T Helper1/T Helper2 Cells and Resistance/Susceptibility to Leishmania Infection: Is This Paradigm Still Relevant?

Work in large part on Leishmania major in the 1980s identified two distinct apparently counter-regulatory CD4+ T cell populations, T helper (h)1 and Th2, that controlled resistance/susceptibility to infection respectively. However, the generation of IL-4−/− mice in the 1990s questioned the paramount role of this Th2 archetypal cytokine in the non-healing response to Leishmania infection. The more recent characterization of CD4+ T cell regulatory populations and further effector CD4+ T helper populations, Th17, Th9, and T follicular (f)h cells as well as the acknowledged plasticity in T helper cell function has further added to the complexity of host pathogen interactions. These interactions are complicated by the multiplicity of cells that respond to CD4+ T cell subset signatory cytokines, as well as the diversity of Leishmania species that are often subject to significantly different immune-regulatory controls. In this article we review current knowledge with regard to the role of CD4+ T cells and their products during Leishmania infection. In particular we update on our studies using conditional IL-4Rα gene-deficient mice that have allowed dissection of the cell interplay dictating the disease outcomes of the major Leishmania species infecting humans

Cloning of a Carcinoembryonic Antigen Gene Family Member Expressed in Leukocytes of Chronic Myeloid Leukemia Patients and Bone Marrow

The carcinoembryonic antigen (CEA) gene family belongs to the immunoglobulin superfamily and can be subdivided into the CEA and pregnancy-specific glycoprotein subgroups. The basic structure of the encoded proteins consists of, in addition to a leader, one IgV-like and 2, 3, or 6 IgC-like domains. These domains are followed by varying COOH-terminal regions responsible for secretion, transmembrane anchoring, or insertion into the membrane by a glycosyl phosphatidylinositol tail. Here we report on the characterization of CGM6, a new member of the CEA gene subgroup, by complementary DNA cloning. The deduced coding region comprises 349 amino acids and consists of a leader, one IgV-like, two IgC-like domains, and a hydrophobic region, which is replaced by a glycosyl phosphatidylinositol moiety in the mature protein. CGM6 transcripts were only found thus far in leukocytes of chronic myeloid leukemia patients, in normal bone marrow, and in marginal amounts in normal granulocytes. The CGM6 gene product might, therefore, represent a myeloid marker. Analyses of CGM6 protein-expressing HeLa transfectants with monoclonal antibodies strongly indicate that the CGM6 gene codes for the CEA family member NCA-95

IgM and IgD B cell receptors differentially respond to endogenous antigens and control B cell fate.

Naive B cells co-express two BCR isotypes, IgM and IgD, with identical antigen-binding domains but distinct constant regions. IgM but not IgD is downregulated on autoreactive B cells. Because these isotypes are presumed to be redundant, it is unknown how this could impose tolerance. We introduced the Nur77-eGFP reporter of BCR signaling into mice that express each BCR isotype alone. Despite signaling strongly in vitro, IgD is less sensitive than IgM to endogenous antigen in vivo and developmental fate decisions are skewed accordingly. IgD-only Lyn-/- B cells cannot generate autoantibodies and short-lived plasma cells (SLPCs) in vivo, a fate thought to be driven by intense BCR signaling induced by endogenous antigens. Similarly, IgD-only B cells generate normal germinal center, but impaired IgG1+ SLPC responses to T-dependent immunization. We propose a role for IgD in maintaining the quiescence of autoreactive B cells and restricting their differentiation into autoantibody secreting cells

Interleukin‐12p70-dependent interferon‐γ production is crucial for resistance in African trypanosomiasis

African trypanosomiasis encompasses diseases caused by pathogenic trypanosomes, infecting both humans and animals. In the present article, we dissected the possible role of members of the interleukin ( IL)-12 family during infection with Trypanosoma brucei brucei and Trypanosoma evansi in mice. IL-12p35(-/-) , IL-12p40(-/-) , and IL-12p35(-/-)/p40(-/-) mice were susceptible to both pathogens, as was demonstrated by the increased mortality among these mice, compared with wild-type C57BL/6 mice. The different IL-12p70(-/-) mouse strains showed similar mortality kinetics, suggesting that IL-12p70 - but not the IL-12p80 homodimer or IL-23 plays a crucial role in survival. Although there were similar plasma levels of immunoglobulin (Ig) M and IgG2a in IL-12-deficient mice and wild-type mice, interferon (IFN) - g production, especially during early infection, was severely impaired in all IL-12p70(-/-) mouse strains, demonstrating an IL-12p70 - dependent mechanism for IFN-gamma production. Because IFN-gamma receptor-deficient mice (IFN-gamma R-/(-)) were also highly susceptible to both Trypanosoma species, IL-12p70 - dependent IFN-gamma production seems to be the important mechanism involved in resistance against both pathogens

Can we harness immune responses to improve drug treatment in leishmaniasis?

Leishmaniasis is a vector-borne parasitic disease that has been neglected in priority for control and eradication of malaria, tuberculosis and HIV/AIDS. Collectively, over one seventh of the world’s population is at risk of being infected with 0.7-1.2 million new infections reported annually. Clinical manifestations range from self-healing cutaneous lesions to fatal visceral disease. The first anti-leishmanial drugs were introduced in the 1950’s and, despite several shortcomings, remain the mainstay for treatment. Regardless of this and the steady increase in infections over the years, particularly among populations of low economic status, research on leishmaniasis remains under funded. This review looks at the drugs currently in clinical use and how they interact with the host immune response. Employing chemoimmunotherapeutic approaches may be one viable alternative to improve the efficacy of novel/existing drugs and extend their lifespan in clinical use

Schistosomiasis Burden and Its Association With Lower Measles Vaccine Responses in School Children From Rural Cameroon

Background and Methods: Schistosomiasis is debilitating and reported to impair immune responsiveness of infected hosts. In Cameroon, mass drug administration (MDA) is used in schoolchildren to reduce transmission of S. haematobium and S. mansoni. The effects of MDA and the impact of schistosomiasis on the titers of antibodies in vaccinated children have been poorly studied. We therefore assessed the prevalence of schistosomiasis in schoolchildren, eight months after MDA, in two locations: Barombi Koto (BK), endemic for S. haematobium (N = 169) and Yoro (Y), endemic for S. mansoni (N = 356). Age, gender, residence time and frequency of contact with river water were assessed as risk factors for infection and morbidity in both localities. In 70 schoolchildren from BK and 83 from Y, ultrasound was used to assess morbidity according to the WHO guidelines. Evaluation of measles antibodies was performed in previously vaccinated schoolchildren (14 with S. haematobium and 12 egg-negative controls from BK and 47 with S. mansoni and12 egg-negative controls from Y).Principal Findings and conclusions: The prevalence of S. haematobium was 25. 4% in BK (43/169) and 34.8% for S. mansoni in Y (124/356), indicating the persistent transmission of schistosomiasis despite MDA. Older age (AOR 1.31; 95%CI 1.12–1.54) and higher frequencies of exposure to river water (AOR 1.99; 95%CI 1.03–3.86) were identified as risks for infection in BK whereas only older age (OR 1.15; 95%CI 1.04–1.27) was a risk for infection in Y. Bladder pathology (score 2 to 5) was observed in 29.2% (7/24) of egg-positive children in BK and liver pathology (pattern C) in 31.1% (19/61) of egg-positive children in Y. There was a positive correlation between S. haematobium egg burden and bladder pathology (AOR 1.01; 95% CI 0.99–1.02) and positive correlation between S. mansoni-driven liver pathology and female gender (AOR 3.01; 95% CI 0.88–10.26). Anti-measles antibodies in vaccinated children were significantly lower in S. mansoni-infected when compared to egg-negative controls (p = 0.001), which was not observed in the S. haematobium-infected group from BK. Our results demonstrate a questionable efficacy of MDA alone in halting schistosomiasis transmission and confirm a possible immunomodulatory effect of S. mansoni on response to vaccines

The Role of Scavenger Receptor B1 in Infection with Mycobacterium tuberculosis in a Murine Model

Peer reviewedPublisher PD

IL-4 Mediated Resistance of BALB/c Mice to Visceral Leishmaniasis Is Independent of IL-4Rα Signaling via T Cells

Previous studies infecting global IL-4Rα-/-, IL-4-/-, and IL-13-/-mice on a BALB/c background with the visceralizing parasite Leishmania donovani have shown that the T helper 2 cytokines, IL-4, and IL-13, play influential but not completely overlapping roles in controlling primary infection. Subsequently, using macrophage/neutrophil-specific IL-4Rα deficient BALB/c mice, we demonstrated that macrophage/neutrophil unresponsiveness to IL-4 and IL-13 did not have a detrimental effect during L. donovani infection. Here we expand on these findings and show that CD4+ T cell-(Lckcre), as well as pan T cell-(iLckcre) specific IL-4Rα deficient mice, on a BALB/c background, unlike global IL-4Rα deficient mice, are also not adversely affected in terms of resistance to primary infection with L. donovani. Our analysis suggested only a transient and tissue specific impact on disease course due to lack of IL-4Rα on T cells, limited to a reduced hepatic parasite burden at day 30 post-infection. Consequently, the protective role(s) demonstrated for IL-4 and IL-13 during L. donovani infection are mediated by IL-4Rα-responsive cell(s) other than macrophages, neutrophils and T cells

Simvastatin enhances protection against Listeria monocytogenes infection in mice by counteracting Listeria-induced phagosomal escape

Statins are well-known cholesterol lowering drugs targeting HMG-CoA-reductase, reducing the risk of coronary disorders and hypercholesterolemia. Statins are also involved in immunomodulation, which might influence the outcome of bacterial infection. Hence, a possible effect of statin treatment on Listeriosis was explored in mice. Statin treatment prior to subsequent L. monocytogenes infection strikingly reduced bacterial burden in liver and spleen (up to 100-fold) and reduced histopathological lesions. Statin-treatment in infected macrophages resulted in increased IL-12p40 and TNF-α and up to 4-fold reduced bacterial burden within 6 hours post infection, demonstrating a direct effect of statins on limiting bacterial growth in macrophages. Bacterial uptake was normal investigated in microbeads and GFP-expressing Listeria experiments by confocal microscopy. However, intracellular membrane-bound cholesterol level was decreased, as analyzed by cholesterol-dependent filipin staining and cellular lipid extraction. Mevalonate supplementation restored statin-inhibited cholesterol biosynthesis and reverted bacterial growth in Listeria monocytogenes but not in listeriolysin O (LLO)-deficient Listeria . Together, these results suggest that statin pretreatment increases protection against L. monocytogenes infection by reducing membrane cholesterol in macrophages and thereby preventing effectivity of the cholesterol-dependent LLO-mediated phagosomal escape of bacteria