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MBio,
2019]
Female <i>Aedes aegypti</i> mosquitoes bite human hosts to obtain a blood meal and, in the process, act as vectors for many disease-causing viruses, including the dengue, chikungunya, yellow fever, and Zika viruses. After a complete meal, the female mosquitoes lose attraction to their hosts for several days. New research shows that pharmacological activation of neuropeptide Y-like receptor (NPYLR) signaling elicits host aversion in female mosquitoes. This behavior of mosquitoes shows remarkable similarities to a bacterial-aversion behavior of the nematode <i>Caenorhabditis elegans</i> Feeding on pathogenic bacteria causes bloating of the gut in <i>C. elegans</i> that leads to activation of NPYLR signaling and bacterial aversion. Several studies suggest that this newly discovered mechanism underlying foraging may be conserved across a large number of species. A better understanding of the regulation of NPYLR signaling pathways could provide molecular targets for the control of eating behaviors in different animals, including human-disease vectors.
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Elife,
2019]
The recognition of pathogens and subsequent activation of defense responses are critical for the survival of organisms. The nematode <i>Caenorhabditis elegans</i> recognizes pathogenic bacteria and elicits defense responses by activating immune pathways and pathogen avoidance. Here we show that chemosensation of phenazines produced by pathogenic <i>Pseudomonas aeruginosa</i>, which leads to rapid activation of DAF-7/TGF- in ASJ neurons, is insufficient for the elicitation of pathogen avoidance behavior. Instead, intestinal infection and bloating of the lumen, which depend on the virulence of <i>P. aeruginosa</i>, regulates both pathogen avoidance and aversive learning by modulating not only the DAF-7/TGF- pathway but also the G-protein coupled receptor NPR-1 pathway, which also controls aerotaxis behavior. Modulation of these neuroendocrine pathways by intestinal infection serves as a systemic feedback that enables animals to avoid virulent bacteria. These results reveal how feedback from the intestine during infection can modulate the behavior, learning, and microbial perception of the host.
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Dev Cell,
2019]
The ability to distinguish harmful and beneficial microbes is critical for the survival of an organism. Here, we show that bloating of the intestinal lumen of Caenorhabditis elegans caused by microbial colonization elicits a microbial aversion behavior. Bloating of the intestinal lumen also activates a broad innate immune response, even in the absence of bacterial pathogens or live bacteria. Neuroendocrine pathway genes are upregulated by intestinal bloating and are required for microbial aversion behavior. We propose that microbial colonization and bloating of the intestine may be perceived as a danger signal that activates an immune fight-and-flight response. These results reveal how inputs from the intestine can aid in the recognition of a broad range of microbes and modulate host behavior via neuroendocrine signaling.
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MBio,
2017]
The unfolded protein response (UPR) is a stress response pathway that is activated upon increased unfolded and/or misfolded proteins in the endoplasmic reticulum (ER), and enhanced ER stress response prolongs life span and improves immunity. However, the mechanism by which ER stress affects immunity remains poorly understood. Using the nematode Caenorhabditis elegans, we show that mutations in the lipoproteins vitellogenins, which are homologs of human apolipoprotein B-100, resulted in upregulation of the UPR. Lipoprotein accumulation in the intestine adversely affects the immune response and the life span of the organism, suggesting that it could be a contributing factor to immunosenescence. We show that lipoprotein accumulation inhibited the expression of several immune genes encoding proteins secreted by the intestinal cells in an IRE-1-independent manner. Our studies provide a mechanistic explanation for adverse effects caused by protein aggregation and ER stress on immunity and highlight the role of an IRE-1-independent pathway in the suppression of the expression of genes encoding secreted proteins.IMPORTANCE Increased accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) leads to enhanced ER stress. However, the mechanism(s) by which ER stress affects immunity remain understudied. Using the nematode C.elegans, we showed that mutations in lipoproteins lead to their accumulation in the intestine, causing ER stress and adversely affecting the life span of the organisms and their resistance to pathogen infection. Our results indicate that the ER stress caused by lipoprotein accumulation significantly reduced the levels of expression of genes encoding secreted immune effectors, contributing to immunosenescence. It is known that ER stress may suppress gene expression via IRE-1, which is a sensor of ER stress. The novel mechanism uncovered in our study is IRE-1 independent, which highlights the role of a novel process by which ER stress suppresses innate immunity.
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Bio Protoc,
2020]
Physical avoidance of pathogens is a crucial defense strategy used by the host to reduce pathogen infection. Hosts display the use of multiple strategies to sense and avoid pathogens, ranging from olfaction to sensing of damage caused by pathogen infection. Understanding various mechanisms of pathogen avoidance has the potential to uncover conserved host defense responses that are important against pathogen infections. Here, we describe protocols for studying pathogen lawn avoidance behavior as well as a change of bacterial preferences in the model nematode <i>Caenorhabditis elegans</i>. Besides, we describe the protocol for measuring preferences for pathogenic and nonpathogenic bacteria after training of the animals on pathogenic bacteria. These assays can be implemented in discovering various mechanisms of host learning that result in the avoidance of pathogens.
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J Biol Chem,
2009]
Activation of the innate immune system results in a rapid microbicidal response against microorganisms, which needs to be fine-tuned because uncontrolled immune responses can lead to infection and cancer, as well as conditions such as Crohn disease, atherosclerosis, and Alzheimer disease. Here we report that excessive activity of the conserved FOXO transcription factor DAF-16 enhances susceptibility to bacterial infections in Caenorhabditis elegans. We found that increased temperature activates not only DAF-16 nuclear import but also a control mechanism involved in DAF-16 nuclear export. The nuclear export of DAF-16 requires heat shock transcription factor HSF-1 and Hsp70/HSP-1. Furthermore, we show that increased expression of the water channel Aquoporin-1 is responsible for the deleterious consequences of excessive DAF-16-mediated immune response. These studies reveal a stress-inducible mechanism involved in the regulation of DAF-16 and indicate that uncontrolled DAF-16 activity and water homeostasis are a cause of the deleterious effects of excessive immune responses.
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Int J Nanomedicine,
2012]
PURPOSE: The currently available drug repertoire against lymphatic filariasis, a major health hazard in the developing world, is inadequate and is fraught with serious limitations. Thus, the development of an effective antifilarial strategy has become a global research thrust mandated by the World Health Organization. Nanoparticles of silver endowed with antibacterial potency are known to induce apoptosis in eukaryotic cells. The present study was designed to investigate the possible microfilaricidal efficacy of silver nanoparticles and to establish the validity of apoptotic rationale in antifilarial drug designing. METHODS: This report analyzed the effect of nanoparticles of silver as well as gold (size range: 10-15 nm) on the microfilariae of Brugia malayi obtained from the lavage of peritoneal cavities of infected jirds (Meriones unguiculatus). The study included a microfilarial motility assay, a trypan blue exclusion test, a poly(adenosine diphosphate-ribose) polymerase activity study, ethidium bromide/acridine orange differential staining, and transmission, as well as scanning electron microscopic evaluation of ultrastructural changes in microfilariae. RESULTS: The study demonstrates that nanoparticles of silver, but not of gold, elicited significant loss in microfilarial motility. Differential staining of parasites with ethidium bromide and acridine orange, poly(adenosine diphosphate-ribose) polymerase activity in microfilarial lysate, and electron microscopic findings underscored apoptotic death of parasites attributable to nanosilver. In a trypan blue exclusion test, the 50% lethal dose of nanosilver was measured to be 101.2 M, which was higher than the recorded complete inhibitory concentration value (50.6 M), thus supporting nanosilver as a potential drug candidate against lymphatic filariasis. CONCLUSION: The present report provides the first ever conclusive proof in support of apoptosis as a novel stratagem in antifilarial drug designing and nanoscale silver as a valid lead in research on antifilarial therapeutics. The main embargo about the current drug diethylcarbamazine citrate is its empirical use without rationale. Effective microfilaricidal activity of nanosilver at relatively low concentrations as reported in this study, with evidence of the induction of apoptosis in microfilariae, projects nanosilver as a potential drug adjuvant against lymphatic filariasis. The much higher 50% lethal dose value of nanosilver compared to the complete inhibitory concentration value reported in this study argues in favor of a safe therapeutic window of this agent in its antifilarial efficacy.
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J Theor Biol,
2017]
We study brain network data of three species, namely, C. elegans, cat and macaque monkey within the framework of network theory and Potts Hamiltonian model, and explore rich fractal nature in it, which could be an important signature of self-organization, and a simple rule to be obeyed in complex patterns of brain networks. Further, this fractal behaviors in topological parameters of brain networks at various network levels could be an indicator of systems level organization in complicated brain functionality. Again, Rich-club formation of leading hubs in brain networks becomes unpredictable as one goes down to different levels of organization. The popularity of these leading hubs in main modules or sub-modules also gets changed at different network levels, with varied attitudes at each level. Moreover, distribution of edges, which involves intra- and inter-modular/sub-modular interactions, inherited from one level of organization to another level follows fractal law. In addition to this, the Hamiltonian function at each network level, which may correspond to the energy cost in network organization at that level, shows fractal nature. Significant motifs, which are building blocks of networks and related to basic functionalities, in brain networks is found to be triangular motif, and its probability distribution at various levels as a function of size of modules or sub-modules follows fractal law.
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J Helminthol,
1980]
The indirect fluorescent antibody technique has been applied to detect antibody levels in jirds (Meriones unguiculatus) infected with Brugia malayi. Sonicated antigens were prepared from microfilariae and adult worms. Sonicated microfilariae were found to be satisfactory for this purpose. Cyanogen bromide-activated sepharose coated with soluble antigens prepared from microfilariae and adult worms was also used to detect antibodies to Brugia infections. The present observations show that these techniques can be usefully applied for detention of filarial infections. Antibody titres in infected jirds generally ranged from 1:16-1:256 and were not affected by treatment with diethylcarbamazine.
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J Cell Sci,
2019]
During animal development, cells need to sense and adapt to mechanical forces from their environment. Ultimately, these forces are transduced through the actomyosin cortex. How the cortex simultaneously responds to and creates forces during cytokinesis is not well understood. Here we show that under mechanical stress, cortical actomyosin flow switches polarization during cytokinesis in the <i>C. elegans</i> embryo. In unstressed embryos, longitudinal cortical flow contributes to contractile ring formation, while rotational cortical flow is additionally induced in uniaxially loaded embryos. Rotational flow depends on astral microtubule signals and is required for the redistribution of the actomyosin cortex in loaded embryos. Rupture of longitudinally aligned cortical fibers during cortex rotation releases tension, initiates orthogonal longitudinal flow and thereby contributes to furrowing in loaded embryos. Moreover, actomyosin regulators involved in RhoA regulation, cortical polarity and chirality are all required for rotational flow and become essential for cytokinesis under mechanical stress. In sum, our findings extend the current framework of mechanical stress response during cell division and show scaling of orthogonal cortical flows to the amount of mechanical stress.