Maintenance Of Host Defense Research Articles

No measurable fitness cost to experimentally evolved host defence in the Caenorhabditis elegans-Serratia marcescens host-parasite system.

Host susceptibility to parasites can vary over space and time. Costs associated with the maintenance of host defence are thought to account for a portion of this variation. Specifically, trade-offs wherein elevated defence is maintained at the cost of fitness in the absence of the parasite may cause levels of host defence to change over time and differ between populations. In previous studies, we found that populations of the host nematode, Caenorhabditis elegans, evolved greater levels of parasite avoidance and resistance against the bacterial parasite, Serratia marcescens. Here, we passaged these host populations either in the presence or absence of the parasite to test for a cost of elevated host defences. After 16 generations, we found that elevated levels of host defence were maintained during evolution in both the presence and absence of the parasite. Further, this maintenance of defence was not the result of limited standing genetic variation, but rather the absence of a measurable cost associated with defence. Therefore, costs associated with host defence may not broadly account for differences in host susceptibility across space and time.

Pathogenic and Protective Roles of MyD88 in Leukocytes and Epithelial Cells in Mouse Models of Inflammatory Bowel Disease

Toll-like receptors (TLR) are innate immune receptors involved in recognition of the intestinal microflora; they are expressed by numerous cell types in the intestine, including epithelial cells, myeloid cells, and lymphocytes. Little is known about the relative contributions of TLR signaling in distinct cellular compartments to intestinal homeostasis. We aimed to define the roles of TLR signals in distinct cell types in the induction and regulation of chronic intestinal inflammation. We assessed the roles of the shared TLR signaling adaptor protein, MyD88, in several complementary mouse models of inflammatory bowel disease, mediated by either innate or adaptive immune activation. MyD88-deficient mice and bone marrow chimeras were used to disrupt TLR signals selectively in distinct cellular compartments in the intestine. MyD88-dependent activation of myeloid cells was required for the development of chronic intestinal inflammation. By contrast, although epithelial cell MyD88 signals were required for host survival, they were insufficient to induce intestinal inflammation in the absence of an MyD88-competent myeloid compartment. MyD88 expression by T cells was not required for their pathogenic and regulatory functions in the intestine. Cellular compartmentalization of MyD88 signals in the intestine allow the maintenance of host defense and prevent deleterious inflammatory responses.

Eradication of the commensal intestinal microflora by oral antimicrobials interferes with the host response to lipopolysaccharide

The host components and commensal microorganisms of the intestinal microenvironment play roles in the development and maintenance of the host defence. Recent observations have suggested that toll-like receptors (TLRs) are involved in the recognition of innate immunity against intestinal microbes. However, little is known regarding the role of TLR in the maintenance of systemic host defence by intestinal microorganisms. We studied the expression and function of TLR4 and TLR2 on alveolar and peritoneal macrophages in mice after 3 weeks of oral administration of streptomycin and cefotaxime. After active treatment, the intestinal microorganisms were nearly completely eradicated, and the surface expression of TLR4 and TLR2 on the peritoneal macrophages was prominently downregulated. When the actively treated mice were challenged with lipopolysaccharide (LPS), a TLR4 ligand, the host response was markedly impaired. Our results suggest that the oral administration of antimicrobials downregulates the expression of surface TLR on the peritoneal macrophages and modulates the host immune responses against LPS by modifying the intestinal environment.

Cutting edge research for novel therapies of heart and lung diseases

Thromb Haemost 2009; 101: 610–612 The contributions collected in this issue of Thrombosis and Haemostasis stem from invited lectures of the first international symposium of the excellence cluster “CardioPulmonary System” (ECCPS), held in 2008 in Bad Nauheim, Germany. Founded in 2006, the ECCPS constitutes an outstanding regional biomedical research network and is based on a firmly established and internationally renowned expertise in cardio-pulmonary research of the Universities of Giessen and Frankfurt and the Max-Planck-Institute in Bad Nauheim. The interdisciplinary work of this “research triangle” is focused on basic research as well as the treatment of heart and lung diseases, which in this combination of direct translation of scientific results into new therapeutic concepts appears to be unique on the international level. Against the background of heart and lung diseases being the leading causes of death and representing the highest socio-economic burden of diseases worldwide, the work of the ECCPS assumes social as well as political importance. With the objective of combining basic research with clinical practice, the ECCPS supports the integration of different research areas from developmental biology to molecular biology and cellular physiology. The following research areas involving various disciplines are addressed in a concerted effort of all ECCPS locations using high calibre technologies in vitro and in vivo: (a) Role of stem/progenitor cells in development and repair of the cardiopulmonary system; employment of stem cells for new treatment strategies. (b) Tailoring of anti-and reverse remodeling strategies for restoration of vascular structural and lung functional integrity. (c) Deciphering of key molecular/cellular players in heart and lung vessel generation and alveolar morphogenesis, identification of targets for the induction of angioand alveogenesis. (d) Decoding pathogenetic pathways involved in lung and heart fibrogenesis, development of new strategies for inhibition and reversal of excessive matrix deposition. (e) Analysis of hypoxia-, ischaemiaand reactive oxygen species-linked pathologies in heart and lung disease; design of specific intervention strategies. (f) Protection and restoration of endoand epithelial barrier properties in the cardio-pulmonary system, including control of inflammation and maintenance of host defense. (g) Molecular pathogenesis of the vascular abnormalities in metabolic syndrome. (h) Elucidation of the molecular changes underlying aging of the cardio-pulmonary system. (i) Employment of transcriptome-, proteome and in-vivo molecular imaging-based signature analysis towards the individualization of therapy in cardio-pulmonary diseases. Research in these areas is strongly supported by focusing on techniques and technology development, translation of basic science into clinical studies and commercial exploitation and education as well as training fellowships. Among these activities the first international ECCPS symposium was organised in 2008 to foster fruitful exchange between all members of the consortium and outside experts as well as to advance junior researchers and promote collaborative research projects.

Pregnancy enhances the innate immune response in experimental cutaneous leishmaniasis through hormone-modulated nitric oxide production

The maintenance of host defense during pregnancy may depend on heightened innate immunity. We evaluated the immune response of pregnant hamsters during early infection with Leishmania (Viannia) panamensis, a cause of American cutaneous leishmaniasis. At 7 days post-infection, pregnant animals showed a lower parasite burden compared with nonpregnant controls at the cutaneous infection site (P=0.0098) and draining lymph node (P=0.02). Resident peritoneal macrophages and neutrophils from pregnant animals had enhanced Leishmania killing capacity compared with nonpregnant controls (P=0.018 each). This enhanced resistance during pregnancy was associated with increased expression of inducible NO synthase (iNOS) mRNA in lymph node cells (P=0.02) and higher NO production by neutrophils (P=0.0001). Macrophages from nonpregnant hamsters infected with L. panamensis released high amounts of NO upon estrogen exposure (P=0.05), and addition of the iNOS inhibitor L-N6-(1-iminoethyl) lysine blocked the induction of NO production (P=0.02). Infected, nonpregnant females treated with estrogen showed a higher percentage of cells producing NO at the infection site than controls (P=0.001), which correlated with lower parasite burdens (P=0.036). Cultured macrophages or neutrophils from estrogen-treated hamsters showed significantly increased NO production and Leishmania killing compared with untreated controls. iNOS was identified as the likely source of estrogen-induced NO in primed and naïve macrophages, as increased transcription was evident by real-time PCR. Thus, the innate defense against Leishmania infection is heightened during pregnancy, at least in part as a result of estrogen-mediated up-regulation of iNOS expression and NO production.

Complement: An Inflammatory Pathway Fulfilling Multiple Roles at the Interface of Innate Immunity and Development

Complement has been long perceived as an innate immune system that plays a pivotal role in the maintenance of host defense against infectious agents and the propagation of pro-inflammatory responses in the context of human disease. Complement activation has been associated with the onset of acute inflammatory reactions leading to complications such as acute graft rejection, local tissue injury and multi-organ failure. However, recent studies have indicated that various complement activation products may exert a beneficial effect by contributing to critical developmental and regenerative processes. Appreciating this extraordinary 'versatility' of complement proteins provides a framework for revisiting the design of effective complement therapeutics. A balanced strategy will have to consider limiting the detrimental proinflammatory effects of complement while preserving those activities that promote tissue repair and regeneration, cell survival and early development.

A novel receptor for calcitonin gene-related peptide (CGRP) mediates secretion in the rat colon: implications for secretory function in colitis.

The receptor responsible for CGRP-induced ion transport and permeability was examined in tissues from animals treated 7 days previously with trinitrobenzenesulfonic acid to induce colitis or in controls. CGRP caused a concentration-dependent increase in short circuit current (I(sc), EC(50) 21 nM), which was abolished in chloride-free buffer but was not blocked by CGRP(8-37) or tetrodotoxin (TTX). Amylin and adrenomedullin caused only a modest increase in I(sc). The responses to the linear CGRP(2) receptor agonists [Cys(Et)(2,7)] hCGRPalpha and [Cys(Acm)(2,7)] hCGRPalpha were considerably smaller than the response to CGRP. These responses were abolished in chloride-free buffer and were TTX sensitive. Atropine, doxantrazole, and indomethacin did not block the effects of CGRP or the CGRP(2) agonists. The response to [Cys(Et)(2,7)] hCGRPalpha was not affected by prior desensitization of the CGRP receptor and vice versa. Inflamed rats had a similar secretory response to CGRP (I(sc), EC(50) 15 nM) and [Cys(Et)(2,7)] hCGRPalpha as control tissues, while being hyporesponsive to carbachol. CGRP application increased electrical conductance of inflamed preparations. Taken together, these data suggest that CGRP may play an important role in the maintenance of host defense in colitis through an apparently novel CGRP receptor located on the colonic enterocyte.