The Role of Natural Killer Cells in the Defense against &lt;i&gt;Listeria&lt;/i&gt;&lt;i&gt;monocytogenes&lt;/i&gt; Lessons from a Rat Model

Naper, Christian; Shegarfi, Hamid; Inngjerdingen, Marit; Rolstad, Bent

doi:10.1159/000324143

Cited by 16 publications

(11 citation statements)

References 146 publications

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“…m . is not an infection commonly associated with sepsis clinically, it can be used to directly probe NK-cell capacity to produce the effector cytokine IFN- γ [ 61 , 62 ]. Similar to data shown before, total numbers of NK-cells were diminished in spleens and livers of CLP hosts one day after L .…”

Section: Resultsmentioning

confidence: 99%

Polymicrobial sepsis influences NK-cell-mediated immunity by diminishing NK-cell-intrinsic receptor-mediated effector responses to viral ligands or infections

et al. 2018

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The sepsis-induced cytokine storm leads to severe lymphopenia and reduced effector capacity of remaining/surviving cells. This results in a prolonged state of immunoparalysis, that contributes to enhanced morbidity/mortality of sepsis survivors upon secondary infection. The impact of sepsis on several lymphoid subsets has been characterized, yet its impact on NK-cells remains underappreciated–despite their critical role in controlling infection(s). Here, we observed numerical loss of NK-cells in multiple tissues after cecal-ligation-and-puncture (CLP)-induced sepsis. To elucidate the sepsis-induced lesions in surviving NK-cells, transcriptional profiles were evaluated and indicated changes consistent with impaired effector functionality. A corresponding deficit in NK-cell capacity to produce effector molecules following secondary infection and/or cytokine stimulation (IL-12,IL-18) further suggested a sepsis-induced NK-cell intrinsic impairment. To specifically probe NK-cell receptor-mediated function, the activating Ly49H receptor, that recognizes the murine cytomegalovirus (MCMV) m157 protein, served as a model receptor. Although relative expression of Ly49H receptor did not change, the number of Ly49H+ NK-cells in CLP hosts was reduced leading to impaired in vivo cytotoxicity and the capacity of NK-cells (on per-cell basis) to perform Ly49H-mediated degranulation, killing, and effector molecule production in vitro was also severely reduced. Mechanistically, Ly49H adaptor protein (DAP12) activation and clustering, assessed by TIRF microscopy, was compromised. This was further associated with diminished AKT phosphorylation and capacity to flux calcium following receptor stimulation. Importantly, DAP12 overexpression in NK-cells restored Ly49H/D receptors-mediated effector functions in CLP hosts. Finally, as a consequence of sepsis-dependent numerical and functional lesions in Ly49H+ NK-cells, host capacity to control MCMV infection was significantly impaired. Importantly, IL-2 complex (IL-2c) therapy after CLP improved numbers but not a function of NK-cells leading to enhanced immunity to MCMV challenge. Thus, the sepsis-induced immunoparalysis state includes numerical and NK-cell-intrinsic functional impairments, an instructive notion for future studies aimed in restoring NK-cell immunity in sepsis survivors.

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Section: Resultsmentioning

confidence: 99%

Polymicrobial sepsis influences NK-cell-mediated immunity by diminishing NK-cell-intrinsic receptor-mediated effector responses to viral ligands or infections

et al. 2018

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“…NK cells respond to sublethal doses of L . monocytogenes during the infection of rats by an induction of IFNγ in the spleen, whereas a lethal dosis of the same pathogen leads to excessive IFNγ production in mice, which impairs granulocyte migration to the spleen and reduces Listeria clearance [ 20 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Natural Killer Cells Mediate Protection against Yersinia pseudotuberculosis in the Mesenteric Lymph Nodes

et al. 2015

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Natural killer cells play a crucial role in the initial defense against bacterial pathogens. The crosstalk between host cells infected with intracellular pathogens and NK cells has been studied intensively, but not much attention has been given to characterize the role of NK cells in the response to extracellular bacterial pathogens such as yersiniae. In this study we used antibody-mediated NK cell depletion to address the importance of this immune cell type in controlling a Y. pseudotuberculosis infection. Analysis of the bacterial counts was used to follow the infection and flow cytometry was performed to characterize the composition and dynamic of immune cells. Depletion of NK cells led to higher bacterial loads within the mesenteric lymph nodes. We further show that in particular CD11b+ CD27+ NK cells which express higher levels of the activation marker CD69 increase within the mesenteric lymph nodes during a Y. pseudotuberculosis infection. Moreover, in response to the activation NK cells secrete higher levels of IFNy, which in turn triggers the production of the proinflammatory cytokine TNFα. These results suggest, that NK cells aid in the clearance of Y. pseudotuberculosis infections mainly by triggering the expression of proinflammatory cytokines manipulating the host immune response.

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“…IFN producing conventional NK cells helps to control many infectious pathogens in the gut. Although NK cells appear to be dispensable for Listeria monocytogenes infection in mice [69], in a rat model of infection, they were essential in they were essential for early control of the bacterium [70]. Investigation of Salmonella infection in mice demonstrated that IL-15 and NK cells were required [71].…”

Section: Role Of Nk Cells In Gastrointestinal Tractmentioning

confidence: 99%

NK Cells in Mucosal Defense against Infection

Ivanova

Krempels

Ryfe

et al. 2014

BioMed Research International

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Conventional natural killer cells (NK cells) provide continual surveillance for cancer and rapid responses to infection. They develop in the bone marrow, emerge as either NK precursor cells, immature, or mature cells, and disperse throughout the body. In the periphery NK cells provide critical defense against pathogens and cancer and are noted to develop features of adaptive immune responses. In the tightly regulated and dynamic mucosal tissues, they set up residency via unknown mechanisms and from sources that are yet to be defined. Once resident, they appear to have the ability to functionally mature dependent on the mucosal tissue microenvironment. Mucosal NK cells play a pivotal role in early protection through their cytolytic function and IFNγ production against bacteria, fungi, viruses, and parasitic infections. This review presents what is known about NK cell development and phenotypes of mucosal tissue resident conventional NK cells. The question of how they come to reside in their tissues and published data on their function against pathogens during mucosal infection are discussed. Dissecting major questions highlighted in this review will be important to the further understanding of NK cell homing and functional diversity and improve rational design of NK cell based therapies against mucosal infection.

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The Role of Natural Killer Cells in the Defense against <i>Listeria</i><i>monocytogenes</i> Lessons from a Rat Model

Cited by 16 publications

References 146 publications

Polymicrobial sepsis influences NK-cell-mediated immunity by diminishing NK-cell-intrinsic receptor-mediated effector responses to viral ligands or infections

Polymicrobial sepsis influences NK-cell-mediated immunity by diminishing NK-cell-intrinsic receptor-mediated effector responses to viral ligands or infections

Natural Killer Cells Mediate Protection against Yersinia pseudotuberculosis in the Mesenteric Lymph Nodes

NK Cells in Mucosal Defense against Infection

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