Alain Dessein

IL-17 and IL-22 are associated with protection against human kala azar caused by Leishmania donovani

IL-17 and IL-22 have been shown to increase protection against certain bacteria and fungal pathogens in experimental models. However, no human studies have demonstrated a crucial role of IL-17 and IL-22 in protection against infections. We show here that Leishmania donovani, which can cause the lethal visceral disease Kala Azar (KA), stimulates the differentiation of Th17 cells, which produce IL-17, IL-22, and IFN-gamma. Analysis of Th1, Th2, and Th17 cytokine responses by cultured PBMCs from individuals in a cohort of subjects who developed KA or were protected against KA during a severe outbreak showed that IL-17 and IL-22 were strongly and independently associated with protection against KA. Our results suggest that, along with Th1 cytokines, IL-17 and IL-22 play complementary roles in human protection against KA, and that a defect in Th17 induction may increase the risk of KA.

Infection and disease in human schistosomiasis mansoni are under distinct major gene control

INSERM U399, Immunology and Genetic of Parasitic Diseases/Laboratory of Parasitology-Mycology, Faculty of Medicine, Universite de la Mediterranee, Marseille, France Institute of Nuclear Medicine and Molecular Biology, University of Gezira, Gezira, Sudan Laboratorio De Imunologia, Faculdade de Medicina do Triangulo Mineiro, Mineiro, Brazil Alzaiem Alazihri University, Omdurman, Sudan Faculty of Medicine, University of Gezira, Gezira, Sudan INSERM U436 Paris, France

Suppressive Effects of Anti-mu Serum On the Development of Collagen Arthritis in Rats

Sprague-Dawley rats were maintained in environmentally isolated conditions and some of them were injected beginning at birth with rabbit anti-mu serum to suppress B-cell maturation. All rats were subsequently immunized with chick type II collagen. Ten (28%) of 36 rats injected with anti-mu antiserum failed to develop serum hemagglutinating antibodies to collagen, and there was a significant (P less than 0.0003) reduction in the IgG-specific antibody titer to collagen in these 10 rats compared to the other 26 rats in this group. Only 1 (10%) of the antibody-suppressed rats developed arthritis compared to 20 (77%) of the 26 other rats in the anti-mu-treated group (P less than 0.001). Twenty-two (61%) of 36 immunized rats administered rabbit anti-ovalbumin serum and 14 (88%) of 16 immunized rats kept in the axenic conditions developed arthritis. Delayed-type hypersensitivity to collagen did not differ significantly between the groups. These data provide indirect evidence that antibodies play a role in the inception of collagen arthritis.

Life-threatening malaria in African children: a prospective study in a mesoendemic urban setting.

Background: The population exposed to malaria within African cities has steadily increased. However, comprehensive data on life-threatening malaria features and risk factors in children from urban areas with seasonal malaria transmission, such as in Bamako (Mali), are lacking. Methods: Children admitted to the Gabriel Touré Hospital in Bamako with severe malarial anemia (SMA) and/or cerebral malaria (CM) were prospectively included in the study. Indicators of either SMA or CM were analyzed using logistic regression; and death hazard ratios (HRs) were estimated through survival analysis. Results: The study included 455 children: 66% presented with CM, 34% with SMA, 3% with hypoglycemia (HG); 5% with dehydration; 17% with respiratory distress (RD); 25% with splenomegaly; and 92% with hepatomegaly. The children with CM were older than those with SMA. CM was more often associated with dehydration, HG, and RD, whereas SMA was more often associated with splenomegaly. The overall case fatality rate was 16%, and 94% of the children who died had CM. HG [HR: 2.37; 95% confidence interval (CI): 1.04–5.39; P = 0.040], RD (HR: 4.23; 95% CI: 2.46–7.30; P < 10−6) and a deep coma with a Blantyre score of less than 3 (HR: 6.78, 95% CI: 2.43–18.91; P < 10−3), were all independent predictors of death. Conclusions: These findings delineate the patterns of severe malaria in children in a West African mesoendemic urban setting. They validate practicable prognostic indicators of life-threatening malaria for use in the limited facilities available in African health centers and provide a frame of reference for further research addressing life-threatening malaria in this setting.

Eosinophil-mediated killing of schistosomula of Schistosoma mansoni: Oxidative requirement for enhancement by eosinophil colony stimulating factor (CSF-α) and supernatants with eosinophil cytotoxicity enhancing activity (E-CEA)

Factors which enhance eosinophil-mediated killing of antibody-coated schistosomula of Schistosoma mansoni include semipurified eosinophil colony stimulating factor (CSF-alpha) and eosinophil cytotoxicity enhancing activity (E-CEA) present in supernatants from cultured mononuclear cells. We have examined the mechanism of enhancement. Both actions require oxygen in order to enhance killing and do not enhance killing under anaerobic conditions (P less than or equal to 0.005). E-CEA had no detectable effect upon oxidative metabolism. In contrast to CSF-alpha which, in our previous studies, increased superoxide anion productions and quantitative leukocyte iodination, E-CEA had no detectable effect upon oxidative metabolism. In order to test whether active oxygen products might mediate enhancement of killing, the effects of the addition of superoxide dismutase and catalase were tested. Neither enzyme showed inhibition of CSF-alpha or E-CEA enhancement of eosinophil-mediated killing. The effects of CSF-alpha and E-CEA were not additive. These studies suggest that both CSF-alpha and E-CEA exert enhancement of killing by means of an as yet unidentified oxygen requiring process.

The IL17F and IL17RA Genetic Variants Increase Risk of Cerebral Malaria in Two African Populations

ABSTRACT Cerebral malaria (CM) is a neurological complication of infection with Plasmodium falciparum that is partly caused by cytokine-mediated inflammation. It is not known whether interleukin-17 (IL-17) cytokines, which regulate inflammation, control the development of CM. To evaluate the involvement of IL-17 cytokines in CM, we analyzed 46 common polymorphisms in IL17A, IL17F, and IL17RA (which encodes the common receptor chain of the members of the IL-17 family) in two independent African populations. A case-control study involving 115 Nigerian children with CM and 160 controls from the community (CC) showed that IL17F reference single nucleotide polymorphism (SNP) 6913472 (rs6913472) (P = 0.004; odds ratio [OR] = 3.12), IL17F rs4715291 (P = 0.004; OR = 2.82), IL17RA rs12159217 (P = 0.01; OR = 2.27), and IL17RA rs41396547 (P = 0.026; OR = 3.15) were independently associated with CM. A replication study was performed in 240 nuclear Malian family trios (two parents with one CM child). We replicated the association for 3 SNPs, IL17F rs6913472 (P = 0.03; OR = 1.39), IL17RA rs12159217 (P = 0.01; OR = 1.52), and IL17RA rs41396547 (P = 0.04; OR = 3.50). We also found that one additional SNP, IL17RA rs41433045, in linkage disequilibrium (LD) with rs41396547, was associated with CM in both Nigeria and Mali (P = 0.002; OR = 4.12 in the combined sample). We excluded the possibility that SNPs outside IL17F and IL17RA, in strong LD with the associated SNPs, could account for the observed associations. Furthermore, the results of a functional study indicated that the aggravating GA genotype of IL17F rs6913472 was associated with lower IL-17F concentrations. Our findings show for the first time that IL17F and IL17RA polymorphisms modulate susceptibility to CM and provide evidence that IL-17F protects against CM.

Potential Use of Interleukin-10 Blockade as a Therapeutic Strategy in Human Cutaneous Leishmaniasis.

Interleukin-10 overproduction has been associated with worse prognosis in human cutaneous leishmaniasis, while IFN-γ-dependent responses are associated with parasite killing and host protection. Innovative strategies are needed to overcome therapeutic failure observed in endemic areas. The use of monoclonal antibody-based immunotherapy targeting IL-10 cytokine was evaluated here. Partial IL-10 blockade in Leishmania braziliensis whole soluble antigen-stimulated cells from endemic area CL patients with active or healed lesions and asymptomatic controls was evaluated. Overall decrease in IL-10, IL-4, and TNF-α production was observed in all groups of subjects. Only patients with active lesions still produced some levels of TNF-α after anti-IL-10 stimulation in association with Leishmania antigens. Moreover, this strategy showed limited modulatory effects on IFN-γ-dependent chemokine CXCL10 production. Results suggest the potential immunotherapeutic use of partial IL-10 blockade in localized cutaneous leishmaniasis.

Exome sequencing identifies two variants of the alkylglycerol monooxygenase gene (AGMO) as a cause of relapses in visceral leishmaniasis in children, in Sudan.

BackgroundnVisceral leishmaniasis (kala-azar, KA) is the most severe form of leishmaniasis, characterized by fever, weight loss, hepatosplenomegaly, and lymphadenopathy. During an outbreak of KA in Babar El Fugara (Sudan), 5.7% of cured patients displayed relapses, with familial clustering in half the cases.nnnMethodsnWe performed whole-exome sequencing on 10 relapsing individuals and 11 controls from 5 nuclear families.nnnResultsnRare homozygous and compound-heterozygous nonsense (c.1213C > T, rs139309795, p.Arg405*) and missense (c.701A > G, rs143439626, p.Lys234Arg) mutations of the alkylglycerol monooxygenase (AGMO) gene were associated with KA relapse in 3 families. Sequencing in additional family members confirmed the segregation of these mutations with relapse and revealed an autosomal dominant mode of transmission. These mutations were detected heterozygous in 2 subjects among 100 unrelated individuals with KA who never relapsed after cure, suggesting incomplete penetrance of AGMO deficiency. AGMO is expressed in hematopoietic cells, and is strongly expressed in the liver. AGMO modulates PAF production by mouse macrophages, suggesting that it may act through the PAF/PAF receptor pathway previously shown to have anti-Leishmania activity.nnnConclusionsnThis is the first demonstration that relapses after a first episode of KA are due to differences in human genetic susceptibility and not to modifications of parasite pathogenicity.

A Functional IL22 Polymorphism (rs2227473) Is Associated with Predisposition to Childhood Cerebral Malaria

Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection. This encephalopathy is characterized by coma and is thought to result from mechanical microvessel obstruction and an excessive activation of immune cells leading to pathological inflammation and blood-brain barrier alterations. IL-22 contributes to both chronic inflammatory and infectious diseases, and may have protective or pathogenic effects, depending on the tissue and disease state. We evaluated whether polymorphisms (nu2009=u200946) of IL22 and IL22RA2 were associated with CM in children from Nigeria and Mali. Two SNPs of IL22, rs1012356 (Pu2009=u20090.016, ORu2009=u20092.12) and rs2227476 (Pu2009=u20090.007, ORu2009=u20092.08) were independently associated with CM in a sample of 115 Nigerian children with CM and 160 controls. The association with rs2227476 (Pu2009=u20090.01) was replicated in 240 nuclear families with one affected child from Mali. SNP rs2227473, in linkage disequilibrium with rs2227476, was also associated with CM in the combined cohort for these two populations, (Pu2009=u20090.004, ORu2009=u20091.55). SNP rs2227473 is located within a putative binding site for the aryl hydrocarbon receptor, a master regulator of IL-22 production. Individuals carrying the aggravating T allele of rs2227473 produced significantly more IL-22 than those without this allele. Overall, these findings suggest that IL-22 is involved in the pathogenesis of CM.

Correction: In Vivo MRI Assessment of Hepatic and Splenic Disease in a Murine Model of Schistosmiasis.

The word “Schistosomiasis” is misspelled in the article title. The correct title is: In Vivo MRI Assessment of Hepatic and Splenic Disease in a Murine Model of Schistosomiasis. The correct citation is: Masi B, Perles-Barbacaru T-A, Laprie C, Dessein H, Bernard M, Dessein A, et al. (2015) In Vivo MRI Assessment of Hepatic and Splenic Disease in a Murine Model of Schistosomiasis. PLoS Negl Trop Dis 9(9): e0004036. doi:10.1371/journal.pntd.0004036