Mannose-Binding Lectin Regulates Host Resistance and Pathology during Experimental Infection with Trypanosoma cruzi

Mannose-binding lectin (MBL) is a humoral pattern-recognition molecule important for host defense. Although recent genetic studies suggest an involvement of MBL/MASP2-associated pathways in Chagas’ disease, it is currently unknown whether MBL plays a role in host resistance to the intracellular protozoan Trypanosoma cruzi, the causative agent of Chagas’ disease. In this study we employed MBL−/− mice to assess the role of MBL in resistance to experimental infection with T. cruzi. T. cruzi infection enhanced tissue expression of MBL both at the mRNA and protein level. Similarly, symptomatic acute Chagas’ disease patients displayed increased serum concentrations of MBL compared to patients with indeterminate, asymptomatic forms of the disease. Furthermore, increased parasite loads in the blood and/or tissue were observed in MBL−/− mice compared to WT controls. This was associated with reduced systemic levels of IL-12/23p40 in MBL−/− mice. Importantly, MBL−/− mice infected with a cardiotropic strain of T. cruzi displayed increased myocarditis and cardiac fibrosis compared to WT controls. The latter was accompanied by elevated hydroxyproline content and mRNA levels of collagen-1 and -6 in the heart. These observations point to a previously unappreciated role for MBL in regulating host resistance and cardiac inflammation during infection with a major human pathogen

The NOD/RIP2 Pathway Is Essential for Host Defenses Against Chlamydophila pneumoniae Lung Infection

Here we investigated the role of the Nod/Rip2 pathway in host responses to Chlamydophila pneumoniae–induced pneumonia in mice. Rip2−/− mice infected with C. pneumoniae exhibited impaired iNOS expression and NO production, and delayed neutrophil recruitment to the lungs. Levels of IL-6 and IFN-γ levels as well as KC and MIP-2 levels in bronchoalveolar lavage fluid (BALF) were significantly decreased in Rip2−/− mice compared to wild-type (WT) mice at day 3. Rip2−/− mice showed significant delay in bacterial clearance from the lungs and developed more severe and chronic lung inflammation that continued even on day 35 and led to increased mortality, whereas WT mice cleared the bacterial load, recovered from acute pneumonia, and survived. Both Nod1−/− and Nod2−/− mice also showed delayed bacterial clearance, suggesting that C. pneumoniae is recognized by both of these intracellular receptors. Bone marrow chimera experiments demonstrated that Rip2 in BM-derived cells rather than non-hematopoietic stromal cells played a key role in host responses in the lungs and clearance of C. pneumoniae. Furthermore, adoptive transfer of WT macrophages intratracheally was able to rescue the bacterial clearance defect in Rip2−/− mice. These results demonstrate that in addition to the TLR/MyD88 pathway, the Nod/Rip2 signaling pathway also plays a significant role in intracellular recognition, innate immune host responses, and ultimately has a decisive impact on clearance of C. pneumoniae from the lungs and survival of the infectious challenge

Dectin-1: a role in antifungal defense and consequences of genetic polymorphisms in humans

The clinical relevance of fungal infections has increased dramatically in recent decades as a consequence of the rise of immunocompromised populations, and efforts to understand the underlying mechanisms of protective immunity have attracted renewed interest. Here we review Dectin-1, a pattern recognition receptor involved in antifungal immunity, and discuss recent discoveries of polymorphisms in the gene encoding this receptor which result in human disease

Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis

Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors (PRR) that play a key role in innate and adaptive immunity by recognizing structural components unique to bacteria, fungi and viruses. TLR4 is the most studied of the TLRs, and its primary exogenous ligand is lipopolysaccharide, a component of Gram-negative bacterial walls. In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling. In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis. In liver, TLR4 is expressed by all parenchymal and non-parenchymal cell types, and contributes to tissue damage caused by a variety of etiologies. Intact TLR4 signaling was identified in hepatic stellate cells (HSCs), the major fibrogenic cell type in injured liver, and mediates key responses including an inflammatory phenotype, fibrogenesis and anti-apoptotic properties. Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies

Versuchseinlagerung hochradioaktiver Abfaelle in der Schachtanlage Asse - technische Durchfuehrung Abschlussbericht - Projektphase 1

SIGLECopy held by FIZ Karlsruhe; available from UB/TIB Hannover / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

<i>T. cruzi</i> infection induces MBL expression <i>in vivo</i>.

<p>WT and MyD88^−/− mice were infected with trypomastigotes of the Y strain of <i>T. cruzi</i> and 9 days after infection, MBL-A and MBL-C mRNA accumulation was determined in spleens from infected and uninfected animals by real-time PCR (A). Detection of MBL-C protein was also performed by immunofluorescence microscopy in splenic sections obtained from WT mice infected as above (B). Micrograph shows MBL-C (red) and B220 (blue) staining in both the red (RP) and white pulp (WP). Scale bar, 100 µm. Infected MBL^−/− spleens were included as a control. All panels shown are representative of 2 independent experiments using 3 to 4 mice per group. Bars indicate the standard error of the mean (SEM). Sera from patients with acute, chronic or indeterminate Chagas’ disease were assayed for MBL as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047835#s4" target="_blank">Material and Methods</a> (C). *, Indicates statistically significant differences between acute vs indeterminate Chagas’ disease groups.</p

Enhanced cardiac pathology and fibrosis in MBL^−/− infected with <i>T.</i><i>cruzi</i> Colombiana strain.

<p>WT and MBL^−/− mice were infected with trypomastigotes of the Colombiana strain of <i>T. cruzi</i> and hearts from these animals obtained 5 weeks after infection. Hearts were formalin-fixed, paraffin embedded, stained with H&E or Gomori’s trichrome and scored for pathology and fibrosis, respectively, as described under <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047835#s4" target="_blank">Materials and Methods</a> (A). Right panels show micrographs of Gomori’s trichrome staining for each group. Bars indicate the standard error of the mean (SEM). Uninfected, or WT and MBL^−/− mice infected as in (A) were harvested 5 wks later for determination of hydroxyproline content in total heart (B). Each symbol corresponds to an individual animal, dashed lines represent the mean of each group and solid lines the standard error of the mean (SEM). Heart samples from uninfected controls or from WT and MBL^−/− mice infected as in (A) were obtained and mRNA accumulation of Collagen-1, -3 and -6 determined by real-time PCR (C). The experiments shown are representative of two performed. *, Indicates statistically significant differences between infected WT and MBL^−/− groups.</p