces résultats.     &nbsp

A toxicology study of Csf2ra complementation and pulmonary macrophage transplantation therapy of hereditary PAP in mice

Pulmonary macrophage transplantation (PMT) is a gene and cell transplantation approach in development as therapy for hereditary pulmonary alveolar proteinosis (hPAP), a surfactant accumulation disorder caused by mutations in CSF2RA/B (and murine homologs). We conducted a toxicology study of PMT of Csf2ra gene-corrected macrophages (mGM-Rα+Mϕs) or saline-control intervention in Csf2raKO or wild-type (WT) mice including single ascending dose and repeat ascending dose studies evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics. Lentiviral-mediated Csf2ra cDNA transfer restored GM-CSF signaling in mGM-Rα+Mϕs. Following PMT, mGM-Rα+Mϕs engrafted, remained within the lungs, and did not undergo uncontrolled proliferation or result in bronchospasm, pulmonary function abnormalities, pulmonary or systemic inflammation, anti-transgene product antibodies, or pulmonary fibrosis. Aggressive male fighting caused a similarly low rate of serious adverse events in saline- and PMT-treated mice. Transient, minor pulmonary neutrophilia and exacerbation of pre-existing hPAP-related lymphocytosis were observed 14 days after PMT of the safety margin dose but not the target dose (5,000,000 or 500,000 mGM-Rα+Mϕs, respectively) and only in Csf2raKO mice but not in WT mice. PMT reduced lung disease severity in Csf2raKO mice. Results indicate PMT of mGM-Rα+Mϕs was safe, well tolerated, and therapeutically efficacious in Csf2raKO mice, and established a no adverse effect level and 10-fold safety margin

Map of the study area, Kwale, Kenya.

<p>Dotted red circles indicate the catchment area from which children attend each school. The position of the participants’ houses is indicated by white circles. The river network is shown by blue lines while the main road is represented by black lines. Altitude (meters): highest, white background; lowest, dark green background.</p

Number (%) of schoolchildren infected with three parasite species in Kwale, Kenya.

<p>Number (%) of schoolchildren infected with three parasite species in Kwale, Kenya.</p

Bivariate negative binomial generalized linear model (NB-GLM) for intensity of hookworm infection among schoolchildren in Kwale, Kenya.

<p>Bivariate negative binomial generalized linear model (NB-GLM) for intensity of hookworm infection among schoolchildren in Kwale, Kenya.</p

Spatial distribution of the intensity of <i>S</i>. <i>haematobium</i> infection in the study area.

<p>The intensity of infection was relatively high among Muslims compared to Christians despite participants sharing locality of residence. It is evident the intensity of infection is not related to the house proximity to the river. “Plus sign” schools combined because of overlap in the distribution of their populations in the study area. “Single asterisk” 1–49 eggs/10 ml urine, “double asterisks” ≥50 eggs/10 ml urine. The numbers in parentheses indicate the geometric mean of the number of eggs in each school based on religion.</p