Co-activation through TLR4 and TLR9 but not TLR2 skews Treg-mediated modulation of Igs and induces IL-17 secretion in Treg: B cell co-cultures.

Whereas Th17 cells are associated with aggravated inflammation, regulatory T cells (Tregs) provide an environment to control overt responses. Nevertheless, Tregs display a certain degree of plasticity demonstrating that T cell differentiation processes are not absolute. Previously, we showed that human Treg clones induced B cells to produce IgG4.

Spontaneous bacterial peritonitis by Pasteurella multocida under treatment with rifaximin.

Spontaneous bacterial peritonitis (SBP) is a life-threatening complication of liver cirrhosis. Recently, rifaximin, a non-absorbable antibiotic which is used to prevent recurrent hepatic encephalopathy, has been proposed as effective prophylaxis for SBP. Here, we present an unusual case of SBP under treatment with rifaximin.

Requirement of lipid II biosynthesis for cell division in cell wall-less Wolbachia, endobacteria of arthropods and filarial nematodes.

Obligate Wolbachia endobacteria have a reduced genome and retained genes are hypothesized to be crucial for survival. Although intracellular bacteria do not need a stress-bearing peptidoglycan cell wall, Wolbachia encode proteins necessary to synthesize the peptidoglycan precursor lipid II. The activity of the enzymes catalyzing the last two steps of this pathway was previously shown, and Wolbachia are sensitive to inhibition of lipid II synthesis.

Onchocerca volvulus-neurotransmitter tyramine is a biomarker for river blindness.

Onchocerciasis, also known as "river blindness", is a neglected tropical disease infecting millions of people mainly in Africa and the Middle East but also in South America and Central America. Disease infectivity initiates from the filarial parasitic nematode Onchocerca volvulus, which is transmitted by the blackfly vector Simulium sp. carrying infectious third-stage larvae.

New quinoline-5,8-dione and hydroxynaphthoquinone derivatives inhibit a chloroquine resistant Plasmodium falciparum strain.

We report on the design, synthesis, and in vitro evaluation of new quinoline-5,8-dione and hydroxynaphthoquinone derivatives. The synthesized compounds were evaluated for in vitro antimalarial activity against Plasmodium falciparum. Of the 15 compounds, 7a-c, 8a, 9b, 11, and 15 were effective in growth inhibition with IC(50) values of below 5 μM.

Differential induction of Th2- and Th1-associated responses by filarial antigens and endosymbiotic Wolbachia in a murine model of river blindness.

Immune responses to filarial parasites like the river blindness inducing Onchocerca volvulus are obscured by combined reactions to the filarial nematodes themselves and their endosymbiont bacteria Wolbachia. Overall, infection with filarial nematodes induces a strong Th2 response characterized by IL-5 production and to a lesser degree a Th1 response and IFNγ production. Neutrophil and eosinophil infiltration into the corneal stroma are hallmark features of Onchocerca volvulus stimulation in a mouse model of river blindness.

Doxycycline improves filarial lymphedema independent of active filarial infection: a randomized controlled trial.

Background: The aim of this study was to determine whether improvement of filarial lymphedema (LE) by doxycycline is restricted to patients with ongoing infection (positive for circulating filarial antigen [CFA]), or whether the majority of CFA-negative patients with LE would also show a reduction in LE severity.

Methods: One hundred sixty-two Ghanaian participants with LE stage 1-5 (Dreyer) were randomized blockwise into 2 groups (CFA positive or negative) and allocated to 3 treatment arms of 6 weeks: (1) amoxicillin (1000 mg/d), (2) doxycycline (200 mg/d), or (3) placebo matching doxycycline. All groups received standard hygiene morbidity management.

Corallopyronin A specifically targets and depletes essential obligate Wolbachia endobacteria from filarial nematodes in vivo.

Doxycycline and rifampicin deplete essential Wolbachia from filarial nematodes that cause lymphatic filariasis or onchocerciasis, resulting in blocked worm development and death. However, doxycycline is contraindicated for children and pregnant/breastfeeding women, as is rifampicin in the latter group with the additional specter of possible resistance development in Mycobacterium spp. Novel antibiotics with a narrower spectrum would aid in eliminating filarial diseases.

Differential expression of toll-like receptor 2 on dendritic cells from asymptomatic and symptomatic atopic donors.

Background: Early microbial exposure may reduce the risk for developing allergies on an atopic genetic background. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns of microbes and modulate innate and adaptive immunity. Different expression of TLRs in symptomatic and asymptomatic atopic donors may contribute to the development of allergic disease.

Immunization with L. sigmodontis microfilariae reduces peripheral microfilaraemia after challenge infection by inhibition of filarial embryogenesis.

Background: Lymphatic filariasis and onchocerciasis are two chronic diseases mediated by parasitic filarial worms causing long term disability and massive socioeconomic problems. Filariae are transmitted by blood-feeding mosquitoes that take up the first stage larvae from an infected host and deliver it after maturation into infective stage to a new host. After closure of vector control programs, disease control relies mainly on mass drug administration with drugs that are primarily effective against first stage larvae and require many years of annual/biannual administration.

The human parasite Loa loa in cytokine and cytokine receptor gene knock out BALB/c mice: survival, development and localization.

Background: Immunological mechanisms involved in the survival and development of human filarial species in the vertebrate host are poorly known due to the lack of suitable experimental models. In order to understand the role of cytokines in the survival and development of filarial larvae in the vertebrate host, we infected different strains of BALB/c mice deficient in a number of cytokine or cytokine receptor genes with Loa loa. The survival and development of larvae were monitored.

Retarded Onchocerca volvulus L1 to L3 larval development in the Simulium damnosum vector after anti-wolbachial treatment of the human host.

Background: The human parasite Onchocerca volvulus harbours Wolbachia endosymbionts essential for worm embryogenesis, larval development and adult survival. In this study, the development of Wolbachia-depleted microfilariae (first stage larvae) to infective third stage larvae (L3) in the insect vector Simulium damnosum was analysed.

Methods: Infected volunteers in Cameroon were randomly and blindly allocated into doxycycline (200 mg/day for 6 weeks) or placebo treatment groups.

Helminth protection against autoimmune diabetes in nonobese diabetic mice is independent of a type 2 immune shift and requires TGF-β.

Leading hypotheses to explain helminth-mediated protection against autoimmunity postulate that type 2 or regulatory immune responses induced by helminth infections in the host limit pathogenic Th1-driven autoimmune responses. We tested these hypotheses by investigating whether infection with the filarial nematode Litomosoides sigmodontis prevents diabetes onset in IL-4-deficient NOD mice and whether depletion or absence of regulatory T cells, IL-10, or TGF-β alters helminth-mediated protection. In contrast to IL-4-competent NOD mice, IL-4-deficient NOD mice failed to develop a type 2 shift in either cytokine or Ab production during L.

Over expression of IL-10 by macrophages overcomes resistance to murine filariasis.

Individuals infected with parasitic helminths are able to tolerate the presence of parasites for considerable time without clinical pathology. Immunosuppressive responses induced by the filarial parasite are considered responsible for this long-lasting relationship, inuring to the benefit of both parasite and host. In order to directly link IL-10 with parasite survival, we infected mice, in which over expression of IL-10 was restricted to macrophages under control of the CD68 promoter (macIL-10tg), with Litomosoides sigmodontis.

Transforming growth factor-β1 variant Leu10Pro is associated with both lack of microfilariae and differential microfilarial loads in the blood of persons infected with lymphatic filariasis.

Antigen testing and ultrasound detection have shown that many persons are infected with Wuchereria bancrofti even though they do not have microfilariae (Mf) in the blood. To ascertain the role of human host immunogenetics on the lack of circulating Mf in the blood, 152 lymphatic filariasis (LF)-infected patients comprising 118 patients with microfilaremic (Mf+, patent) infection and 34 patients with latent (Mf-, antigen-positive) infection were recruited and genotyped for association of single nucleotide polymorphisms of TGF-β1 and differential Mf load and/or lack of Mf in the blood from infected persons in Ghana. An association was found between the TGF-β1 Leu10Pro variant and lack of Mf in the blood.

Onchocerciasis: the role of Wolbachia bacterial endosymbionts in parasite biology, disease pathogenesis, and treatment.

The discovery of Wolbachia intracellular bacteria within filarial nematodes, including Onchocerca volvulus, the causative agent of onchocerciasis or "river blindness," has delivered a paradigm shift in our understanding of the parasite's biology, to where we now know that the bacterial endosymbionts are essential for normal development of larvae and embryos and may support the long-term survival of adult worms. The apparent mutualistic dependency has also offered a novel approach to the treatment of onchocerciasis through the use of antibiotics to eliminate Wolbachia, delivering for the first time a treatment which has significant macrofilaricidal efficacy. Studies with other filarial nematode species have also highlighted a role for Wolbachia in transmission and infection of the mammalian host through a fascinating manipulation of mast cell-mediated vasodilation to enhance infectivity of vector-borne larvae.

Filariasis in Africa--treatment challenges and prospects.

Lymphatic filariasis (LF) and onchocerciasis are parasitic nematode infections that are responsible for a major disease burden in the African continent. Disease symptoms are induced by the immune reactions of the host, with lymphoedema and hydrocoele in LF, and dermatitis and ocular inflammation in onchocerciasis. Wuchereria bancrofti and Onchocerca volvulus, the species causing LF and onchocerciasis in Africa, live in mutual symbiosis with Wolbachia endobacteria, which cause a major part of the inflammation leading to symptoms and are antibiotic targets for treatment.

The IFN-γ-inducible GTPase, Irga6, protects mice against Toxoplasma gondii but not against Plasmodium berghei and some other intracellular pathogens.

Clearance of infection with intracellular pathogens in mice involves interferon-regulated GTPases of the IRG protein family. Experiments with mice genetically deficient in members of this family such as Irgm1(LRG-47), Irgm3(IGTP), and Irgd(IRG-47) has revealed a critical role in microbial clearance, especially for Toxoplasma gondii. The in vivo role of another member of this family, Irga6 (IIGP, IIGP1) has been studied in less detail.

Macrofilaricidal Activity in Wuchereria bancrofti after 2 Weeks Treatment with a Combination of Rifampicin plus Doxycycline.

Infection with the filarial nematode Wuchereria bancrofti can lead to lymphedema, hydrocele, and elephantiasis. Since adult worms cause pathology in lymphatic filariasis (LF), it is imperative to discover macrofilaricidal drugs for the treatment of the infection. Endosymbiotic Wolbachia in filariae have emerged as a new target for antibiotics which can lead to macrofilaricidal effects.

In Vitro and In Vivo Antimalarial Activity Assays of Seeds from Balanites aegyptiaca: Compounds of the Extract Show Growth Inhibition and Activity against Plasmodial Aminopeptidase.

Balanites aegyptiaca (Balanitaceae) is a widely grown desert plant with multiuse potential. In the present paper, a crude extract from B. aegyptiaca seeds equivalent to a ratio of 1 : 2000 seeds to the extract was screened for antiplasmodial activity.

Induction of pro-inflammatory mediators in Plasmodium berghei infected BALB/c mice breaks blood-brain-barrier and leads to cerebral malaria in an IL-12 dependent manner.

A severe complication of Plasmodium infection is cerebral malaria, a condition mainly attributed to overwhelming inflammatory immune reactions of the host. Murine models differing in susceptibility to experimental cerebral malaria (ECM) allow detailed studies of the host response. We show that ECM- resistant BALB/c mice were driven into interferon gamma- and IL-12-dependent ECM and subsequent death if they received CpG-oligonucleotides after Plasmodium berghei ANKA (PbA) infection.

A new class of phenazines with activity against a chloroquine resistant Plasmodium falciparum strain and antimicrobial activity.

New phenazines were synthesized by oxygenation of 1- and 2-naphthol with transition metal peroxo complexes and in situ reaction with 1,2-diamines. The title compounds were evaluated for in vitro antimalarial activity against Plasmodium falciparum and chloroquine-resistant strains. Phenazines 12, 27, and 28 were most prominent in growth inhibition.

CCL17 controls mast cells for the defense against filarial larval entry.

Filarial parasites have to trespass many barriers to successfully settle within their mammalian host, which is equipped with mechanical borders and complex weaponry of an evolved immune system. However, little is known about mechanisms of early local events in filarial infections. In this study, bone marrow-derived dendritic cells not only upregulated activation markers CD40 and CD80 upon in vitro stimulation with filarial extracts, but also secreted CCL17, a chemokine known to be produced upon microbial challenge.