Unknown,Transcriptomics,Genomics,Proteomics

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Localized complement activation in the development of protective immunity against Ostertagia ostertagi infections in cattle

ABSTRACT: The gastrointestinal nematode Ostertagia ostertagi is one of major causal agents that contribute to production inefficiency in cattle industry in the temperate region of the world. One of pathophysiological factors that lead to reduced weight gain and milk yield is altered gastrointestinal functions, resulting from considerable tissue damage in the abomasal mucosa during infections. Protective immunity to Ostertagia ostertagi infections in cattle develops very slowly. Resistance to reinfection becomes manifest only after a prolonged period of exposure. Mechanisms underlying the development of protective immunity remain largely unexplored. Immune animals, with significantly reduced worm burdens, were developed after multiple drug-attenuated experimental infections and were compared to the primary infected group and their respective uninfected controls. In this study, transcriptomic analysis identified 3 signaling pathways, the complement system, leukocyte extravasation and acute phase responses, significantly impacted during both primary and repeat infections. The markedly increased mRNA levels of complement components C3, factor B (CFB), and factor I (CFI) in the abomasal mucosa of the infected cattle were confirmed using quantitative PCR. Western blot analysis established the presence of elevated levels of activated C3 proteins in the mucosa. One of the iniators of local complement activation could be related with secretory IgA and IgM because infections significantly upregulated expression of J chain (IGJ) as well as polymeric Ig receptor (PIGR) and an IgM-specific receptor (FAIM3), suggesting sustained increase in both synthesis and transepithelial transport of IgA and IgM during the infection. The elevated levels of pro-inflammatory cytokines, such as IL-4 and IL-1Î², during the infection may be involved in gene regulation of complement components. Our data suggested enhanced tissue repair and mucin secretion in immune animals may also contribute to protective immunity. Our results presented the first piece of evidence that local complement activation may be involved in the development of long term protective immunity and provided a novel mechanistic insight into resistance against Ostertagia ostertagi in cattle. There were four treatment groups: naive control (never infected), primary infection, drug-attenuated control, and drug-attenuated 5th reinfection. Each group had 4 biolgical replicates. A total of 16 arrays were used for this experiment. The 2 major contrast were 1). The primary infection vs naive control; and 2). The drug-attenuated 5th reinfection vs the drug-attenuated control.

ORGANISM(S): Bos taurus

SUBMITTER: Congjun Li

PROVIDER: E-GEOD-20927 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The gastrointestinal nematode Ostertagia ostertagi is one of major causal agents that contribute to production inefficiency in cattle industry in the temperate region of the world. One of pathophysiological factors that lead to reduced weight gain and milk yield is altered gastrointestinal functions, resulting from considerable tissue damage in the abomasal mucosa during infections. Protective immunity to Ostertagia ostertagi infections in cattle develops very slowly. Resistance to reinfection becomes manifest only after a prolonged period of exposure. Mechanisms underlying the development of protective immunity remain largely unexplored. Immune animals, with significantly reduced worm burdens, were developed after multiple drug-attenuated experimental infections and were compared to the primary infected group and their respective uninfected controls. In this study, transcriptomic analysis identified 3 signaling pathways, the complement system, leukocyte extravasation and acute phase responses, significantly impacted during both primary and repeat infections. The markedly increased mRNA levels of complement components C3, factor B (CFB), and factor I (CFI) in the abomasal mucosa of the infected cattle were confirmed using quantitative PCR. Western blot analysis established the presence of elevated levels of activated C3 proteins in the mucosa. One of the iniators of local complement activation could be related with secretory IgA and IgM because infections significantly upregulated expression of J chain (IGJ) as well as polymeric Ig receptor (PIGR) and an IgM-specific receptor (FAIM3), suggesting sustained increase in both synthesis and transepithelial transport of IgA and IgM during the infection. The elevated levels of pro-inflammatory cytokines, such as IL-4 and IL-1β, during the infection may be involved in gene regulation of complement components. Our data suggested enhanced tissue repair and mucin secretion in immune animals may also contribute to protective immunity. Our results presented the first piece of evidence that local complement activation may be involved in the development of long term protective immunity and provided a novel mechanistic insight into resistance against Ostertagia ostertagi in cattle.

Project description:Cooperia oncophora is an economically important gastrointestinal nematode in ruminants. Acquired resistance to Cooperia oncophora infection in cattle develops rapidly as a result of prior infections. Naïve cattle, when given a primary infection of high-dose infective L3 larvae, develop a strong immunity to subsequent reinfection. Compared to primary infection, reinfection resulted in a marked reduction in worm establishment. In order to understand molecular mechanisms underlying the development of acquired resistance, we characterized the transcriptomic responses of the bovine small intestine to a primary infection and reinfection. A total of 23 pathways were significantly impacted during infection. The vitamin D receptor activation was strongly induced only during reinfection, suggesting that this pathway may play an important role in the development of acquired resistance via its potential roles in immune regulation and intestinal mucosal integrity maintenance. The expression of inducible nitric oxide synthase (NOS2) was strongly induced during reinfection but now during primary infection. As a result, several canonical pathways associated with NOS2 were impacted. The genes involved in eicosanoid synthesis, including prostaglandin synthase 2 (PTGS2 or COX2), remained largely unchanged during infection. The rapid development of acquired resistance may help explain the lack of relative pathogenicity by Cooperia oncophora infection in cattle. Our findings will undoubtedly facilitate understanding of molecular mechanisms underlying the development of acquired resistance, which could have an important implication in vaccine design. The transcriptomic profiles of the bovine small intestine in response to both a primary infection and a drug-attenuated reinfection were compared. The data were analyzed using the same condition and procedure. The gene expression profiles of calves 14 days after a primary Cooperia oncophora infection and a drug-attenuated reinfection were compared to their respective age-matched controls (naive controls and drug-drenched worm-free controls)

Project description:The immune response to Neisseria gonorrhoeae is poorly understood, but its extensive antigenic variability and resistance to complement are thought to allow it to evade destruction by the host’s immune defenses. We propose that N. gonorrhoeae also avoids inducing protective immune responses in the first place. We previously found that N. gonorrhoeae induces IL-17-dependent innate responses in mice and suppresses Th1/Th2-dependent adaptive responses in murine cells in vitro through the induction of TGF-β. In this study using a murine model of vaginal gonococcal infection, mice treated with anti-TGF-β antibody during primary infection showed accelerated clearance of N. gonorrhoeae with incipient development of Th1 and Th2 responses and diminished Th17 responses in genital tract tissue. Upon secondary reinfection, mice that had been treated with anti-TGF-β during primary infection showed anamnestic recall of both Th1 and Th2 responses, with the development of anti-gonococcal antibodies in serum and secretions, and enhanced resistance to reinfection. In knockout mouse strains defective in Th1 or Th2 responses, accelerated clearance of primary infection due to anti-TGF-β treatment was dependent on Th1 but not Th2 activity, whereas resistance to secondary infection resulting from anti-TGF-β treatment during primary infection was due to both Th1- and Th2-dependent memory responses. We propose that N. gonorrhoeae proactively elicits Th-17-driven innate responses that it can resist, and suppresses Th1/Th2-driven specific adaptive immunity that would protect the host. Blockade of TGF-β reverses this pattern of host immune responsiveness and facilitates the emergence of protective anti-gonococcal immunity. We only did microarray assay for wild-type mice with or without anti-TGF-b treatment. Experiment A: Totally there are three groups: Sham-infected mice without treatment; N.gonorrhoeae-infected with control IgG treatment; N.gonorrhoeae-infected with anti-TGF-β treatment. For each group, two mice were studied. Total RNA from mouse vagina were analysed. Experiment B: Totally there are three groups: Sham-reinfected mice without treatment; N.gonorrhoeae-reinfected with control IgG treatment; N.gonorrhoeae-reinfected with anti-TGF-β treatment. For each group, two mice were studied. Total RNA from mouse vagina were analysed.

Project description:Introduction Chlamydia trachomatis (C. trachomatis) is a Gram-negative bacterium and a common human pathogen. The World Health Organization (WHO) estimates that over 130 million people are infected with C. trachomatis globally each year and with increasing incidence. C. trachomatis causes long-lasting and recurrent infections that over time induce severe tissue damage in the female genital tract that can lead to ectopic pregnancy and infertility. Thus, the human immune system fails to control and eradicate C. trachomatis during primary infection and fails to develop protective immunity against secondary infections. In vivo infection models, using complement knock out mice, suggest that the complement system is critically involved in both anti-chlamydial immunity and infection-induced pathology. To increase our understanding of complement-mediated immunity against C. trachomatis we analyzed global complement deposition on serum-incubated C. trachomatis by mass spectrometry. Methods Purified C. trachomatis was incubated in seronegative normal human serum (NHS) or heat-inactivated normal human serum (HI-NHS) for 30 min, thoroughly washed, and processed for mass spectrometry. All samples were lysed, reduced and alkylated and digested with trypsin. Some samples were chemically modified to acetylate free amino groups (N-terminal and lysine amino groups) before trypsin digestion. Peptides were analyzed on a UltimateTM 3500 RSLCnano coupled to a Q Exactive HF-X mass spectrometer. Raw data files were searched against the Uniprot human reference proteome using MaxQuant. Results We demonstrate that C. trachomatis elicits potent complement activation demonstrated by deposition of both early and late complement factors together with several complement regulators. We further demonstrate proteolytically processing of complement C3b to “inactive” C3 cleavage fragments. Conclusion We demonstrate the deposition of several novel complement-associated proteins and -cleavage fragments on the surface of C. trachomatis.

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Localized complement activation in the development of protective immunity against Ostertagia ostertagi infections in cattle

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