Modulation of nematode surplus killing behavior by bacterial diet
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ABSTRACT:
PROVIDER: PRJEB33410 | ENA |
REPOSITORIES: ENA
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2012-03-29 | E-GEOD-36906 | biostudies-arrayexpress
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Project description:Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although bacterial lung infection and the resulting inflammation cause most of the morbidity and mortality, how loss of CFTR first disrupts airway host defense has remained uncertain. We asked what abnormality impairs elimination when a bacterium lands on the pristine surface of a newborn CF airway? To investigate this defect, we interrogated the viability of individual bacteria immobilized on solid grids and placed on the airway surface. As a model we studied CF pigs, which spontaneously develop hallmark features of CF lung disease. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria. Here we show that in newborn wild-type pigs, the thin layer of airway surface liquid (ASL) rapidly killed bacteria in vivo, when removed from the lung, and in primary epithelial cultures. Lack of CFTR reduced bacterial killing. We found that ASL pH was more acidic in CF, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defense defect to loss of CFTR, an anion channel that facilitates HCO3- transport. Without CFTR, airway epithelial HCO3- secretion is defective, ASL pH falls and inhibits antimicrobial function, and thereby impairs killing of bacteria that enter the newborn lung. These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF and that assaying ASL pH or bacterial killing could report on the benefit of therapeutic interventions.
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Project description:Ascariasis is a global health problem for humans and animals. Adult Ascaris nematodes are long-lived in the host intestine where they interact with host cells as well as members of the microbiota resulting in chronic infections. Nematode interactions with host cells and the microbial environment are prominently mediated by parasite-secreted proteins and peptides possessing immunomodulatory and antimicrobial activities. Previously, we discovered the C-type lectin protein AsCTL-42 in the secreted products of adult Ascaris worms. Here we tested recombinant AsCTL-42 for its ability to interact with bacterial and host cells. We found that AsCTL-42 lacks bactericidal activity but neutralized bacterial cells without killing them. Treatment of bacterial cells with AsCTL-42 reduced invasion of intestinal epithelial cells by Salmonella. Furthermore, AsCTL-42 interacted with host myeloid C-type lectin receptors. Thus, AsCTL-42 is a parasite protein involved in the triad relationship between Ascaris, host cells, and the microbiota.
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Project description:Although the microbiota is known to affect host development, metabolism, and immunity, its impact on host behavior is only beginning to be understood. In order to better characterize behavior modulation by host-associated microorganisms, we investigated how bacteria modulate complex behaviors in the nematode model organism Pristionchus pacificus. This nematode is a predator that feeds on the larvae of other nematodes, including Caenorhabditis elegans. By growing P. pacificus on different bacteria and testing their ability to kill C. elegans, we reveal large differences in killing efficiencies, with a Novosphingobium species showing the strongest enhancement. This enhanced killing was not accompanied by an increase in feeding, which is a phenomenon known as surplus killing, whereby predators kill more prey than necessary for sustenance. Our RNA-seq data demonstrate widespread metabolic rewiring upon exposure to Novosphingobium, which facilitated screening of bacterial mutants with altered transcriptional responses. We identified bacterial production of vitamin B12 as an important cause of such enhanced predatory behavior. Although vitamin B12 is an essential cofactor for detoxification and metabolite biosynthesis, shown previously to accelerate development in C. elegans, supplementation with this enzyme cofactor amplified surplus killing in P. pacificus, whereas mutants in vitamin B12-dependent pathways reduced surplus killing. By demonstrating that production of vitamin B12 by host-associated microbiota can affect complex host behaviors, we reveal new connections between animal diet, microbiota, and nervous system.
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Project description:Mycobacterium smegmatis is a model non-pathogenic mycobacterium that is efficiently killed by macrophages. Here, we explore the role of NF-?B in the innate immune response, focusing in detail on the mechanisms of the first killing period (1-4h) of M. smegmatis which coincides with phagosome-lysosome fusion. We show that infection of macrophages with M. smegmatis induces an activation of NF-?B and this activation is required for killing since treatment of macrophages with NF-?B inhibitors or siRNA silencing of the NF-?B subunit p65 increases bacterial survival. NF-?B induced proteins were thus hypothesized to be essential during the first phase of M. smegmatis killing. We therefore identified, using RNA microarray, the genes that were regulated during infection in the absence and presence of NF-?B inhibitors. By subtraction this provided a list of pro-inflammatory proteins that were under the control of NF-?B and putatively involved in the killing response. Among these category of genes were those for lysosomal enzymes and membrane trafficking regulators, including Cathepsins, LAMP-2 and Rab34, are regulated by NF-?B. Moreover, inhibition of NF-?B signaling retarded the delivery of v-ATPase, LAMP-2, CtsZ and CtsH thereby impairing the maturation of mycobacterial phagosomes. Collectively; our data provide the first compelling evidence that the innate immune response via NF-?B activation is linked to phagosome fusion with lysosomes that is essential for killing of mycobacteria. Keywords: NFkB inhibitor treated vs untreated The study includes J774 macrophage cell lines which are infected with Mycobacterium smegmatis in the presence and absense of NFkB inhibitor SC-514.Total RNA was isolated from individual samples and each sample was hybridised to CodeLink Mouse whole genome bioarray slides.This study was intended to know the role of NFkB regulated genes in killing non-pathogenic mycobacteria during 4 hour post infection of macrophages.
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