Essential Role of Interleukin-1 Signaling in Host Defenses Against Group B Streptococcus

Biondo, Carmelo; Mancuso, Giuseppe; Midiri, Angelina; Signorino, Giacomo; Domina, Maria; Cariccio, Veronica Lanza; Venza, Mario; Venza, Isabella; Teti, Giuseppe; Beninati, Concetta

doi:10.1128/mbio.01428-14

Cited by 45 publications

(64 citation statements)

References 49 publications

(67 reference statements)

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“…Our observation that sensing of IL-1 family cytokines contributes to inflammation in the nasopharynx following pneumococcal colonization is consistent with previous reports that IL-1␤ and IL-1 receptor signaling is important for host defense against disease states caused by other mucosal pathogens, including Staphylococcus aureus (34) and group B Streptococcus (GBS) (35). Both of these organisms trigger IL-1␤ secretion through toxin-dependent activation of the inflammasome (36,37), which drives neutrophil activation and proinflammatory cytokine production that controls infection (38,39).…”

Section: Discussionsupporting

confidence: 80%

Sensing of Interleukin-1 Cytokines during Streptococcus pneumoniae Colonization Contributes to Macrophage Recruitment and Bacterial Clearance

2015

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Streptococcus pneumoniae (the pneumococcus), a leading cause of bacterial disease, is most commonly carried in the human nasopharynx. Colonization induces inflammation that promotes the organism's growth and transmission. This inflammatory response is dependent on intracellular sensing of bacterial components that access the cytosolic compartment via the pneumococcal pore-forming toxin pneumolysin. In vitro, cytosolic access results in cell death that includes release of the proinflammatory cytokine interleukin-1␤ (IL-1␤). IL-1 family cytokines, including IL-1␤, are secreted upon activation of inflammasomes, although the role of this activation in the host immune response to pneumococcal carriage is unknown. Using a murine model of pneumococcal nasopharyngeal colonization, we show that mice deficient in the interleukin-1 receptor type 1 (Il1r1 ؊/؊ ) have reduced numbers of neutrophils early after infection, fewer macrophages later in carriage, and prolonged bacterial colonization. Moreover, intranasal administration of Il-1␤ promoted clearance. Macrophages are the effectors of clearance, and characterization of macrophage chemokines in colonized mice revealed that Il1r1 ؊/؊ mice have lower expression of the C-C motif chemokine ligand 6 (CCL6), correlating with reduced macrophage recruitment to the nasopharynx. IL-1 family cytokines are known to promote adaptive immunity; however, we observed no difference in the development of humoral or cellular immunity to pneumococcal colonization between wild-type and Il1r1 ؊/؊ mice. Our findings show that sensing of IL-1 cytokines during colonization promotes inflammation without immunity, which may ultimately benefit the pneumococcus. Streptococcus pneumoniae (the pneumococcus) is an opportunistic bacterial pathogen that is responsible for over 1 million deaths annually, mostly in children under the age of 5 years (1). The pneumococcus serially colonizes the mucosal surfaces of the human upper respiratory tract, and carriage of the organism provides the reservoir for all pneumococcal disease (2). Colonization induces airway inflammation that is characterized by a suppurative rhinitis and increased mucus secretion. These secretions promote bacterial growth (3), and inflammation is important for bacterial transmission in a viral coinfection model (4). Human studies have demonstrated that higher bacterial burdens are correlated with a more profound rhinitis (5); however, as a result of this inflammatory response, colonization is normally cleared by the host's immune system within several weeks (6).A well-defined murine model of pneumococcal colonization (7) has elucidated bacterial and host factors that are critical to immune recognition of the pneumococcus, which drives the eventual resolution of the carrier state. Although early colonization triggers the recruitment of neutrophils, these are ineffective at resolving the infection. Clearance of pneumococci from the upper airway over a period of weeks requires a sustained presence of macrophages in the nasopharynx (8). Althou...

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Section: Discussionsupporting

confidence: 80%

Sensing of Interleukin-1 Cytokines during Streptococcus pneumoniae Colonization Contributes to Macrophage Recruitment and Bacterial Clearance

2015

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“…Harvesting was repeated after 7 days using the same procedure. Murine resident peritoneal macrophages were isolated from the peritoneal cavity of WT and KO mice by washing with ice-cold DPBS, as previously described (58). Briefly, after centrifugation, cells were resuspended in RPMI 1640 supplemented with heat-inactivated 10% FCS, penicillin (50 IU/ml), and streptomycin (50 g/ml); seeded into the wells of 96-well cell culture plates (5 ϫ 10 5 per well); and incubated at 37°C with 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Nucleic Acid-Sensing Toll-Like Receptors Play a Dominant Role in Innate Immune Recognition of Pneumococci

Famà

Midiri

Mancuso

et al. 2020

mBio

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Streptococcus pneumoniae (or pneumococcus) is a highly prevalent human pathogen. Toll-like receptors (TLRs) function as immune sensors that can trigger host defenses against this bacterium. Defects in TLR-activated signaling pathways, including deficiency in the adaptor protein myeloid differentiation factor 88 (MyD88), are associated with markedly increased susceptibility to infection. However, the individual MyD88-dependent TLRs predominantly involved in antipneumococcal defenses have not been identified yet. Here we find that triple knockout mice simultaneously lacking TLR7, TLR9, and TLR13, which sense the presence of bacterial DNA (TLR9) and RNA (TLR7 and TLR13) in the phagolysosomes of phagocytic cells, display a phenotype that largely resembles that of MyD88-deficient mice and rapidly succumb to pneumococcal pneumonitis due to defective neutrophil influx into the lung. Accordingly, TLR7/9/13 triple knockout resident alveolar macrophages were largely unable to respond to pneumococci with the production of neutrophil-attracting chemokines and cytokines. Mice with single deficiencies of TLR7, TLR9, or TLR13 showed unaltered ability to control lung infection but were moderately more susceptible to encephalitis, in association with a decreased ability of microglia to mount cytokine responses in vitro. Our data point to a dominant, tissue-specific role of nucleic acid-sensing pathways in innate immune recognition of S. pneumoniae and also show that endosomal TLRs are largely capable of compensating for the absence of each other, which seems crucial to prevent pneumococci from escaping immune recognition. These results may be useful to develop novel strategies to treat infections by antibiotic-resistant pneumococci based on stimulation of the innate immune system. IMPORTANCE The pneumococcus is a bacterium that frequently causes infections in the lungs, ears, sinus cavities, and meninges. During these infections, body defenses are triggered by tissue-resident cells that use specialized receptors, such as Toll-like receptors (TLRs), to sense the presence of bacteria. We show here that pneumococci are predominantly detected by TLRs that are located inside intracellular vacuoles, including endosomes, where these receptors can sense the presence of nucleic acids released from ingested bacteria. Mice that simultaneously lacked three of these receptors (specifically, TLR7, TLR9, and TLR13) were extremely susceptible to lung infection and rapidly died after inhalation of pneumococci. Moreover, tissue-resident macrophages from these mice were impaired in their ability to respond to the presence of pneumococci by producing inflammatory mediators capable of recruiting polymorphonuclear leucocytes to infection sites. This information may be useful to develop drugs to treat pneumococcal infections, particularly those caused by antibiotic-resistant strains.

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“…IL-1β is synthesized as a precursor peptide (pro-IL-1β) that is cut to generate its mature form (mIL-1β); this process involves caspase 1, and the proenzyme (procaspase-1) requires it to be cut by the inflammasome, which is a multimeric cytosolic protein complex, composed of NLR family-pyrin domain containing 3 (NALP3) and the adapter protein containing CARD (ASC) and caspase-1; once IL-1β is cut by this complex, it binds to the IL-1R1 receptor, thus initiating the signaling that induces the expression of adhesion molecules in the endothelial cells and promotes the recruitment of neutrophils to the site of inflammation, as well as of the monocytes. It also has a potent stimulatory effect on phagocytosis, and it produces a chemotactic effect on leukocytes and induces the production of other inflammatory mediators of the lipid type, as well as other cytokines [41]. In vivo studies show that IL-1β is an important cytokine for the host defense against some microbial pathogens.…”

Section: Cytokine Profile In Bacterial Infectionsmentioning

confidence: 99%

Cytokine Profiling Plays a Crucial Role in Activating Immune System to Clear Infectious Pathogens

Muñoz‐Carrillo¹,

Contreras-Cordero²,

Gutiérrez-Coronado³

et al. 2019

Immune Response Activation and Immunomodulation

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Pathogen infections are recognized by the immune system, which consists of two types of responses: an innate immune response that recognizes pathogenassociated molecular patterns (PAMPs) and an antigen-specific adaptive immune response. In both responses, there are several activated cells of the immune system, which play a key role in establishing the environment of cytokines, thus directing their differentiation either suppressing or promoting the immune response. This immune response is crucial against pathogen infections. In this chapter, we will describe the crucial role played by different families of cytokines during activation of the immune system to eliminate infectious pathogens.

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Essential Role of Interleukin-1 Signaling in Host Defenses Against Group B Streptococcus

Cited by 45 publications

References 49 publications

Sensing of Interleukin-1 Cytokines during Streptococcus pneumoniae Colonization Contributes to Macrophage Recruitment and Bacterial Clearance

Sensing of Interleukin-1 Cytokines during Streptococcus pneumoniae Colonization Contributes to Macrophage Recruitment and Bacterial Clearance

Nucleic Acid-Sensing Toll-Like Receptors Play a Dominant Role in Innate Immune Recognition of Pneumococci

Cytokine Profiling Plays a Crucial Role in Activating Immune System to Clear Infectious Pathogens

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