<i>Brucella</i>Intracellular Life Relies on the Transmembrane Protein CD98 Heavy Chain

Keriel, Anne; Botella, Eric; Estrach, Soline; Bragagnolo, Gabriel; Vergunst, Annette C.; Feral, Chloé C.; O’Callaghan, David

doi:10.1093/infdis/jiu673

Cited by 14 publications

(16 citation statements)

References 46 publications

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“…Trophoblastic functions are tightly controlled, and defects may lead to severe complications during pregnancy. Interestingly, several of these functions involve CD98hc, which we found to be essential for Brucella infection of other cell types (Keriel et al, 2015). CD98hc (SLC3A2) is a surface glycoprotein mediating amino-acid transport, regulation of integrin-dependent signalling and cell fusion (Nguyen & Merlin, 2012).…”

Section: Introductionmentioning

confidence: 92%

Infection by Brucella melitensis or Brucella papionis modifies essential physiological functions of human trophoblasts

García‐Méndez

Hielpos

Soler-Lloréns

et al. 2019

Cellular Microbiology

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Brucellosis is a zoonosis caused by bacteria of the Brucella genus. In ruminants, brucellosis causes abortion, followed by chronic infection and secretion of bacteria in milk. In humans, it usually presents as flu‐like symptoms, with serious complications if untreated. Epidemiological studies have only recently established that brucellosis can also cause pregnancy complications in women, but the pathogenic mechanisms are unknown. Pioneering studies in ruminants showed that Brucella infect trophoblasts and then colonise the placenta where they grow to high density. A recent study showed that the main zoonotic Brucella species can infect human cytotrophoblasts (CTB) and extravillous trophoblasts (EVT). In this work, we show that Brucella papionis (associated with stillbirth in primates) also infects human trophoblasts. However, it replicates actively in CTB, whereas its replication is very restricted within EVT. We also observed alteration of several trophoblastic functions upon infection by B. papionis or Brucella melitensis (the most prevalent species in human brucellosis). Infection altered the production of hormones, the ability of CTB to form syncytiotrophoblasts, and the invasion capacity of EVT. We also found that infection can spread between different types of trophoblasts. These findings constitute a new step in understanding how Brucella infection causes adverse pregnancy outcomes.

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Section: Introductionmentioning

confidence: 92%

Infection by Brucella melitensis or Brucella papionis modifies essential physiological functions of human trophoblasts

García‐Méndez

Hielpos

Soler-Lloréns

et al. 2019

Cellular Microbiology

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“…Recent studies have identified some new players such as the flagellum-like structure, the transporter-like protein BacA and phosphatidylcholine required for intracellular survival within host cells (Roop et al, 2009 ). In addition to Brucella T4SS, the CD98hc transmembrane protein is recognized as essential for intracellular proliferation and modulates different signaling pathways (Keriel et al, 2015 ).…”

Section: Brucella Pathogenesismentioning

confidence: 99%

Establishment of Chronic Infection: Brucella's Stealth Strategy

Waqas

Zheng

Liu

2016

Front. Cell. Infect. Microbiol.

108

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Brucella is a facultative intracellular pathogen that causes zoonotic infection known as brucellosis which results in abortion and infertility in natural host. Humans, especially in low income countries, can acquire infection by direct contact with infected animal or by consumption of animal products and show high morbidity, severe economic losses and public health problems. However for survival, host cells develop complex immune mechanisms to defeat and battle against attacking pathogens and maintain a balance between host resistance and Brucella virulence. On the other hand as a successful intracellular pathogen, Brucella has evolved multiple strategies to evade immune response mechanisms to establish persistent infection and replication within host. In this review, we mainly summarize the “Stealth” strategies employed by Brucella to modulate innate and the adaptive immune systems, autophagy, apoptosis and possible role of small noncoding RNA in the establishment of chronic infection. The purpose of this review is to give an overview for recent understanding how this pathogen evades immune response mechanisms of host, which will facilitate to understanding the pathogenesis of brucellosis and the development of novel, more effective therapeutic approaches to treat brucellosis.

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“…2 and Table S1). Among all these factors we can highlight the Ras related protein RAB7A, which is needed for Brucella trafficking to the replicative niche (10), the small GTPases RAC1 and CDC42, which are involved in Brucella internalization into non-phagocytic cells (13) as well as the transmembrane glycoprotein SLC3A2 (CD98hc), involved in both bacterial uptake and intracellular multiplication (28). Since the role of these individual components has already been described in the context of Brucella infection, they can be considered as benchmark to our results, and globally validate our systems-level perspective of the human infectome for Brucella infection.…”

Section: Resultsmentioning

confidence: 99%

“…Clusters with common predicted cellular function are colored and their prominent function are indicated. Hits previously reported to be involved in Brucella pathogenicity are highlighted: ARPC3 (29); TGFBR2 (22); SEC61G and TMED2 (35); RAC1 and CDC42 (13); SLC3A2 (28); RAB7A (10); SYK (63); ULK1 (64); For clarity, disconnected components are not displayed. The complete list of down- and up-hits is presented in Tables S1-S2.…”

Section: Resultsmentioning

confidence: 99%

A role for the VPS retromer inBrucellaintracellular replication revealed by genome-wide siRNA screening

Casanova

Low

Québatte

et al. 2018

Preprint

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26Brucella, the causing agent of brucellosis, is a major zoonotic pathogen with worldwide 27 distribution. Brucella resides and replicates inside infected host cells in membrane-bound 28 compartments called BCVs (Brucella-containing vacuoles). Following uptake, Brucella 29 resides in eBCVs (endosomal BCVs) that gradually mature from early to late endosomal 30 features. Through a poorly understood process that is key to the intracellular lifestyle of 31 Brucella, the eBCV escapes fusion with lysosomes by transitioning to the rBCV (replicative 32 BCV), a replicative niche directly connected to the endoplasmic reticulum (ER). Despite the 33 notion that this complex intracellular lifestyle must depend on a multitude of host factors, a 34 holistic view on which of these components control Brucella cell entry, trafficking and 35 replication is still missing. Here we used a systematic cell-based siRNA knockdown screen in 36HeLa cells infected with Brucella abortus and identified 425 components of the human 37 infectome for Brucella infection. These include multiple components of pathways involved in 38 central processes such as cell cycle, actin cytoskeleton dynamics or vesicular trafficking. Using 39 assays for pathogen entry, knockdown complementation and co-localization at single-cell 40 resolution, we identified the requirement of the VPS retromer for Brucella to escape the 41 lysosomal degradative pathway and to establish its intracellular replicative niche. We thus 42 validated a component of the VPS retromer as novel host factor critical for Brucella 43 intracellular trafficking. Further, our genome-wide data shed light on the interplay between 44 central host processes and the biogenesis of the Brucella replicative niche. 45 46 3 Importance 47With >300,000 new cases of human brucellosis annually, Brucella is regarded as one of the 48 most important zoonotic bacterial pathogen worldwide. The causing agent of brucellosis 49 resides inside host cells within vacuoles termed Brucella containing vacuoles (BCVs). 50Although few host components required to escape the degradative lysosomal pathway and to 51 establish the ER-derived replicative BCV (rBCV) have already been identified, the global 52 understanding of this highly coordinated process is still partial and many factors remain 53 unknown. To gain a deeper insight into these fundamental questions we performed a genome-54 wide RNA interference (RNAi) screen aiming at discovering novel host factors involved in the 55Brucella intracellular cycle. We identified 425 host proteins that contribute to Brucella cellular 56 entry, intracellular trafficking, and replication. Together, this study sheds light on previously 57 unknown host pathways required for the Brucella infection cycle and highlights the VPS 58 retromer components as critical factors for the establishment of the Brucella intracellular 59 replicative niche. 60 61 62Cellular invasion is a common strategy shared by many bacterial pathogens of human and 63 animals in order to escape host defenses and to establ...

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BrucellaIntracellular Life Relies on the Transmembrane Protein CD98 Heavy Chain

Cited by 14 publications

References 46 publications

Infection by Brucella melitensis or Brucella papionis modifies essential physiological functions of human trophoblasts

Infection by Brucella melitensis or Brucella papionis modifies essential physiological functions of human trophoblasts

Establishment of Chronic Infection: Brucella's Stealth Strategy

A role for the VPS retromer inBrucellaintracellular replication revealed by genome-wide siRNA screening

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