Modulation of the Bovine Trophoblastic Innate Immune Response by<i>Brucella abortus</i>

Neta, Alcina V. Carvalho; Stynen, Ana Paula Reinato; Paixão, Tatiane Alves da; Miranda, Karina Leite; Silva, Fabiana Lima; Roux, Christelle M.; Tsolis, Renée M.; Everts, Robin E.; Lewin, Harris A.; Adams, L. Garry; Carvalho, Alex F.; Lage, Andrey Pereira; Santos, Renato L.

doi:10.1128/iai.01554-07

Cited by 56 publications

(63 citation statements)

References 50 publications

(61 reference statements)

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“…In mice, a lack of proinflammatory response during infection with B. abortus has been observed (6). In addition, B. abortus is able to impair proinflammatory responses by bovine trophoblastic cells (10). Therefore, in good agreement with these previous studies, we demonstrated here that B. melitensis can invade through the digestive tract without inducing a strong local inflammatory response.…”

Section: Discussionsupporting

confidence: 80%

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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

Paixão

Roux²,

Hartigh³

et al. 2009

Infect Immun

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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.Brucella spp. are facultative intracellular gram-negative bacteria that cause chronic infections in mammalian hosts. Brucella melitensis infects mainly goats and sheep, causing abortion, placentitis, and infertility, and it is considered the most pathogenic species of Brucella to humans (15). Human brucellosis is an important worldwide zoonosis that causes social and economic impacts on public health and animal production. The disease is prevalent mostly in the Middle East, Mediterranean, Central Asia, Latin America, and North Africa, with over 500,000 new cases of human brucellosis registered annually (41).Human brucellosis usually does not present with specific clinical symptoms. It is frequently associated with intermittent fever, anorexia, weakness, soreness, and inflammation affecting several organs. Spondylitis, arthritis, osteomyelitis, and epididymo-orchitis are common manifestations of the infection. However, infection of the heart and brain may also occur and can result in death (34). Human brucellosis caused by B. melitensis results mostly from ingestion of unpasteurized milk and dairy products from infected goats, sheep, camels, and cattle. The importance of food-borne infection is underlined by a recent study in Mexico, which reported that in 98% of cases, the major risk factor for brucellosis was ingestion of contaminated dairy p...

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Section: Discussionsupporting

confidence: 80%

“…are stealth pathogens that avoid activation of the innate immune response during establishment of infection (6,10,12,51). In mice, a lack of proinflammatory response during infection with B. abortus has been observed (6).…”

Section: Discussionmentioning

confidence: 99%

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

Paixão

Roux²,

Hartigh³

et al. 2009

Infect Immun

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“…17 Once adapted to the intramacrophage environment, Brucella extends its intracellular persistence indefinitely, which contributes to systemic metastasis and infection of preferred targeted cells or tissues, such as placental trophoblasts, fetal lung, male genitalia, skeletal tissues, reticuloendothelial system, and endothelium. Currently, there is minimal information available to describe the interaction of Brucella with these target cells and tissue 18,19 to provide a more holistic systems biology analysis of the pathogenesis of brucellosis at the level of the whole host organism.…”

Section: Biology Of Brucellamentioning

confidence: 99%

Pathogenesis and Immunobiology of Brucellosis

Figueiredo

Ficht

Rice‐Ficht

et al. 2015

The American Journal of Pathology

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This review of Brucellaehost interactions and immunobiology discusses recent discoveries as the basis for pathogenesis-informed rationales to prevent or treat brucellosis. Brucella spp., as animal pathogens, cause human brucellosis, a zoonosis that results in worldwide economic losses, human morbidity, and poverty. Although Brucella spp. infect humans as an incidental host, 500,000 new human infections occur annually, and no patient-friendly treatments or approved human vaccines are reported. Brucellae display strong tissue tropism for lymphoreticular and reproductive systems with an intracellular lifestyle that limits exposure to innate and adaptive immune responses, sequesters the organism from the effects of antibiotics, and drives clinical disease manifestations and pathology. Stealthy brucellae exploit strategies to establish infection, including i) evasion of intracellular destruction by restricting fusion of type IV secretion systemdependent Brucella-containing vacuoles with lysosomal compartments, ii) inhibition of apoptosis of infected mononuclear cells, and iii) prevention of dendritic cell maturation, antigen presentation, and activation of naive T cells, pathogenesis lessons that may be informative for other intracellular pathogens. Data sets of next-generation sequences of Brucella and host time-series global expression fused with proteomics and metabolomics data from in vitro and in vivo experiments now inform interactive cellular pathways and gene regulatory networks enabling full-scale systems biology analysis. The newly identified effector proteins of Brucella may represent targets for improved, safer brucellosis vaccines and therapeutics. It is noteworthy that long ago in his publication Epidemics, Hippocrates described brucellosis-type syndromes in humans living in the Mediterranean littoral. Many centuries later, British physician, David Bruce, and Greek physician, Themistokles Zammit, in 1886 would discover the causative agent, Micrococcus melitensis, of brucellosis and would identify milk products of goats as the source of infection for military troops on the island of Malta. Even after more than a century of extensive research, Brucella spp. are still serious animal pathogens that cause brucellosis, a zoonosis that results in substantial economic losses, human morbidity, and perpetuates poverty worldwide.1 These Gram-negative bacteria infect a diverse array of land and aquatic mammals,

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“…However, in these cases, many other proinflammatory genes were also downregulated. In B. abortus strain 2308-infected trophoblastic cells (6), proinflammatory responses were also suppressed at the early stage of infection and followed by a delayed and mild expression of proinflammatory chemokines (6). In general, smooth virulent Brucella behaves as a furtive pathogen that circumvents killing via a dramatically subdued proinflammatory response (2).…”

mentioning

confidence: 99%

“…Necrosis is also often inflammatory and considered a common end of many types of cell death (e.g., oncosis) (13). Proinflammatory responses in Brucella-infected host cells were also studied (2,6,9,18,27). For example, microarray studies revealed that the transcriptional levels of many proinflammatory genes were upregulated in murine macrophages infected with smooth B. abortus strain 2308 (9) or smooth B. melitensis strain 16M at 4 h postinfection (18).…”

mentioning

confidence: 99%

Proinflammatory Caspase-2-Mediated Macrophage Cell Death Induced by a Rough Attenuated Brucella suis Strain

Chen

Ding

et al. 2011

Infect Immun

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Brucella spp. are intracellular bacteria that cause an infectious disease called brucellosis in humans and many domestic and wildlife animals. B. suis primarily infects pigs and is pathogenic to humans. The macrophage-Brucella interaction is critical for the establishment of a chronic Brucella infection. Our studies showed that smooth virulent B. suis strain 1330 (S1330) prevented programmed cell death of infected macrophages and rough attenuated B. suis strain VTRS1 (a vaccine candidate) induced strong macrophage cell death. To further investigate the mechanism of VTRS1-induced macrophage cell death, microarrays were used to analyze temporal transcriptional responses of murine macrophage-like J774.A1 cells infected with S1330 or VTRS1. In total 17,685 probe sets were significantly regulated based on the effects of strain, time and their interactions. A miniTUBA dynamic Bayesian network analysis predicted that VTRS1-induced macrophage cell death was mediated by a proinflammatory gene (the tumor necrosis factor alpha [TNF-␣] gene), an NF-B pathway gene (the IB-␣ gene), the caspase-2 gene, and several other genes. VTRS1 induced significantly higher levels of transcription of 40 proinflammatory genes than S1330. A Mann-Whitney U test confirmed the proinflammatory response in VTRS1-infected macrophages. Increased production of TNF-␣ and interleukin 1␤ (IL-1␤) were also detected in the supernatants in VTRS1-infected macrophage cell culture. Hyperphosphorylation of IB-␣ was observed in macrophages infected with VTRS1 but not S1330. The important roles of TNF-␣ and IB-␣ in VTRS1-induced macrophage cell death were further confirmed by individual inhibition studies. VTRS1-induced macrophage cell death was significantly inhibited by a caspase-2 inhibitor but not a caspase-1 inhibitor. The role of caspase-2 in regulating the programmed cell death of VTRS1-infected macrophages was confirmed in another study using caspase-2-knockout mice. In summary, VTRS1 induces a proinflammatory, caspase-2-and NF-B-mediated macrophage cell death. This unique cell death differs from apoptosis, which is not proinflammatory. It is also different from classical pyroptosis, which is caspase-1 mediated.Brucella spp. are facultative, intracellular, Gram-negative bacteria that cause a zoonotic disease called brucellosis in swine, cattle, other animals, and humans. Human brucellosis remains the most common zoonotic disease worldwide, with more than 500,000 new cases reported annually (28). B. suis is the main causative agent of brucellosis in swine and humans (28). Brucella enters and replicates efficiently in a variety of cells, including macrophages, epithelial cells, dendritic cells, and trophoblasts (34). Interaction between Brucella and macrophages is critical for the establishment of a chronic infection. The virulence of Brucella relies on its ability to survive and replicate in the vacuolar compartments of macrophages (18). In contrast, many rough derivatives of B. suis, B. abortus, and B. melitensis, which are deficient in the O antigen (o...

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Modulation of the Bovine Trophoblastic Innate Immune Response byBrucella abortus

Cited by 56 publications

References 50 publications

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

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

Pathogenesis and Immunobiology of Brucellosis

Proinflammatory Caspase-2-Mediated Macrophage Cell Death Induced by a Rough Attenuated Brucella suis Strain

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