Mucosal bacterial dissemination in a rhesus macaque model of experimental brucellosis

Russell‐Lodrigue, Kasi; Killeen, Stephanie Z.; Ficht, Thomas A.; Roy, Chad J.

doi:10.1111/jmp.12282

Cited by 6 publications

(8 citation statements)

References 16 publications

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“…In our experiments, the B. neotomae infectious course in BALB/c mice showed similarity to B. abortus, B. melitensis, and B. suis infection of domesticated farm animals and primates. For example, during aerosol infection of rhesus monkeys with B. melitensis with inocula ranging generally from 10 5 to 6 ϫ 10 6 organisms, both liver and spleen CFU were prominent early in infection (27)(28)(29); liver counts dropped from 10 6 to 10 4 CFU from days 15 to 45 (29); and organisms were isolated at low levels from liver and spleen 8 to 9 weeks after infection (27,28), similar to observations in the B. neotomae murine model. Additionally, significant quantities of organisms were isolated from lymph nodes during B. melitensis infection of rhesus monkeys; during B. abortus strain 1308 and/or 544 McEwen infection of cows and bison (30)(31)(32); and during human infection, especially in children (33,34).…”

Section: Discussionsupporting

confidence: 61%

Brucella neotomae Recapitulates Attributes of Zoonotic Human Disease in a Murine Infection Model

Kang

Brown

2019

Infect Immun

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Members of the genus Brucella are Gram-negative pathogens that cause chronic systemic infection in farm animals and zoonotic infection in humans. Study of the genus Brucella has been hindered by the need for biosafety level 3 select agent containment. Brucella neotomae, originally isolated from the desert pack rat, presented an opportunity to develop an alternative, non-select agent experimental model. Our prior in vitro work indicated that the cell biology and type IV secretion system (T4SS) dependence of B. neotomae intracellular replication were similar to observations for humanpathogenic select agent Brucella species. Therefore, here, we investigated the pathobiology of B. neotomae infection in the BALB/c mouse. During a sustained infectious course, B. neotomae replicated and persisted in reticuloendothelial organs. Bioluminescent imaging and histopathological and PCR-based analysis demonstrated that the T4SS contributed to efficient early infection of the liver, spleen, and lymph nodes; granuloma formation and hepatosplenomegaly; and early induction of Th1-associated cytokine gene expression. The infectious course and pathologies in the murine model showed similarity to prior observations of primate and native host infection with zoonotic Brucella species. Therefore, the B. neotomae BALB/c infection model offers a promising system to accelerate and complement experimental work in the genus Brucella. KEYWORDS Brucella, Brucella neotomae, brucellosis, bioluminescent imaging, murine model, pathogenesis, pathology, type IV secretion system, undulant fever M embers of the genus Brucella, Gram-negative coccobacilli, cause systemic bacterial infections in domesticated farm animals and other vertebrates (1). Humans may be infected through ingestion of unpasteurized dairy products, inhalation of organisms from birthing farm animals, and during occupational exposure in abattoir and meat packing industries. Disease in humans is characterized by chronicity and a waxing and waning fever (so-called undulant fever). Lymph node infection and enlargement are common (2); endovascular and osteoarticular infection are unwelcome and not infrequent complications (3,4).Based on the low aerosol infectious dose and debilitating disease, the major zoonotic species, Brucella melitensis, Brucella abortus, and Brucella suis, are classified as biosafety level 3, category B overlap select agents (5). Biosafety containment and select agent regulations represent significant impediments to experimental investigation.Brucella organisms have been studied in several in vitro and in vivo model systems (6)(7)(8)(9). In vitro assays have demonstrated the capability of Brucella species to grow within specialized vacuoles inside of macrophages, endothelial cells, and other cell types. In particular, Brucella species alter the normal process of phagosomal maturation. Remodeling of the phagosome occurs in a temporal fashion in which organisms are first found within endocytic vacuoles that subsequently take on properties of the endoplasmic reticulum an...

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Section: Discussionsupporting

confidence: 61%

Brucella neotomae Recapitulates Attributes of Zoonotic Human Disease in a Murine Infection Model

Kang

Brown

2019

Infect Immun

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“…which is similar to human brucellosis, in which the Brucella location in the male reproductive tract is observed in approximately 2% to 10% of reported cases. In other study, B. melitensis was cultured from the saliva and vaginal vault of infected animals, demonstrating bacterial dissemination to other target tissues [39]. Infection with aerosolized B. melitensis only generates changes in some clinical laboratory parameters, such as an increase in C-reactive protein and in certain liver enzymes, which is consistent with what has been observed in human brucellosis [37].…”

Section: Course Of Respiratory Brucella Infection In Animal Modelssupporting

confidence: 79%

Pathogenesis and immune response in Brucella infection acquired by the respiratory route

Ferrero

Paiva

González

et al. 2020

Microbes and Infection

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…Like other Gram-negative organisms, Brucella strains express a lipopolysaccharide (LPS) lacking endotoxin activity. Importantly, BmΔ vjbR has been shown to be safe in immunocompetent and immunocompromised mice 9 , goats 10 , sheep 11 , and non-human primates 12 . We also have shown that BmΔ vjbR can combat cancer in a murine model by remodeling the tumor microenvironment (TME) to a pro-inflammatory state 8 .…”

Section: Mainmentioning

confidence: 99%

A metabolically engineered bacterium controls autoimmunity by remodeling the pro-inflammatory microenvironment

Das

Guo

Hunt

et al. 2022

Preprint

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Immunotherapy has led to impressive advances in the treatment of autoimmune and pro-inflammatory disorders; yet, its clinical outcomes remain limited by a variety of factors including the pro-inflammatory microenvironment (IME). Discovering effective immunomodulatory agents, and the mechanisms by which they control disease, will lead to innovative strategies for enhancing the effectiveness of current immunotherapeutic approaches. We have metabolically engineered an attenuated bacterial strain (i.e., Brucella melitensis 16M ∆vjbR, Bm∆vjbR) to produce indole, a tryptophan metabolite that controls the fate and function of regulatory T cells (Tregs). We demonstrated that treatment with this strain polarized M2 macrophages (Mφ) which produced anti-inflammatory cytokines (e.g., IL-10) and promoted Treg function; moreover, when combined with adoptive cell transfer (ACT) of Tregs, a single treatment with our engineered bacterial strain dramatically reduced the incidence and score of autoimmune arthritis and decreased joint damage. These findings show how a metabolically engineered bacterium can constitute a powerful vehicle for improving the efficacy of immunotherapy, defeating autoimmunity and reducing inflammation by remodeling the IME and augmenting Treg function.

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Mucosal bacterial dissemination in a rhesus macaque model of experimental brucellosis

Cited by 6 publications

References 16 publications

Brucella neotomae Recapitulates Attributes of Zoonotic Human Disease in a Murine Infection Model

Brucella neotomae Recapitulates Attributes of Zoonotic Human Disease in a Murine Infection Model

Pathogenesis and immune response in Brucella infection acquired by the respiratory route

A metabolically engineered bacterium controls autoimmunity by remodeling the pro-inflammatory microenvironment

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