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Pathogens
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Host Immune Responses and Pathogenesis to Brucella spp. Infection
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Host Immune Responses and Pathogenesis to Brucella spp. Infection

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Bacterial Pathogens".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 38921

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Sergio Costa Oliveira

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Guest Editor
Departmento de Bioquimica e Imunologia, Universidade Federal de Minas Gerais, 31270-901, Brazil
Interests: innate immunity; inflammasomes; cytosolic sensors; STING; caspase-11
Special Issues, Collections and Topics in MDPI journals
Dr. Guillermo Giambartolomei

E-Mail Website
Guest Editor
Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
Interests: innate immunity; intracellular infections; immunopathology of CNS
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Brucellosis, caused by the facultative intracellular bacteria Brucella species, is one the most prevalent zoonosis worldwide. Brucella causes >500,000 human infections per year, and brucellosis is underreported in endemic areas. Between livestock losses and human morbidity, brucellosis imposes a significant economic impact, perpetuating poverty in endemic regions. There is a considerable amount of evidence that indicates the capacity of Brucella sp. to avoid or interfere with components of the host immune responses that plays a critical role in their virulence. It has been suggested that Brucella has developed a stealth strategy through PAMP reduction, modification and hiding, to ensure low stimulatory activity and toxicity for cells. This strategy allows Brucella to reach its replication niche before activating antimicrobial mechanisms by host immune responses. However, inside the host cells, Brucella releases vital molecules for the bacteria that trigger the activation of host cytosolic receptors. However, further studies are required to elucidate this complex circuit by which the host immune system recognizes Brucella-derived molecules. These aspects of host–parasite relationship will be discussed here, and these findings will help to advance the comprehension of bacterial pathogenesis and contribute to the future development of drugs or vaccines to control brucellosis.

For this Special Issue of Pathogens, we invite you to submit a review or research article related to host immune responses, inflammation, vaccine development, pathology, and pathogenesis of Brucella spp. infections. We look forward to your contribution.

Prof. Sergio Costa Oliveira
Prof. Guillermo Giambartolomei
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pathogens is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Brucella
  • Brucella spp. Infections
  • Brucellosis
  • immune responses
  • inflammation
  • vaccines
  • pathology
  • pathogenesis

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Published Papers (10 papers)

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Editorial

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3 pages, 187 KiB  
Editorial
Host Immune Responses and Pathogenesis to Brucella spp. Infection
by Sergio C. Oliveira
Pathogens 2021, 10(3), 288; https://doi.org/10.3390/pathogens10030288 - 3 Mar 2021
Cited by 5 | Viewed by 2318
Abstract
Brucellosis, caused by the facultative intracellular bacteria Brucella species, is one the most prevalent zoonoses worldwide [...] Full article
(This article belongs to the Special Issue Host Immune Responses and Pathogenesis to Brucella spp. Infection)

Research

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15 pages, 2675 KiB  
Article
ASC-Mediated Inflammation and Pyroptosis Attenuates Brucella abortus Pathogenesis Following the Recognition of gDNA
by Juselyn D. Tupik, Sheryl L. Coutermarsh-Ott, Angela H. Benton, Kellie A. King, Hanna D. Kiryluk, Clayton C. Caswell and Irving C. Allen
Pathogens 2020, 9(12), 1008; https://doi.org/10.3390/pathogens9121008 - 30 Nov 2020
Cited by 9 | Viewed by 2797
Abstract
Brucella abortus is a zoonotic pathogen that causes brucellosis. Because of Brucella’s unique LPS layer and intracellular localization predominately within macrophages, it can often evade immune detection. However, pattern recognition receptors are capable of sensing Brucella pathogen-associated molecular patterns (PAMPS). For example, NOD-like [...] Read more.
Brucella abortus is a zoonotic pathogen that causes brucellosis. Because of Brucella’s unique LPS layer and intracellular localization predominately within macrophages, it can often evade immune detection. However, pattern recognition receptors are capable of sensing Brucella pathogen-associated molecular patterns (PAMPS). For example, NOD-like receptors (NLRs) can form a multi-protein inflammasome complex to attenuate Brucella pathogenesis. The inflammasome activates IL-1β and IL-18 to drive immune cell recruitment. Alternatively, inflammasome activation also initiates inflammatory cell death, termed pyroptosis, which augments bacteria clearance. In this report, we assess canonical and non-canonical inflammasome activation following B. abortus infection. We conducted in vivo studies using Asc−/− mice and observed decreased mouse survival, immune cell recruitment, and increased bacteria load. We also conducted studies with Caspase-11−/− mice and did not observe any significant impact on B. abortus pathogenesis. Through mechanistic studies using Asc−/− macrophages, our data suggests that the protective role of ASC may result from the induction of pyroptosis through a gasdermin D-dependent mechanism in macrophages. Additionally, we show that the recognition of Brucella is facilitated by sensing the PAMP gDNA rather than the less immunogenic LPS. Together, these results refine our understanding of the role that inflammasome activation and pyroptosis plays during brucellosis. Full article
(This article belongs to the Special Issue Host Immune Responses and Pathogenesis to Brucella spp. Infection)
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17 pages, 2876 KiB  
Article
Brucella abortus-Stimulated Platelets Activate Brain Microvascular Endothelial Cells Increasing Cell Transmigration through the Erk1/2 Pathway
by Ana María Rodríguez, Aldana Trotta, Agustina P. Melnyczajko, M. Cruz Miraglia, Kwang Sik Kim, M. Victoria Delpino, Paula Barrionuevo and Guillermo Hernán Giambartolomei
Pathogens 2020, 9(9), 708; https://doi.org/10.3390/pathogens9090708 - 27 Aug 2020
Cited by 5 | Viewed by 3124
Abstract
Central nervous system invasion by bacteria of the genus Brucella results in an inflammatory disorder called neurobrucellosis. A common feature associated with this pathology is blood–brain barrier (BBB) activation. However, the underlying mechanisms involved with such BBB activation remain unknown. The aim of [...] Read more.
Central nervous system invasion by bacteria of the genus Brucella results in an inflammatory disorder called neurobrucellosis. A common feature associated with this pathology is blood–brain barrier (BBB) activation. However, the underlying mechanisms involved with such BBB activation remain unknown. The aim of this work was to investigate the role of Brucella abortus-stimulated platelets on human brain microvascular endothelial cell (HBMEC) activation. Platelets enhanced HBMEC activation in response to B. abortus infection. Furthermore, supernatants from B. abortus-stimulated platelets also activated brain endothelial cells, inducing increased secretion of IL-6, IL-8, CCL-2 as well as ICAM-1 and CD40 upregulation on HBMEC compared with supernatants from unstimulated platelets. Outer membrane protein 19, a B. abortus lipoprotein, recapitulated B. abortus-mediated activation of HBMECs by platelets. In addition, supernatants from B. abortus-activated platelets promoted transendothelial migration of neutrophils and monocytes. Finally, using a pharmacological inhibitor, we demonstrated that the Erk1/2 pathway is involved in the endothelial activation induced by B. abortus-stimulated platelets and also in transendothelial migration of neutrophils. These results describe a mechanism whereby B. abortus-stimulated platelets induce endothelial cell activation, promoting neutrophils and monocytes to traverse the BBB probably contributing to the inflammatory pathology of neurobrucellosis. Full article
(This article belongs to the Special Issue Host Immune Responses and Pathogenesis to Brucella spp. Infection)
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13 pages, 3654 KiB  
Article
Intracellular Growth and Cell Cycle Progression are Dependent on (p)ppGpp Synthetase/Hydrolase in Brucella abortus
by Mathilde Van der Henst, Elodie Carlier and Xavier De Bolle
Pathogens 2020, 9(7), 571; https://doi.org/10.3390/pathogens9070571 - 14 Jul 2020
Cited by 6 | Viewed by 3050
Abstract
Brucella abortus is a pathogenic bacterium able to proliferate inside host cells. During the first steps of its trafficking, it is able to block the progression of its cell cycle, remaining at the G1 stage for several hours, before it reaches its replication [...] Read more.
Brucella abortus is a pathogenic bacterium able to proliferate inside host cells. During the first steps of its trafficking, it is able to block the progression of its cell cycle, remaining at the G1 stage for several hours, before it reaches its replication niche. We hypothesized that starvation mediated by guanosine tetra- or penta-phosphate, (p)ppGpp, could be involved in the cell cycle arrest. Rsh is the (p)ppGpp synthetase/hydrolase. A B. abortus ∆rsh mutant is unable to grow in minimal medium, it is unable to survive in stationary phase in rich medium and it is unable to proliferate inside RAW 264.7 macrophages. A strain producing the heterologous constitutive (p)ppGpp hydrolase Mesh1b is also unable to proliferate inside these macrophages. Altogether, these data suggest that (p)ppGpp is necessary to allow B. abortus to adapt to its intracellular growth conditions. The deletion of dksA, proposed to mediate a part of the effect of (p)ppGpp on transcription, does not affect B. abortus growth in culture or inside macrophages. Expression of a gene coding for a constitutively active (p)ppGpp synthetase slows down growth in rich medium and inside macrophages. Using an mCherry–ParB fusion able to bind to the replication origin of the main chromosome of B. abortus, we observed that expression of the constitutive (p)ppGpp synthetase gene generates an accumulation of bacteria at the G1 phase. We thus propose that (p)ppGpp accumulation could be one of the factors contributing to the G1 arrest observed for B. abortus in RAW 264.7 macrophages. Full article
(This article belongs to the Special Issue Host Immune Responses and Pathogenesis to Brucella spp. Infection)
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14 pages, 2224 KiB  
Article
Hepatic Stellate Cells and Hepatocytes as Liver Antigen-Presenting Cells during B. abortus Infection
by Paula Constanza Arriola Benitez, Ayelén Ivana Pesce Viglietti, María Mercedes Elizalde, Guillermo Hernán Giambartolomei, Jorge Fabián Quarleri and María Victoria Delpino
Pathogens 2020, 9(7), 527; https://doi.org/10.3390/pathogens9070527 - 30 Jun 2020
Cited by 5 | Viewed by 2970
Abstract
In Brucellosis, the role of hepatic stellate cells (HSCs) in the induction of liver fibrosis has been elucidated recently. Here, we study how the infection modulates the antigen-presenting capacity of LX-2 cells. Brucella abortus infection induces the upregulation of class II transactivator protein [...] Read more.
In Brucellosis, the role of hepatic stellate cells (HSCs) in the induction of liver fibrosis has been elucidated recently. Here, we study how the infection modulates the antigen-presenting capacity of LX-2 cells. Brucella abortus infection induces the upregulation of class II transactivator protein (CIITA) with concomitant MHC-I and -II expression in LX-2 cells in a manner that is independent from the expression of the type 4 secretion system (T4SS). In concordance, B. abortus infection increases the phagocytic ability of LX-2 cells and induces MHC-II-restricted antigen processing and presentation. In view of the ability of B. abortus-infected LX-2 cells to produce monocyte-attracting factors, we tested the capacity of culture supernatants from B. abortus-infected monocytes on MHC-I and –II expression in LX-2 cells. Culture supernatants from B. abortus-infected monocytes do not induce MHC-I and -II expression. However, these supernatants inhibit MHC-II expression induced by IFN-γ in an IL-10 dependent mechanism. Since hepatocytes constitute the most abundant epithelial cell in the liver, experiments were conducted to determine the contribution of these cells in antigen presentation in the context of B. abortus infection. Our results indicated that B. abortus-infected hepatocytes have an increased MHC-I expression, but MHC-II levels remain at basal levels. Overall, B. abortus infection induces MHC-I and -II expression in LX-2 cells, increasing the antigen presentation. Nevertheless, this response could be modulated by resident or infiltrating monocytes/macrophages. Full article
(This article belongs to the Special Issue Host Immune Responses and Pathogenesis to Brucella spp. Infection)
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15 pages, 3122 KiB  
Article
Brucella abortus Proliferates in Decidualized and Non-Decidualized Human Endometrial Cells Inducing a Proinflammatory Response
by Lucía Zavattieri, Mariana C. Ferrero, Iván M. Alonso Paiva, Agustina D. Sotelo, Andrea M. Canellada and Pablo C. Baldi
Pathogens 2020, 9(5), 369; https://doi.org/10.3390/pathogens9050369 - 12 May 2020
Cited by 8 | Viewed by 3045
Abstract
Brucella spp. have been associated with abortion in humans and animals. Although the mechanisms involved are not well established, it is known that placental Brucella infection is accompanied by inflammatory phenomena. The ability of Brucella abortus to infect and survive in human endometrial [...] Read more.
Brucella spp. have been associated with abortion in humans and animals. Although the mechanisms involved are not well established, it is known that placental Brucella infection is accompanied by inflammatory phenomena. The ability of Brucella abortus to infect and survive in human endometrial stromal cells (T-HESC cell line) and the cytokine response elicited were evaluated. B. abortus was able to infect and proliferate in both non-decidualized and decidualized T-HESC cells. Intracellular proliferation depended on the expression of a functional virB operon in the pathogen. B. abortus internalization was inhibited by cytochalasin D and to a lower extent by colchicine, but was not affected by monodansylcadaverine. The infection did not induce cytotoxicity and did not alter the decidualization status of cells. B. abortus infection elicited the secretion of IL-8 and MCP-1 in either decidualized or non-decidualized T-HESC, a response also induced by heat-killed B. abortus and outer membrane vesicles derived from this bacterium. The stimulation of T-HESC with conditioned media from Brucella-infected macrophages induced the production of IL-6, MCP-1 and IL-8 in a dose-dependent manner, and this effect was shown to depend on IL-1β and TNF-α. The proinflammatory responses of T-HESC to B. abortus and to factors produced by infected macrophages may contribute to the gestational complications of brucellosis. Full article
(This article belongs to the Special Issue Host Immune Responses and Pathogenesis to Brucella spp. Infection)
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16 pages, 2057 KiB  
Article
The Role of ST2 Receptor in the Regulation of Brucella abortus Oral Infection
by Raiany Santos, Priscila C. Campos, Marcella Rungue, Victor Rocha, David Santos, Viviani Mendes, Fabio V. Marinho, Flaviano Martins, Mayra F. Ricci, Diego C. dos Reis, Geovanni D. Cassali, José Carlos Alves-Filho, Angelica T. Vieira and Sergio C. Oliveira
Pathogens 2020, 9(5), 328; https://doi.org/10.3390/pathogens9050328 - 28 Apr 2020
Cited by 4 | Viewed by 2731
Abstract
The ST2 receptor plays an important role in the gut such as permeability regulation, epithelium regeneration, and promoting intestinal immune modulation. Here, we studied the role of ST2 receptor in a murine model of oral infection with Brucella abortus, its influence on [...] Read more.
The ST2 receptor plays an important role in the gut such as permeability regulation, epithelium regeneration, and promoting intestinal immune modulation. Here, we studied the role of ST2 receptor in a murine model of oral infection with Brucella abortus, its influence on gut homeostasis and control of bacterial replication. Balb/c (wild-type, WT) and ST2 deficient mice (ST2−/−) were infected by oral gavage and the results were obtained at 3 and 14 days post infection (dpi). Our results suggest that ST2−/− are more resistant to B. abortus infection, as a lower bacterial colony-forming unit (CFU) was detected in the livers and spleens of knockout mice, when compared to WT. Additionally, we observed an increase in intestinal permeability in WT-infected mice, compared to ST2−/− animals. Breakage of the intestinal epithelial barrier and bacterial dissemination might be associated with the presence of the ST2 receptor; since, in the knockout mice no change in intestinal permeability was observed after infection. Together with enhanced resistance to infection, ST2−/− produced greater levels of IFN-γ and TNF-α in the small intestine, compared to WT mice. Nevertheless, in the systemic model of infection ST2 plays no role in controlling Brucella replication in vivo. Our results suggest that the ST2 receptor is involved in the invasion process of B. abortus by the mucosa in the oral infection model. Full article
(This article belongs to the Special Issue Host Immune Responses and Pathogenesis to Brucella spp. Infection)
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12 pages, 1297 KiB  
Article
Simultaneous Immunization with Omp25 and L7/L12 Provides Protection against Brucellosis in Mice
by Sonal Gupta, Surender Mohan, Vikas Kumar Somani, Somya Aggarwal and Rakesh Bhatnagar
Pathogens 2020, 9(2), 152; https://doi.org/10.3390/pathogens9020152 - 24 Feb 2020
Cited by 12 | Viewed by 3629
Abstract
Currently used Brucella vaccines, Brucella abortus strain 19 and RB51, comprises of live attenuated Brucella strains and prevent infection in animals. However, these vaccines pose potential risks to recipient animals such as attenuation reversal and virulence in susceptible hosts on administration. In this [...] Read more.
Currently used Brucella vaccines, Brucella abortus strain 19 and RB51, comprises of live attenuated Brucella strains and prevent infection in animals. However, these vaccines pose potential risks to recipient animals such as attenuation reversal and virulence in susceptible hosts on administration. In this context, recombinant subunit vaccines emerge as a safe and competent alternative in combating the disease. In this study, we formulated a divalent recombinant vaccine consisting of Omp25 and L7/L12 of B. abortus and evaluated vaccine potential individually as well as in combination. Sera obtained from divalent vaccine (Omp25+L7/L12) immunized mice group exhibited enhanced IgG titers against both components and indicated specificity upon immunoblotting reiterating its authenticity. Further, the IgG1/IgG2a ratio obtained against each antigen predicted a predominant Th2 immune response in the Omp25+L7/L12 immunized mice group. Upon infection with virulent B. abortus 544, Omp25+L7/L12 infected mice exhibited superior Log10 protection compared to individual vaccines. Consequently, this study recommends that simultaneous immunization of Omp25 and L7/L12 as a divalent vaccine complements and triggers a Th2 mediated immune response in mice competent of providing protection against brucellosis. Full article
(This article belongs to the Special Issue Host Immune Responses and Pathogenesis to Brucella spp. Infection)
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Review

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21 pages, 4165 KiB  
Review
Brucella: Reservoirs and Niches in Animals and Humans
by Gabriela González-Espinoza, Vilma Arce-Gorvel, Sylvie Mémet and Jean-Pierre Gorvel
Pathogens 2021, 10(2), 186; https://doi.org/10.3390/pathogens10020186 - 9 Feb 2021
Cited by 59 | Viewed by 10162
Abstract
Brucella is an intracellular bacterium that causes abortion, reproduction failure in livestock and leads to a debilitating flu-like illness with serious chronic complications if untreated in humans. As a successful intracellular pathogen, Brucella has developed strategies to avoid recognition by the immune system [...] Read more.
Brucella is an intracellular bacterium that causes abortion, reproduction failure in livestock and leads to a debilitating flu-like illness with serious chronic complications if untreated in humans. As a successful intracellular pathogen, Brucella has developed strategies to avoid recognition by the immune system of the host and promote its survival and replication. In vivo, Brucellae reside mostly within phagocytes and other cells including trophoblasts, where they establish a preferred replicative niche inside the endoplasmic reticulum. This process is central as it gives Brucella the ability to maintain replicating-surviving cycles for long periods of time, even at low bacterial numbers, in its cellular niches. In this review, we propose that Brucella takes advantage of the environment provided by the cellular niches in which it resides to generate reservoirs and disseminate to other organs. We will discuss how the favored cellular niches for Brucella infection in the host give rise to anatomical reservoirs that may lead to chronic infections or persistence in asymptomatic subjects, and which may be considered as a threat for further contamination. A special emphasis will be put on bone marrow, lymph nodes, reproductive and for the first time adipose tissues, as well as wildlife reservoirs. Full article
(This article belongs to the Special Issue Host Immune Responses and Pathogenesis to Brucella spp. Infection)
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20 pages, 955 KiB  
Review
Adhesins of Brucella: Their Roles in the Interaction with the Host
by Magalí G. Bialer, Gabriela Sycz, Florencia Muñoz González, Mariana C. Ferrero, Pablo C. Baldi and Angeles Zorreguieta
Pathogens 2020, 9(11), 942; https://doi.org/10.3390/pathogens9110942 - 12 Nov 2020
Cited by 19 | Viewed by 3932
Abstract
A central aspect of Brucella pathogenicity is its ability to invade, survive, and replicate in diverse phagocytic and non-phagocytic cell types, leading to chronic infections and chronic inflammatory phenomena. Adhesion to the target cell is a critical first step in the invasion process. [...] Read more.
A central aspect of Brucella pathogenicity is its ability to invade, survive, and replicate in diverse phagocytic and non-phagocytic cell types, leading to chronic infections and chronic inflammatory phenomena. Adhesion to the target cell is a critical first step in the invasion process. Several Brucella adhesins have been shown to mediate adhesion to cells, extracellular matrix components (ECM), or both. These include the sialic acid-binding proteins SP29 and SP41 (binding to erythrocytes and epithelial cells, respectively), the BigA and BigB proteins that contain an Ig-like domain (binding to cell adhesion molecules in epithelial cells), the monomeric autotransporters BmaA, BmaB, and BmaC (binding to ECM components, epithelial cells, osteoblasts, synoviocytes, and trophoblasts), the trimeric autotransporters BtaE and BtaF (binding to ECM components and epithelial cells) and Bp26 (binding to ECM components). An in vivo role has also been shown for the trimeric autotransporters, as deletion mutants display decreased colonization after oral and/or respiratory infection in mice, and it has also been suggested for BigA and BigB. Several adhesins have shown unipolar localization, suggesting that Brucella would express an adhesive pole. Adhesin-based vaccines may be useful to prevent brucellosis, as intranasal immunization in mice with BtaF conferred high levels of protection against oral challenge with B. suis. Full article
(This article belongs to the Special Issue Host Immune Responses and Pathogenesis to Brucella spp. Infection)
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