Production of Type I IFN Sensitizes Macrophages to Cell Death Induced by<i>Listeria monocytogenes</i>

Stockinger, Silvia; Materna, Tilo; Stoiber, Dagmar; Bayr, Lourdes; Steinborn, Ralf; Kolbe, Thomas; Unger, Hermann; Chakraborty, Trinad; Levy, David E.; Müller, Mathias; Decker, Thomas

doi:10.4049/jimmunol.169.11.6522

Cited by 147 publications

(186 citation statements)

References 72 publications

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“…This late tyrosine phosphorylation is similar to challenges with other bacteria (e.g. Listeria monocytogenes) that do not induce IFN synthesis through direct engagement of an IFN-inducing TLR (23). Consistently, Stat1 activation proceeded independently of MyD88 and TLR2, TLR4, and TLR9 signaling, as shown by GAS infection of BMDMs from MyD88 Ϫ/Ϫ (Fig.…”

Section: Gas Activates Inflammatory Signaling Independently Of Tlr2 supporting

confidence: 54%

“…The IFN production did not require the presence of the GAS-encoded cytolysins SLO and SLS. This finding is surprising, since during infections with other Gram-positive bacteria, either the cytolysin itself or cytolysin-mediated cytoplasmic escape of bacteria from phagocytic vesicles was implicated in triggering IFN production (12,(23)(24)(25). However, the requirement for IRF3 in the IFN production suggested that other aspects of the GAS-induced IFN production resembled the well established TBK1/IRF3 signaling pathway.…”

Section: Bacterial Pathogens Are Recognized By the Innate Immune Systcontrasting

confidence: 39%

“…For the so far characterized induction of IFN-␤ production by Gram-positive bacteria, the expression of cytolysins was required (12,23,24). Cytolysins are thought to enable cytoplasmic escape of phagocytosed bacteria.…”

Section: Ifn-␣smentioning

confidence: 99%

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Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9

Gratz

Siller

Schaljo

et al. 2008

Journal of Biological Chemistry

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Bacterial pathogens are recognized by the innate immune system through pattern recognition receptors, such as Toll-like receptors (TLRs). Engagement of TLRs triggers signaling cascades that launch innate immune responses. Activation ofMAPKs and NF-B, elements of the major signaling pathways induced by TLRs, depends in most cases on the adaptor molecule MyD88. In addition, Gram-negative or intracellular bacteria elicit MyD88-independent signaling that results in production of type I interferon (IFN). Here we show that in mouse macrophages, the activation of MyD88-dependent signaling by the extracellular Gram-positive human pathogen group A streptococcus (GAS; Streptococcus pyogenes) does not require TLR2, a receptor implicated in sensing of Gram-positive bacteria, or TLR4 and TLR9. Redundant engagement of either of these TLR molecules was excluded by using TLR2/4/9 triple-deficient macrophages. We further demonstrate that infection of macrophages by GAS causes IRF3 (interferon-regulatory factor 3)-dependent, MyD88-independent production of IFN. Surprisingly, IFN is induced also by GAS lacking slo and sagA, the genes encoding cytolysins that were shown to be required for IFN production in response to other Gram-positive bacteria. Our data indicate that (i) GAS is recognized by a MyD88-dependent receptor other than any of those typically used by bacteria, and (ii) GAS as well as GAS mutants lacking cytolysin genes induce type I IFN production by similar mechanisms as bacteria requiring cytoplasmic escape and the function of cytolysins.Group A streptococcus (GAS 4 ; Streptococcus pyogenes) is an important human Gram-positive pathogen responsible for a wide spectrum of infections, ranging from mild diseases (e.g. tonsillitis) to serious illness (e.g. necrotizing fasciitis, sepsis, or severe poststreptococcal sequelae) (1). The persistence of GAS in the human population and the severity of some GAS diseases are the result of activities of a number of virulence factors that enable the pathogen to escape immune surveillance or, on contrary, induce an overreaction of the immune system (2, 3). Although GAS is generally regarded as an extracellular pathogen, recent findings suggest that GAS can survive (although not multiply) within various host cells, such as neutrophils, macrophages, epithelial cells, and fibroblasts (4 -7). The surviving bacteria may serve as a reservoir for recurrent GAS diseases.Immune responses to bacteria are initiated by recognition of bacterial components called pathogen-associated molecular patterns through host cell-encoded pattern recognition receptors (PRRs) (8, 9). Typically, pathogen-associated molecular patterns are components of the bacterial cell wall (e.g. lipopolysaccharide and lipoteichoic acid), but they may also be derived from the inside of bacteria (e.g. DNA). The primary function of PRRs is to trigger signaling cascades that activate antimicrobial defense programs. The best studied class of PRRs is the Toll-like receptor (TLR) family, which consists of 13 transmembrane glycoprote...

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Section: Gas Activates Inflammatory Signaling Independently Of Tlr2 supporting

confidence: 54%

Section: Bacterial Pathogens Are Recognized By the Innate Immune Systcontrasting

confidence: 39%

See 1 more Smart Citation

Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9

Gratz

Siller

Schaljo

et al. 2008

Journal of Biological Chemistry

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“…Surprisingly, three recent studies indicate that type I IFN signaling may actually decrease host resistance against L. monocytogenes infection (16 -18). The mechanisms underlying these detrimental effects are presently unknown, but may be related to the proapoptotic effects of Listeria-induced type I IFN (17)(18)(19).…”

mentioning

confidence: 99%

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

Mancuso

Midiri

Biondo

et al. 2007

The Journal of Immunology

223

214

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It is known that host cells can produce type I IFNs (IFN-αβ) after exposure to conserved bacterial products, but the functional consequences of such responses on the outcome of bacterial infections are incompletely understood. We show in this study that IFN-αβ signaling is crucial for host defenses against different bacteria, including group B streptococci (GBS), pneumococci, and Escherichia coli. In response to GBS challenge, most mice lacking either the IFN-αβR or IFN-β died from unrestrained bacteremia, whereas all wild-type controls survived. The effect of IFN-αβR deficiency was marked, with mortality surpassing that seen in IFN-γR-deficient mice. Animals lacking both IFN-αβR and IFN-γR displayed additive lethality, suggesting that the two IFN types have complementary and nonredundant roles in host defenses. Increased production of IFN-αβ was detected in macrophages after exposure to GBS. Moreover, in the absence of IFN-αβ signaling, a marked reduction in macrophage production of IFN-γ, NO, and TNF-α was observed after stimulation with live bacteria or with purified LPS. Collectively, our data document a novel, fundamental function of IFN-αβ in boosting macrophage responses and host resistance against bacterial pathogens. These data may be useful to devise alternative strategies to treat bacterial infections.

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“…Type I IFNs were shown to increase lymphocyte apoptosis (53,59,60), enhance macrophage cell death (61,62), antagonize IFN-g signaling by downregulating the IFNGR on APCs (63), inhibit neutrophil migration (64), and reduce the production of protective IL-12 and TNF-a (58,59). Together, these findings suggest that the bacteriuminduced type I IFNs can modulate multiple protective mechanisms to impair survival of the infected host.…”

Section: Listeriamentioning

confidence: 99%

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

Stifter¹,

Feng²

2015

The Journal of Immunology

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Type I IFNs are known to inhibit viral replication and mediate protection against viral infection. However, recent studies revealed that these cytokines play a broader and more fundamental role in host responses to infections beyond their well-established antiviral function. Type I IFN induction, often associated with microbial evasion mechanisms unique to virulent microorganisms, is now shown to increase host susceptibility to a diverse range of pathogens, including some viruses. This article presents an overview of the role of type I IFNs in infections with bacterial, fungal, parasitic, and viral pathogens and discusses the key mechanisms mediating the regulatory function of type I IFNs in pathogen clearance and tissue inflammation.

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Production of Type I IFN Sensitizes Macrophages to Cell Death Induced byListeria monocytogenes

Cited by 147 publications

References 72 publications

Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9

Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

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