scholarly journals Analysis of the Human Mucosal Response to Cholera Reveals Sustained Activation of Innate Immune Signaling Pathways

2017 ◽  
Vol 86 (2) ◽  
Author(s):  
Daniel L. Bourque ◽  
Taufiqur Rahman Bhuiyan ◽  
Diane P. Genereux ◽  
Rasheduzzaman Rashu ◽  
Crystal N. Ellis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Signaling Pathways ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Immune Signaling ◽  
Content Type ◽  
Upstream Regulators

ABSTRACTTo better understand the innate immune response toVibrio choleraeinfection, we tracked gene expression in the duodenal mucosa of 11 Bangladeshi adults with cholera, using biopsy specimens obtained immediately after rehydration and 30 and 180 days later. We identified differentially expressed genes and performed an analysis to predict differentially regulated pathways and upstream regulators. During acute cholera, there was a broad increase in the expression of genes associated with innate immunity, including activation of the NF-κB, mitogen-activated protein kinase (MAPK), and Toll-like receptor (TLR)-mediated signaling pathways, which, unexpectedly, persisted even 30 days after infection. Focusing on early differences in gene expression, we identified 37 genes that were differentially expressed on days 2 and 30 across the 11 participants. These genes included the endosomal Toll-like receptor geneTLR8, which was expressed in lamina propria cells. Underscoring a potential role for endosomal TLR-mediated signalingin vivo, our pathway analysis found that interferon regulatory factor 7 and beta 1 and alpha 2 interferons were among the top upstream regulators activated during cholera. Among the innate immune effectors, we found that the gene for DUOX2, an NADPH oxidase involved in the maintenance of intestinal homeostasis, was upregulated in intestinal epithelial cells during cholera. Notably, the observed increases inDUOX2andTLR8expression were also modeledin vitrowhen Caco-2 or THP-1 cells, respectively, were stimulated with liveV. choleraebut not with heat-killed organisms or cholera toxin alone. These previously unidentified features of the innate immune response toV. choleraeextend our understanding of the mucosal immune signaling pathways and effectors activatedin vivofollowing cholera.

scholarly journals Ursodeoxycholic Acid (UDCA) Mitigates the Host Inflammatory Response during Clostridioides difficile Infection by Altering Gut Bile Acids

2020 ◽  
Vol 88 (6) ◽  
Author(s):  
Jenessa A. Winston ◽  
Alissa J. Rivera ◽  
Jingwei Cai ◽  
Rajani Thanissery ◽  
Stephanie A. Montgomery ◽  
...  
Keyword(s):  
Immune Response ◽  
Bile Acid ◽  
Inflammatory Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Colonization Resistance ◽  
Content Type ◽  
Clostridioides Difficile

ABSTRACT Clostridioides difficile infection (CDI) is associated with increasing morbidity and mortality posing an urgent threat to public health. Recurrence of CDI after successful treatment with antibiotics is high, thus necessitating discovery of novel therapeutics against this enteric pathogen. Administration of the secondary bile acid ursodeoxycholic acid (UDCA; ursodiol) inhibits the life cycles of various strains of C. difficile in vitro, suggesting that the FDA-approved formulation of UDCA, known as ursodiol, may be able to restore colonization resistance against C. difficile in vivo. However, the mechanism(s) by which ursodiol is able to restore colonization resistance against C. difficile remains unknown. Here, we confirmed that ursodiol inhibits C. difficile R20291 spore germination and outgrowth, growth, and toxin activity in a dose-dependent manner in vitro. In a murine model of CDI, exogenous administration of ursodiol resulted in significant alterations in the bile acid metabolome with little to no changes in gut microbial community structure. Ursodiol pretreatment resulted in attenuation of CDI pathogenesis early in the course of disease, which coincided with alterations in the cecal and colonic inflammatory transcriptome, bile acid-activated receptors nuclear farnesoid X receptor (FXR) and transmembrane G-protein-coupled membrane receptor 5 (TGR5), which are able to modulate the innate immune response through signaling pathways such as NF-κB. Although ursodiol pretreatment did not result in a consistent decrease in the C. difficile life cycle in vivo, it was able to attenuate an overly robust inflammatory response that is detrimental to the host during CDI. Ursodiol remains a viable nonantibiotic treatment and/or prevention strategy against CDI. Likewise, modulation of the host innate immune response via bile acid-activated receptors FXR and TGR5 represents a new potential treatment strategy for patients with CDI.

scholarly journals RIG-I-Like Receptor and Toll-Like Receptor Signaling Pathways Cause Aberrant Production of Inflammatory Cytokines/Chemokines in a Severe Fever with Thrombocytopenia Syndrome Virus Infection Mouse Model

2018 ◽  
Vol 92 (13) ◽  
pp. e02246-17 ◽  
Author(s):  
Shintaro Yamada ◽  
Masayuki Shimojima ◽  
Ryo Narita ◽  
Yuta Tsukamoto ◽  
Hiroki Kato ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Immune Response ◽  
Signaling Pathways ◽  
Inflammatory Cytokines ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Cytokines And Chemokines ◽  
Severe Fever

ABSTRACT Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a tick-borne phlebovirus of the family Bunyaviridae, SFTS virus (SFTSV). Wild-type and type I interferon (IFN-I) receptor 1-deficient (IFNAR1−/−) mice have been established as nonlethal and lethal models of SFTSV infection, respectively. However, the mechanisms of IFN-I production in vivo and the factors causing the lethal disease are not well understood. Using bone marrow-chimeric mice, we found that IFN-I signaling in hematopoietic cells was essential for survival of lethal SFTSV infection. The disruption of IFN-I signaling in hematopoietic cells allowed an increase in viral loads in serum and produced an excess of multiple inflammatory cytokines and chemokines. The production of IFN-I and inflammatory cytokines was abolished by deletion of the signaling molecules IPS-1 and MyD88, essential for retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) and Toll-like receptor (TLR) signaling, respectively. However, IPS-1−/− MyD88−/− mice exhibited resistance to lethal SFTS with a moderate viral load in serum. Taken together, these results indicate that adequate activation of RLR and TLR signaling pathways under low to moderate levels of viremia contributed to survival through the IFN-I-dependent antiviral response during SFTSV infection, whereas overactivation of these signaling pathways under high levels of viremia resulted in abnormal induction of multiple inflammatory cytokines and chemokines, causing the lethal disease. IMPORTANCE SFTSV causes a severe infectious disease in humans, with a high fatality rate of 12 to 30%. To know the pathogenesis of the virus, we need to clarify the innate immune response as a front line of defense against viral infection. Here, we report that a lethal animal model showed abnormal induction of multiple inflammatory cytokines and chemokines by an uncontrolled innate immune response, which triggered the lethal SFTS. Our findings suggest a new strategy to target inflammatory humoral factors to treat patients with severe SFTS. Furthermore, this study may help the investigation of other tick-borne viruses.

scholarly journals Identification of PGN_1123 as the Gene Encoding Lipid A Deacylase, an Enzyme Required for Toll-Like Receptor 4 Evasion, inPorphyromonas gingivalis

2019 ◽  
Vol 201 (11) ◽  
Author(s):  
Sumita Jain ◽  
Ana M. Chang ◽  
Manjot Singh ◽  
Jeffrey S. McLean ◽  
Stephen R. Coats ◽  
...  
Keyword(s):  
Immune Response ◽  
Porphyromonas Gingivalis ◽  
Innate Immune Response ◽  
Lipid A ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Gene Encoding ◽  
Content Type ◽  
Chronic Inflammatory Condition

ABSTRACTRemoval of one acyl chain from bacterial lipid A by deacylase activity is a mechanism used by many pathogenic bacteria to evade the host's Toll-like receptor 4 (TLR4)-mediated innate immune response. InPorphyromonas gingivalis, a periodontal pathogen, lipid A deacylase activity converts a majority of the initially synthesized penta-acylated lipid A, a TLR4 agonist, to tetra-acylated structures, which effectively evade TLR4 sensing by being either inert or antagonistic at TLR4. In this paper, we report successful identification of the gene that encodes theP. gingivalislipid A deacylase enzyme. This gene, PGN_1123 inP. gingivalis33277, is highly conserved withinP. gingivalis, and putative orthologs are phylogenetically restricted to theBacteroidetesphylum. Lipid A of ΔPGN_1123 mutants is penta-acylated and devoid of tetra-acylated structures, and the mutant strain provokes a strong TLR4-mediated proinflammatory response, in contrast to the negligible response elicited by wild-typeP. gingivalis. Heterologous expression of PGN_1123 inBacteroides thetaiotaomicronpromoted lipid A deacylation, confirming that PGN_1123 encodes the lipid A deacylase enzyme.IMPORTANCEPeriodontitis, commonly referred to as gum disease, is a chronic inflammatory condition that affects a large proportion of the population.Porphyromonas gingivalisis a bacterium closely associated with periodontitis, although how and if it is a cause for the disease are not known. It has a formidable capacity to dampen the host's innate immune response, enabling its persistence in diseased sites and triggering microbial dysbiosis in animal models of infection.P. gingivalisis particularly adept at evading the host's TLR4-mediated innate immune response by modifying the structure of lipid A, the TLR4 ligand. In this paper, we report identification of the gene encoding lipid A deacylase, a key enzyme that modifies lipid A to TLR4-evasive structures.

scholarly journals Toll-Like Receptor 6 Plays an Important Role in Host Innate Resistance to Brucella abortus Infection in Mice

2013 ◽  
Vol 81 (5) ◽  
pp. 1654-1662 ◽  
Author(s):  
Leonardo A. de Almeida ◽  
Gilson C. Macedo ◽  
Fábio A. V. Marinho ◽  
Marco T. R. Gomes ◽  
Patrícia P. Corsetti ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Brucella Abortus ◽  
Proinflammatory Cytokine ◽  
Cytokine Production ◽  
Innate Immune ◽  
Proinflammatory Cytokine Production ◽  
Toll Like Receptor ◽  
Content Type

ABSTRACTBrucella abortusis recognized by several Toll-like receptor (TLR)-associated pathways triggering proinflammatory responses that affect both the nature and intensity of the immune response. Previously, we demonstrated thatB. abortus-mediated dendritic cell (DC) maturation and control of infection are dependent on the adaptor molecule MyD88. However, the involvement of all TLRs in response toB. abortusinfection is not completely understood. Therefore, we decided to evaluate the requirement for TLR6 in host resistance toB. abortus. Here, we demonstrated that TLR6 is an important component for triggering an innate immune response againstB. abortus. Anin vitroluciferase assay indicated that TLR6 cooperates with TLR2 to senseBrucellaand further activates NF-κB signaling. However,in vivoanalysis showed that TLR6, not TLR2, is required for the efficient control ofB. abortusinfection. Additionally,B. abortus-infected dendritic cells require TLR6 to induce tumor necrosis factor alpha (TNF-α) and interleukin-12 (IL-12). Furthermore, our findings demonstrated that the mitogen-activated protein kinase (MAPK) signaling pathway is impaired in TLR2, TLR6, and TLR2/6 knockout (KO) DCs when infected withB. abortus, which may account for the lower proinflammatory cytokine production observed in TLR6 KO mouse dendritic cells. In summary, the results presented here indicate that TLR6 is required to trigger innate immune responses againstB. abortusin vivoand is required for the full activation of DCs to induce robust proinflammatory cytokine production.

The dysfunctional innate immune response triggered by Toll-like receptor activation is restored by TLR7/TLR8 and TLR9 ligands in cutaneous lichen planus

2014 ◽  
Vol 172 (1) ◽  
pp. 48-55 ◽  
Author(s):  
R. Domingues ◽  
G. Costa de Carvalho ◽  
L.M. da Silva Oliveira ◽  
E. Futata Taniguchi ◽  
J.M. Zimbres ◽  
...  
Keyword(s):  
Immune Response ◽  
Lichen Planus ◽  
Innate Immune Response ◽  
Receptor Activation ◽  
Innate Immune ◽  
Toll Like Receptor

scholarly journals Characterization of Host Responses duringPseudomonas aeruginosaAcute Infection in the Lungs and Blood and after Treatment with the Synthetic Immunomodulatory Peptide IDR-1002

2018 ◽  
Vol 87 (1) ◽  
Author(s):  
Kelli Wuerth ◽  
Amy H. Y. Lee ◽  
Reza Falsafi ◽  
Erin E. Gill ◽  
Robert E. W. Hancock
Keyword(s):  
Gene Expression ◽  
Bacterial Resistance ◽  
Lymphocyte Activation ◽  
Lavage Fluid ◽  
Innate Immune ◽  
Microbial Infection ◽  
Content Type ◽  
Innate Defense ◽  
Lung Infections

ABSTRACTPseudomonas aeruginosais an opportunistic pathogen that causes nosocomial pneumonia and infects patients with cystic fibrosis.P. aeruginosalung infections are difficult to treat due to bacterial resistance to antibiotics, and strains with multidrug resistance are becoming more prevalent. Here, we examined the use of a small host defense peptide, innate defense regulator 1002 (IDR-1002), in an acuteP. aeruginosalung infectionin vivo. IDR-1002 significantly reduced the bacterial burden in bronchoalveolar lavage fluid (BALF), as well as MCP-1 in BALF and serum, KC in serum, and interleukin 6 (IL-6) in BALF. Transcriptome sequencing (RNA-Seq) was conducted on lungs and whole blood, and the effects ofP. aeruginosa, IDR-1002, and the combination ofP. aeruginosaand IDR-1002 were evaluated. Differential gene expression analysis showed thatP. aeruginosaincreased multiple inflammatory and innate immune pathways, as well as affected hemostasis, matrix metalloproteinases, collagen biosynthesis, and various metabolism pathways in the lungs and/or blood. Infected mice treated with IDR-1002 had significant changes in gene expression compared to untreated infected mice, with fewer differentially expressed genes associated with the inflammatory and innate immune responses to microbial infection, and treatment also affected morphogenesis, certain metabolic pathways, and lymphocyte activation. Overall, these results showed that IDR-1002 was effective in treatingP. aeruginosaacute lung infections and associated inflammation.

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