Yves Carlier

iNOS-producing inflammatory dendritic cells constitute the major infected cell type during the chronic Leishmania major infection phase of C57BL/6 resistant mice.

Leishmania major parasites reside and multiply in late endosomal compartments of host phagocytic cells. Immune control of Leishmania growth absolutely requires expression of inducible Nitric Oxide Synthase (iNOS/NOS2) and subsequent production of NO. Here, we show that CD11b+ CD11c+ Ly-6C+ MHC-II+ cells are the main iNOS-producing cells in the footpad lesion and in the draining lymph node of Leishmania major-infected C57BL/6 mice. These cells are phenotypically similar to iNOS-producing inflammatory DC (iNOS-DC) observed in the mouse models of Listeria monocytogenes and Brucella melitensis infection. The use of DsRed-expressing parasites demonstrated that these iNOS-producing cells are the major infected population in the lesions and the draining lymph nodes. Analysis of various genetically deficient mouse strains revealed the requirement of CCR2 expression for the recruitment of iNOS-DC in the draining lymph nodes, whereas their activation is strongly dependent on CD40, IL-12, IFN-γ and MyD88 molecules with a partial contribution of TNF-α and TLR9. In contrast, STAT-6 deficiency enhanced iNOS-DC recruitment and activation in susceptible BALB/c mice, demonstrating a key role for IL-4 and IL-13 as negative regulators. Taken together, our results suggest that iNOS-DC represent a major class of Th1-regulated effector cell population and constitute the most frequent infected cell type during chronic Leishmania major infection phase of C57BL/6 resistant mice.

MyD88-Dependent Activation of B220−CD11b+LY-6C+ Dendritic Cells during Brucella melitensis Infection

IFN-γ is a key cytokine controlling Brucella infection. One of its major function is the stimulation of Brucella-killing effector mechanisms, such as inducible NO synthase (iNOS)/NOS2 activity, in phagocytic cells. In this study, an attempt to identify the main cellular components of the immune response induced by Brucella melitensis in vivo is made. IFN-γ and iNOS protein were analyzed intracellularly using flow cytometry in chronically infected mice. Although TCRβ+CD4+ cells were the predominant source of IFN-γ in the spleen, we also identified CD11b+LY-6C+LY-6G−MHC-II+ cells as the main iNOS-producing cells in the spleen and the peritoneal cavity. These cells appear similar to inflammatory dendritic cells recently described in the mouse model of Listeria monocytogenes infection and human psoriasis: the TNF/iNOS-producing dendritic cells. Using genetically deficient mice, we demonstrated that the induction of iNOS and IFN-γ-producing cells due to Brucella infection required TLR4 and TLR9 stimulation coupled to Myd88-dependent signaling pathways. The unique role of MyD88 was confirmed by the lack of impact of Toll-IL-1R domain-containing adaptor inducing IFN-β deficiency. The reduction of IFN-γ+ and iNOS+ cell frequency observed in MyD88-, TLR4-, and TLR9-deficient mice correlated with a proportional lack of Brucella growth control. Taken together, our results provide new insight into how immune responses fight Brucella infection.

Congenital Chagas Disease: Recommendations for Diagnosis, Treatment and Control of Newborns, Siblings and Pregnant Women

In May 2010, the sixty-third World Health Assembly adopted resolution WHA63.20 on the control and elimination of Chagas disease, highlighting the need “to promote the development of public health measures in disease-endemic and disease non-endemic countries, with special focus on endemic areas, for the early diagnosis of congenital transmission and management of cases” [1]. This article summarizes the recommendations of the Technical Group IVa on “Prevention and Control of Congenital Transmission and Case Management of Congenital Infections” of the World Health Organizations Programme on Control of Chagas disease (infection with Trypanosoma cruzi). The present recommendations derive from those obtained in the meetings listed in Box 1. Box 1. Meetings from Which the Present Recommendations Derive Meeting ULB (Belgium)/UMSS (Bolivia)), Cochabamba, Bolivia, November 6–8, 2002: “Congenital Infection with Trypanosoma cruzi: From Mechanisms of Transmission to Strategies for Diagnosis And Control”, Carlier Y and Torico F, Revista da Sociedade Brasileira de Medicina Tropical 2003, 6: 767–771. Meeting PAHO/CLAP/ULB (Belgium)/IRD (France), Montevideo, Uruguay, June 24–25, 2004: “Congenital Chagas Disease: Its Epidemiology and Management”, http://www.paho.org/English/AD/DPC/CD/dch-chagas-congenita-2004.htm Meeting PAHO/CLAP/ULB (Belgium), Montevideo, Uruguay, May 17–18, 2007: “Information, Education and Communication in Congenital Chagas Disease”, http://www.paho.org/English/AD/DPC/CD/dch-congenita-iec-07.doc Meeting WHO, Geneva, Switzerland, July 4–6, 2007: “Revisiting Chagas Disease: From a Latin American Health Perspective to a Global Health Perspective” Meeting of the WHO TG IVa (congenital and paediatric Chagas disease), New Orleans, Louisiana, United States, December 11, 2008, satellite meeting to the ASTMH 57th annual meeting Meeting of the 6th European Congress of Tropical Medicine and International Health, Verona, Italy, September 6–10, 2009: “Chagas Disease in Europe” Meeting of WHO-HQ and the WHO regional office for Europe, Geneva, Switzerland, December 17–18, 2009: “Consultation on Chagas Disease in Europe”

Influence of maternal infection on offspring resistance towards parasites.

Immunoglobulins, parasite circulating antigens, immune cells, cytokines and other cell-related products can be transferred from infected mothers to their young. They can combine their effects to interact with the invading parasites, as well as to induce a long-term modulation of the offsprings capacity to mount an immune response to subsequent exposure to parasites. The protective effect of maternally derived antibodies may be limited by the selective transfer of immunoglobulin isotypes. Maternal antibodies may also prevent the priming of specific cells in offspring or inhibit the progenys antibody production by interacting with B-cell receptors or with the idiotypic repertoire. The potentially beneficial priming effect of transferred parasitic antigens may be altered by the Th2-cell-biased foetal environment and such antigens may also induce deletion or anergy of T- and B-cell clones in offspring. Therefore, besides protective effects, maternal infection may downregulate the offsprings immune response. If such hyporesponsiveness may be clearly harmful (in increasing the risk or in worsening congenital or postnatally acquired infections in offspring), it can also be beneficial (in limiting the pathogenesis of some infections). Here, Yves Carlier and Carine Truyens review the rationale of these complex foeto-maternal relationships in parasitic diseases.

Congenital infection with Trypanosoma cruzi: from mechanisms of transmission to strategies for diagnosis and control

The transmission rate of congenital T. cruzi infection (number of congenital cases/number of chagasic mothers) in the Southern Cone countries varies widely, from 1% in Brazil to 4 to 12% Argentina, Bolivia, Chile and Paraguay. These differences were discussed at length, and attributed to the different methodologies used for detection of congenital cases, and/or possible special characteristics from the infecting parasites, differences in the immunological, genetical or nutritional status of the mother, or specific epidemiological situations remaining to be studied.

Frequency of the congenital transmission of Trypanosoma cruzi: A systematic review and meta-analysis

Chagas disease is caused by the parasite Trypanosoma cruzi and is endemic in much of Latin America. With increased globalisation and immigration, it is a risk in any country, partly through congenital transmission. The frequency of congenital transmission is unclear.

Congenital parasitic infections: A review

This review defines the concepts of maternal-fetal (congenital) and vertical transmissions (mother-to-child) of pathogens and specifies the human parasites susceptible to be congenitally transferred. It highlights the epidemiological features of this transmission mode for the three main congenital parasitic infections due to Toxoplasma gondii, Trypanosoma cruzi and Plasmodium sp. Information on the possible maternal-fetal routes of transmission, the placental responses to infection and timing of parasite transmission are synthesized and compared. The factors susceptible to be involved in parasite transmission and development of congenital parasitic diseases, such as the parasite genotypes, the maternal co-infections and parasitic load, the immunological features of pregnant women and the capacity of some fetuses/neonates to overcome their immunological immaturity to mount an immune response against the transmitted parasites are also discussed and compared. Analysis of clinical data indicates that parasitic congenital infections are often asymptomatic, whereas symptomatic newborns generally display non-specific symptoms. The long-term consequences of congenital infections are also mentioned, such as the imprinting of neonatal immune system and the possible trans-generational transmission. The detection of infection in pregnant women is mainly based on standard serological or parasitological investigations. Amniocentesis and cordocentesis can be used for the detection of some fetal infections. The neonatal infection can be assessed using parasitological, molecular or immunological methods; the place of PCR in such neonatal diagnosis is discussed. When such laboratory diagnosis is not possible at birth or in the first weeks of life, standard serological investigations can also be performed 8-10 months after birth, to avoid detection of maternal transmitted antibodies. The specific aspects of treatment of T. gondii, T. cruzi and Plasmodium congenital infections are mentioned. The possibilities of primary and secondary prophylaxes, as well as the available WHO corresponding recommendations are also presented.

Trypanosoma cruzi infection in mice induces a polyisotypic hypergammaglobulinaemia and parasite-specific response involving high IgG2a concentrations and highly avid IgG1 antibodies

Trypanosoma cruzi infection in BALB/c mice induced a reversible polyisotypic hypergammaglobulinaemia, with particularly high levels of IgG2a, IgM and IgE. Hypergammaglobulinaemia started during the acute phase of infection and persisted during chronic disease until 11–13 weeks post‐infection (w.p.i.), when immunoglobulin levels, with the exception of IgE, returned near normal values. Parasite‐specific antibodies counted for 14 to 23% of gammaglobulinaemia, in acute and chronic infection respectively. The titres of IgM antibodies rose from two w.p.i. IgA, IgE and IgG subclass antibodies built up gradually over the time of parasite clearance (i.e., between three and six w.p.i.). All antibody isotypes, including IgM reached significant and stable titres throughout chronic infection. IgG2a, IgG1 and IgM antibodies had constantly higher titres than the other antibody isotypes. The dominance of IgG2a antibodies was due to their high plasma concentrations, around 70% of all antibodies available in the chronic infection. IgG1 had the highest functional avidity, whereas its concentration corresponded to only 10% of the whole antibody fraction. These results indicate that T. cruzi infection in mice induces a polyisotypic humoral immune response, dominated by some antibody isotypes, with major differences in concentrations and functional avidities. This could be of crucial importance in determining the outcome of infection.

Maternal Trypanosoma cruzi Infection Upregulates Capacity of Uninfected Neonate Cells To Produce Pro- and Anti-Inflammatory Cytokines

ABSTRACT The possibility of maternal in utero modulation of the innate and/or adaptive immune responses of uninfected newborns fromTrypanosoma cruzi-infected mothers was investigated by studying the capacity of their whole blood cells to produce cytokines in response to T. cruzi lysate or lipopolysaccharide-plus-phytohemagglutinin (LPS-PHA) stimulation. Cells of such newborns occasionally released gamma interferon (IFN-γ) and no interleukin-2 (IL-2) and IL-4 upon specific stimulation, while their mothers responded by the production of IFN-γ, IL-2, and IL-4. Infection in mothers was also associated with a hyperactivation of maternal cells and also, strikingly, of cells of their uninfected neonates, since their release of proinflammatory (IL-1β, IL-6, and tumor necrosis factor alpha [TNF-α]) as well as of anti-inflammatory (IL-10 and soluble TNF receptor) cytokines or factors was upregulated in the presence of LPS-PHA and/or parasite lysate. These results show that T. cruzi infection in mothers induces profound perturbations in the cytokine response of their uninfected neonates. Such maternal influence on neonatal innate immunity might contribute to limit the occurrence and severity of congenital infection.

Chagas disease, France.

Chagas Disease, France