Uncovering the Hidden Credentials of Brucella Virulence

SUMMARY Bacteria in the genus Brucella are important human and veterinary pathogens. The abortion and infertility they cause in food animals produce economic hardships in areas where the disease has not been controlled, and human brucellosis is one of the world’s most common zoonoses. Brucella strains have also been isolated from wildlife, but we know much less about the pathobiology and epidemiology of these infections than we do about brucellosis in domestic animals. The brucellae maintain predominantly an intracellular lifestyle in their mammalian hosts, and their ability to subvert the host immune response and survive and replicate in macrophages and placental trophoblasts underlies their success as pathogens. We are just beginning to understand how these bacteria evolved from a progenitor alphaproteobacterium with an environmental niche and diverged to become highly host-adapted and host-specific pathogens. Two important virulence determinants played critical roles in this evolution: (i) a type IV secretion system that secretes effector molecules into the host cell cytoplasm that direct the intracellular trafficking of the brucellae and modulate host immune responses and (ii) a lipopolysaccharide moiety which poorly stimulates host inflammatory responses. This review highlights what we presently know about how these and other virulence determinants contribute to Brucella pathogenesis. Gaining a better understanding of how the brucellae produce disease will provide us with information that can be used to design better strategies for preventing brucellosis in animals and for preventing and treating this disease in humans.

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The organization of Helicobacter pylori cag-pathogenicity island (cagPAI) genes in multiracial population with histopathological changes of gastric mucosa

10.21203/rs.2.9601/v1 ◽

2019 ◽

Author(s):

Alfizah Hanafiah ◽

Shaza Azlin Razak ◽

Hui-min Neoh ◽

Noraziah Mohamad Zin ◽

Bruno S. Lopes

Keyword(s):

Helicobacter Pylori ◽

Gastric Mucosa ◽

Pathogenicity Island ◽

Type Iv Secretion ◽

Virulence Determinants ◽

Gastric Diseases ◽

Cag Pathogenicity Island ◽

Type Iv ◽

Inflammatory Score ◽

H Pylori

Abstract Background: Helicobacter pylori is a Gram-negative bacillus that colonises only the mucus layer of the human stomach and is implicated in gastric diseases. Virulent H. pylori harbouring cag-pathogenicity island (cagPAI) which encodes genes for type IV secretion system (T4SS) and CagA protein is one of the major virulence determinants involved in disease development. We examined the entire cagPAI genes in 95 H. pylori isolates from a multiracial population and examined the intactness of cagPAI region with histopathological scores of the gastric mucosa. Results: 95.8% of H. pylori isolates were cagPAI-positive with 23.2% having an intact cagPAI, whereas 72.6% had a partial/rearranged cagPAI. In our study, cag2 and cag4 were found to be significantly higher in H. pylori isolated from Malays, whereas cag4 was predominant in Chinese isolates. We also detected cag24 in significantly high proportion in isolates from the Malays and the Indians compared to the Chinese isolates. The intactness of cagPAI region showed an association with histopathological scores of the gastric mucosa. Significant association was observed between H. pylori harbouring partial cagPAI and higher density of H. pylori and neutrophil activity, whereas strains which lacked cagPAI was associated with higher inflammatory score. Conclusions: The screening of the entire cagPAI genes provides an accurate overview of the cagPAI organisation in H. pylori isolates in a multiracial population. The genotypes of H. pylori strains with various cagPAI rearrangement associated with patients’ ethnicities and histopathological scores might contribute to the pathogenesis of H. pylori infection in a multi-ethnic population.

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Identification of Genes Required for Chronic Persistence of Brucella abortus in Mice

Infection and Immunity ◽

10.1128/iai.68.7.4102-4107.2000 ◽

2000 ◽

Vol 68 (7) ◽

pp. 4102-4107 ◽

Cited By ~ 169

Author(s):

Priscilla C. Hong ◽

Renée M. Tsolis ◽

Thomas A. Ficht

Keyword(s):

Brucella Abortus ◽

Chronic Infection ◽

Type Iv Secretion ◽

Virulence Determinants ◽

Type Iv ◽

Transposon Insertion ◽

Lipopolysaccharide Biosynthesis ◽

Comparison Of The Results ◽

Transposon Insertions

ABSTRACT The genetic basis for chronic persistence of Brucella abortus in lymphoid organs of mice, cows, and humans is currently unknown. We identified B. abortus genes involved in chronic infection, by assessing the ability of 178 signature-tagged mutants to establish and maintain persistent infection in mice. Each mutant was screened for its ability to colonize the spleens of mice at 2 and 8 weeks after inoculation. Comparison of the results from both time points identified two groups of mutants attenuated for chronic infection in mice. The first group was not recovered at either 2 or 8 weeks postinfection and was therefore defective in establishing infection. Mutants in this group carried transposon insertions in genes involved in lipopolysaccharide biosynthesis (wbkA), in aromatic amino acid biosynthesis, and in type IV secretion (virB1 and virB10). The second group, which was recovered at wild-type levels 2 weeks postinfection but not 8 weeks postinfection was able to establish infection but was unable to maintain chronic infection. One mutant in this group carried a transposon insertion in a gene with homology to gcvB ofMycobacterium tuberculosis, encoding glycine dehydrogenase, an enzyme whose activity is increased during the state of nonreplicating persistence. These results suggest that some mechanisms for long-term persistence may be shared among chronic intracellular pathogens. Furthermore, identification of two groups of genes, those required for initiating infection and those required only for long-term persistence, suggests that B. abortus uses distinct sets of virulence determinants to establish and maintain chronic infection in mice.

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Establishment of Systemic Brucella melitensis Infection through the Digestive Tract Requires Urease, the Type IV Secretion System, and Lipopolysaccharide O Antigen

Infection and Immunity ◽

10.1128/iai.00417-09 ◽

2009 ◽

Vol 77 (10) ◽

pp. 4197-4208 ◽

Cited By ~ 58

Author(s):

Tatiane A. Paixão ◽

Christelle M. Roux ◽

Andreas B. den Hartigh ◽

Sumathi Sankaran-Walters ◽

Satya Dandekar ◽

...

Keyword(s):

Digestive Tract ◽

Cell Model ◽

Brucella Melitensis ◽

Secretion System ◽

Type Iv Secretion ◽

Human Brucellosis ◽

Type Iv Secretion System ◽

Wild Type ◽

Type Iv ◽

Mutant Strains

ABSTRACT Human brucellosis is caused mainly by Brucella melitensis, which is often acquired by ingesting contaminated goat or sheep milk and cheese. Bacterial factors required for food-borne infection of humans by B. melitensis are poorly understood. In this study, a mouse model of oral infection was characterized to assess the roles of urease, the VirB type IV secretion system, and lipopolysaccharide for establishing infection through the digestive tract. B. melitensis strain 16M was consistently recovered from the mesenteric lymph node (MLN), spleen, and liver beginning at 3 or 7 day postinfection (dpi). In the gut, persistence of the inoculum was observed up to 21 dpi. No inflammatory lesions were observed in the ileum or colon during infection. Mutant strains lacking the ureABC genes of the ure1 operon, virB2, or pmm encoding phosphomannomutase were constructed and compared to the wild-type strain for infectivity through the digestive tract. Mutants lacking the virB2 and pmm genes were attenuated in the spleen (P < 0.05) and MLN (P < 0.001), respectively. The wild-type and mutant strains had similar levels of resistance to low pH and 5 or 10% bile, suggesting that the reduced colonization of mutants was not the result of reduced resistance to acid pH or bile salts. In an in vitro lymphoepithelial cell (M-cell) model, B. melitensis transited rapidly through polarized enterocyte monolayers containing M-like cells; however, transit through monolayers containing only enterocytes was reduced or absent. These results indicate that B. melitensis is able to spread systemically from the digestive tract after infection, most likely through M cells of the mucosa-associated lymphoid tissue.

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GABA transporter sustains IL-1β production in macrophages

Science Advances ◽

10.1126/sciadv.abe9274 ◽

2021 ◽

Vol 7 (15) ◽

pp. eabe9274

Author(s):

Yaoyao Xia ◽

Fang He ◽

Xiaoyan Wu ◽

Bie Tan ◽

Siyuan Chen ◽

...

Keyword(s):

Immune Responses ◽

High Fat Diet ◽

Inflammatory Responses ◽

Innate Immune ◽

Innate Immune Cells ◽

High Fat ◽

Gaba Transporter ◽

Host Immune Responses ◽

Diet Induced Obesity

Accumulating evidence shows that nervous system governs host immune responses; however, how γ-aminobutyric acid (GABA)ergic system shapes the function of innate immune cells is poorly defined. Here, we demonstrate that GABA transporter (GAT2) modulates the macrophage function. GAT2 deficiency lowers the production of interleukin-1β (IL-1β) in proinflammatory macrophages. Mechanistically, GAT2 deficiency boosts the betaine/S-adenosylmethionine (SAM)/hypoxanthine metabolic pathway to inhibit transcription factor KID3 expression through the increased DNA methylation in its promoter region. KID3 regulates oxidative phosphorylation (OXPHOS) via targeting the expression of OXPHOS-related genes and is also critical for NLRP3–ASC–caspase-1 complex formation. Likewise, GAT2 deficiency attenuates macrophage-mediated inflammatory responses in vivo, including lipopolysaccharide-induced sepsis, infection-induced pneumonia, and high-fat diet-induced obesity. Together, we propose that targeting GABAergic system (e.g., GABA transporter) could provide previously unidentified therapeutic opportunities for the macrophage-associated diseases.

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MicroRNA-155 Expression With Brucella Infection in vitro and in vivo and Decreased Serum Levels of MicroRNA-155 in Patients With Brucellosis

10.21203/rs.3.rs-1095772/v1 ◽

2021 ◽

Author(s):

Xi Zhang ◽

Jingjing Chen ◽

Huimin Cheng ◽

Jinying Zhu ◽

Qiao Dong ◽

...

Keyword(s):

Immune Responses ◽

Early Stage ◽

Serum Levels ◽

Human Brucellosis ◽

Host Immune Responses ◽

Contrasting Effect ◽

Antibody Titers ◽

Unique Mechanism

Abstract Infection by Brucella is characterized by the inhibition of host immune responses. MicroRNA-155 (miR-155) has been implicated in the immune response to many diseases. In this study, miR-155 expression during Brucella 16M infection of macrophages and mice were analyzed. Expression of miR-155 was significantly induced in macrophages at 24 hours post infection. Analysis of infected mice showed that miR-155 was inhibited at 7 and 14 days, but induced at 28 days. Very interestingly, the induction or inhibition trend was reversed at 7 and 14 days in 16M△virB-infected mice. This suggested that decreased expression of miR-155 at an early stage of infection was dependent on intracellular replication. In humans with brucellosis, serum levels of miR-155 were significantly decreased compared to those without brucellosis and healthy volunteers. Significant correlations were observed between serum level of miR-155 and serum anti-Brucella antibody titers and symptom of sweat. The decrease in miR-155 with Brucella infection contrasts with the increase in miR-155 observed in Mycobacterium tuberculosis infection. This contrasting effect suggests that Brucella interferes with miR-155-regulated immune responses through a unique mechanism. Taken together, data from this study indicate that Brucella infection affects miR-155 expression, and that human brucellosis patients show decreased serum levels of miR-155.

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Ostertagia ostertagi Mediates Early Host Immune Responses via Macrophage and Toll-Like Receptor Pathways

Infection and Immunity ◽

10.1128/iai.00017-21 ◽

2021 ◽

Vol 89 (6) ◽

Author(s):

Mariam Bakshi ◽

Deborah Hebert ◽

Connor Gulbronson ◽

Gary Bauchan ◽

Wenbin Tuo ◽

...

Keyword(s):

Immune Responses ◽

Time Course ◽

Mononuclear Cells ◽

Inflammatory Responses ◽

Peripheral Blood Mononuclear ◽

Necrosis Factor Alpha ◽

Ostertagia Ostertagi ◽

Host Immune Responses ◽

Tnf Α ◽

Anti Inflammatory

ABSTRACT Ostertagia ostertagi is an abomasal parasite with significant economic impact on the cattle industry. Early host immune responses are poorly understood. Here, we examined time course expression of Toll-like receptors (TLRs) in peripheral blood mononuclear cells (PBMC) during infection where PBMC macrophages (Mϕ) generated both pro- and anti-inflammatory responses when incubated with excretory/secretory products (ESP) from fourth-stage larvae (OoESP-L4) or adult worms (OoESP-Ad). First, changes in cell morphology clearly showed that both OoESP-L4 and OoESP-Ad activated PBMC-Mϕ in vitro, resulting in suppressed CD40 and increased CD80 expression. Expression of mRNAs for TLR1, -4, -5, and -7 peaked 7 days postinfection (dpi) (early L4), decreased by 19 dpi (postemergent L4 and adults) and then increased at 27 dpi (late adults). The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) (transcript and protein) increased in the presence of OoESP-Ad, and the anti-inflammatory cytokine interleukin 10 (IL-10) (protein) decreased in the presence of OoESP-L4 or OoESP-Ad; however, IL-10 mRNA was upregulated, and IL-6 (protein) was downregulated by OoESP-L4. When PBMC-Mϕ were treated with ligands for TLR4 or TLR5 in combination with OoESP-Ad, the transcripts for TNF-α, IL-1, IL-6, and IL-10 were significantly downregulated relative to treatment with TLR4 and TLR5 ligands only. However, the effects of TLR2 ligand and OoESP-Ad were additive, but only at the lower concentration. We propose that O. ostertagi L4 and adult worms utilize competing strategies via TLRs and Mϕ to confuse the immune system, which allows the worm to evade the host innate responses.

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Multifaceted Roles of Chemokines and Chemokine Receptors in Tumor Immunity

Cancers ◽

10.3390/cancers13236132 ◽

2021 ◽

Vol 13 (23) ◽

pp. 6132

Author(s):

Kazuhiko Matsuo ◽

Osamu Yoshie ◽

Takashi Nakayama

Keyword(s):

T Cell ◽

Immune Responses ◽

Tumor Immunity ◽

Immune Cells ◽

Chemokine Receptors ◽

Th17 Cells ◽

Inflammatory Responses ◽

T Cell Subsets ◽

Th2 Cells ◽

Host Immune Responses

Various immune cells are involved in host tumor immune responses. In particular, there are many T cell subsets with different roles in tumor immunity. T-helper (Th) 1 cells are involved in cellular immunity and thus play the major role in host anti-tumor immunity by inducing and activating cytotoxic T lymphocytes (CTLs). On the other hand, Th2 cells are involved in humoral immunity and suppressive to Th1 responses. Regulatory T (Treg) cells negatively regulate immune responses and contribute to immune evasion of tumor cells. Th17 cells are involved in inflammatory responses and may play a role in tumor progression. However, recent studies have also shown that Th17 cells are capable of directly inducting CTLs and thus may promote anti-tumor immunity. Besides these T cell subsets, there are many other innate immune cells such as dendritic cells (DCs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs) that are involved in host immune responses to cancer. The migratory properties of various immune cells are critical for their functions and largely regulated by the chemokine superfamily. Thus, chemokines and chemokine receptors play vital roles in the orchestration of host immune responses to cancer. In this review, we overview the various immune cells involved in host responses to cancer and their migratory properties regulated by the chemokine superfamily. Understanding the roles of chemokines and chemokine receptors in host immune responses to cancer may provide new therapeutic opportunities for cancer immunotherapy.

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Cytokines mediated hyperinflammation in SARS-CoV2: An Overview

Life and Science ◽

10.37185/lns.1.1.147 ◽

2020 ◽

Vol 1 (supplement) ◽

pp. 7

Author(s):

Liaqat Ali

Keyword(s):

Middle East ◽

Severe Acute Respiratory Syndrome ◽

Immune Responses ◽

T Lymphocyte ◽

Lymphoid Tissue ◽

Inflammatory Responses ◽

Cytokine Storm ◽

Host Immune Responses ◽

Lymphocyte Responses

Hyperinflammation induced by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV2) is a major cause of disease severity and mortality in infected patients. The immunopathogenesis of SARS-CoV2 infection is similar to the previous Middle East Respiratory Syndrome-related coronavirus (MERS-CoV) and SARS-CoV coronavirus with severe inflammatory responses. Therefore, severity of this viral infection is not only associated with the virus but also due to host immune responses. Hyperinflammatory responses due to cytokine storm are a centerpiece of SARS-CoV2 pathogenesis with overwhelming consequences for the host. Virus infected monocyte derived macrophages produce cytokines and this contributes to damage of lymphoid tissue and limits the lymphocyte responses. Blocking the deadly cytokine storm and T lymphocyte stimulation is a vital defense for treating SARS-CoV2. Here, we will describe the role of hyperinflamation and the involvement of cytokines in severe SARS-CoV2 infection.

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Insights Into Host Cell Cytokines in Chlamydia Infection

Frontiers in Immunology ◽

10.3389/fimmu.2021.639834 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wenjing Xiang ◽

Nanyan Yu ◽

Aihua Lei ◽

Xiaofang Li ◽

Shui Tan ◽

...

Keyword(s):

Immune Responses ◽

Chlamydial Infection ◽

Inflammatory Responses ◽

Host Cells ◽

Chlamydia Infection ◽

Significant Morbidity ◽

Host Immune Responses ◽

Infection Biology ◽

Severe Tissue ◽

Host Tissues

Chlamydial infection causes a number of clinically relevant diseases and induces significant morbidity in humans. Immune and inflammatory responses contribute to both the clearance of Chlamydia infection and pathology in host tissues. Chlamydia infection stimulates host cells to produce a large number of cytokines that trigger and regulate host immune responses against Chlamydia. However, inappropriate responses can occur with excessive production of cytokines, resulting in overreactive inflammatory responses and alterations in host or Chlamydia metabolism. As a result, Chlamydia persists and causes wound healing delays, leading to more severe tissue damage and triggering long-lasting fibrotic sequelae. Here, we summarize the roles of cytokines in Chlamydia infection and pathogenesis, thus advancing our understanding chlamydial infection biology and the pathogenic mechanisms involved.

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