Decreased Expression of the Fractalkine Receptor CX3CR1 on Circulating Monocytes as New Feature of Sepsis-Induced Immunosuppression

Pachot, Alexandre; Cazalis, Marie-Angélique; Venet, Fabienne; Turrel, Fanny; Faudot, Caroline; Voirin, Nicolas; Diasparra, Jennifer; Bourgoin, Naïck; Poitevin, Françoise; Mougin, Bruno; Lepape, Alain; Monneret, Guillaume

doi:10.4049/jimmunol.180.9.6421

Cited by 108 publications

(104 citation statements)

References 63 publications

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“…CX3CR1 mRNA is downregulated in PBMCs from MARV-exposed animals at the late stage of infection. Studies of patients succumbing to septic shock found that CX3CR1 downregulation at both the mRNA and protein levels was associated with poor prognosis and immune exhaustion (32,39). Our results suggest that this downregulation also occurs in Marburg virus infection and that CX3CR1 levels could be monitored in Marburg virus-infected patients as a prognostic marker.…”

Section: Discussionmentioning

confidence: 75%

“…Interestingly, transcripts of the fractalkine receptor CX3CR1 were upregulated early (day 1 through 5) during MARV infection and were significantly down-modulated during late-stage disease (Fig. 5C), a behavior similar to its downregulation in sepsis patients (32). Appearance of Th2-associated cytokines.…”

Section: Evidence Of An Early Innate Immune Response In Marv-infectedmentioning

confidence: 82%

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Transcriptional Profiling of the Immune Response to Marburg Virus Infection

Connor

Yen

Caballero

et al. 2015

J Virol

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Marburg virus is a genetically simple RNA virus that causes a severe hemorrhagic fever in humans and nonhuman primates. The mechanism of pathogenesis of the infection is not well understood, but it is well accepted that pathogenesis is appreciably driven by a hyperactive immune response. To better understand the overall response to Marburg virus challenge, we undertook a transcriptomic analysis of immune cells circulating in the blood following aerosol exposure of rhesus macaques to a lethal dose of Marburg virus. Using two-color microarrays, we analyzed the transcriptomes of peripheral blood mononuclear cells that were collected throughout the course of infection from 1 to 9 days postexposure, representing the full course of the infection. The response followed a 3-stage induction (early infection, 1 to 3 days postexposure; midinfection, 5 days postexposure; late infection, 7 to 9 days postexposure) that was led by a robust innate immune response. The host response to aerosolized Marburg virus was evident at 1 day postexposure. Analysis of cytokine transcripts that were overexpressed during infection indicated that previously unanalyzed cytokines are likely induced in response to exposure to Marburg virus and further suggested that the early immune response is skewed toward a Th2 response that would hamper the development of an effective antiviral immune response early in disease. Late infection events included the upregulation of coagulation-associated factors. These findings demonstrate very early host responses to Marburg virus infection and provide a rich data set for identification of factors expressed throughout the course of infection that can be investigated as markers of infection and targets for therapy. IMPORTANCEMarburg virus causes a severe infection that is associated with high mortality and hemorrhage. The disease is associated with an immune response that contributes to the lethality of the disease. In this study, we investigated how the immune cells circulating in the blood of infected primates respond following exposure to Marburg virus. Our results show that there are three discernible stages of response to infection that correlate with presymptomatic, early, and late symptomatic stages of infection, a response format similar to that seen following challenge with other hemorrhagic fever viruses. In contrast to the ability of the virus to block innate immune signaling in vitro, the earliest and most sustained response is an interferon-like response. Our analysis also identifies a number of cytokines that are transcriptionally upregulated during late stages of infection and suggest that there is a Th2-skewed response to infection. When correlated with companion data describing the animal model from which our samples were collected, our results suggest that the innate immune response may contribute to overall pathogenesis.

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Section: Discussionmentioning

confidence: 75%

Section: Evidence Of An Early Innate Immune Response In Marv-infectedmentioning

confidence: 82%

Transcriptional Profiling of the Immune Response to Marburg Virus Infection

Connor

Yen

Caballero

et al. 2015

J Virol

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“…The gene most highly expressed in survivors, relative to non-survivors, was that encoding the chemokine receptor CX3CR1 (fractalkine receptor). In a subsequent validation study, these same investigators provided further evidence supporting the novel concept that dysregulation of CX3CR1 in monocytes contributes to immune-paralysis in human sepsis [52]. These studies further demonstrate the potential to discover novel pathways through discovery-oriented expression profiling.…”

Section: Discovery Of Novel Targets and Pathwaysmentioning

confidence: 76%

“…Theoretically, any gene that is consistently differentially regulated between survivors and non-survivors in a microarray dataset may warrant further investigation as a potential outcome biomarker. For example, a microarray study by Pachot and colleagues [27,52] identified CX3CR1 (fractalkine receptor) as a potential outcome biomarker in sepsis. Similarly, Nowak and colleagues [53] have leveraged microarray data to identify chemokine (C-C motif) ligand 4 (CCL4) as an outcome biomarker in children with septic shock.…”

Section: Biomarker Discoverymentioning

confidence: 99%

Clinical review: Sepsis and septic shock - the potential of gene arrays

Wong

2012

Critical Care

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Over the past decade several investigators have applied microarray technology and related bioinformatic approaches to clinical sepsis and septic shock, thus allowing for an assessment of how, or if, this branch of genomic medicine has meaningfully impacted the field of sepsis research. The ability to simultaneously and efficiently measure the steady-state mRNA abundance of thousands of transcripts from a given tissue source (that is, 'transcriptomics') has provided an unprecedented opportunity to gain a broader, genome-level 'picture' of complex and heterogeneous clinical syndromes such as sepsis. A trancriptomic approach to sepsis and septic shock is technically challenging on multiple levels, but nonetheless modest, tangible advances are being realized. These include a genome-level understanding of the complexity of sepsis and septic shock, identification of novel candidate pathways and targets for potential intervention, discovery of novel, candidate diagnostic and stratification biomarkers, and the ability to stratify patients into clinically relevant, expression-based subclasses. The challenges moving forward include robust validation studies, standardization of technical approaches, standardization and further development of analytical algorithms, and large-scale collaborations.

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“…Similarly, acute HIV infection has also been associated with a dramatic increase in IL-8 (CXCR1 ligand) in both plasma [52,53] and lymphoid tissues [54], also potentially driving the recruitment of CXCR1 1 lymphocytes to the sites of infection or inflamed tissues [55]. However, several studies have demonstrated that persistent expression of IL-8 or fractalkine results in the internalization and downregulation of CXCR1 [56,57] and CX 3 CR1 [58] in multiple inflammatory conditions. Thus, it is likely that elevated expression of these chemokine receptor ligands during HIV infection may result in the downregulation of their receptors on NK cells, in an effort to regulate cytolytic lymphocyte recruitment to tissues.…”

Section: Discussionmentioning

confidence: 99%

Early viral replication in lymph nodes provides HIV with a means by which to escape NK‐cell‐mediated control

et al. 2011

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Acute HIV infection is marked by dramatic viral replication associated with preferential replication within secondary lymphoid tissues, such as lymph nodes (LNs), that is rapidly but incompletely contained to a viral setpoint. Accumulating evidence supports a role for natural killer (NK) cells in the early control of HIV infection; however, little is known about the location of their antiviral control. Given that HIV replicates profusely in LNs during early infection, we sought to define whether changes occurred in the NK cell infiltrate within these sites during the first year of HIV infection. Surprisingly, NK cell numbers and distribution were unaltered during early HIV infection. LN NK cells expressed decreased inhibitory receptors, were more highly activated, and expressed elevated TRAIL, potentially conferring a superior capacity for NK cells to become activated and control infection. Most noticeably, KIR+ NK cells were rarely detected in the LN during HIV infection, associated with diminished migratory capacity in the setting of reduced expression of CX3CR1 and CXCR1. Thus, incomplete control of HIV viral replication during early disease may be due to the inefficient recruitment of KIR+ NK cells to this vulnerable site, providing HIV a niche where it can replicate unabated by early NK‐cell‐mediated innate pressure.

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Decreased Expression of the Fractalkine Receptor CX3CR1 on Circulating Monocytes as New Feature of Sepsis-Induced Immunosuppression

Cited by 108 publications

References 63 publications

Transcriptional Profiling of the Immune Response to Marburg Virus Infection

Transcriptional Profiling of the Immune Response to Marburg Virus Infection

Clinical review: Sepsis and septic shock - the potential of gene arrays

Early viral replication in lymph nodes provides HIV with a means by which to escape NK‐cell‐mediated control

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