Lung epithelium and myeloid cells cooperate to clear acute pneumococcal infection

Dudek, Markus; Puttur, Franz; Arnold-Schrauf, Catharina; Kühl, Anja A.; Holzmann, Bernhard; Henriques‐Normark, Birgitta; Berod, Luciana; Sparwasser, Tim

doi:10.1038/mi.2015.128

Cited by 25 publications

(26 citation statements)

References 62 publications

(102 reference statements)

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“…Moreover, release of IL-12p70 and IFN-␥, which are also involved in phagocyte recruitment and potentiation of phagocytic killing (38)(39)(40)(41), was almost completely abrogated in the triple KO mice. Thus, the mechanisms underlying the hypersusceptibility of TLR7/9/13 triple KO mice to pneumonia are similar to those previously identified in MyD88-deficient mice, in which chemokine production and neutrophil recruitment to the lung were severely impaired (11). In the present study, the defects in chemokine and cytokine production observed in vivo were mirrored in vitro by impaired release of these mediators by AM and other resident macrophages after stimulation with pneumococci.…”

Section: Discussionsupporting

confidence: 87%

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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Section: Discussionsupporting

confidence: 87%

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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“…To investigate the importance of MyD88 in DCs, we next crossed ItgaxCre mice (Caton et al, 2007) or pDCre mice (Puttur et al, 2013) with MyD88 OFF mice. The mice generated from these crossings, here termed DC-MyD88 ON and pDC-MyD88 ON , reactivate Myd88 gene expression in CD11c + cells or in Siglec-H + cells, respectively, and have been carefully characterized in our previous work (Arnold-Schrauf et al, 2014;Berod et al, 2014;Dudek et al, 2016). Reactivation of MyD88 in CD11c + cells (DC-MyD88 ON ) significantly improved clearance of MCMV compared to mice that reactivated MyD88 only in a representative fraction of pDCs (pDC-MyD88 ON ) or mice that lacked MyD88 in all cells (MyD88 OFF ) ( Figures 1H and 1I).…”

Section: (Legend Continued On Next Page)mentioning

confidence: 99%

Conventional Dendritic Cells Confer Protection against Mouse Cytomegalovirus Infection via TLR9 and MyD88 Signaling

et al. 2016

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Cytomegalovirus (CMV) is an opportunistic virus severely infecting immunocompromised individuals. In mice, endosomal Toll-like receptor 9 (TLR9) and downstream myeloid differentiation factor 88 (MyD88) are central to activating innate immune responses against mouse CMV (MCMV). In this respect, the cell-specific contribution of these pathways in initiating anti-MCMV immunity remains unclear. Using transgenic mice, we demonstrate that TLR9/MyD88 signaling selectively in CD11c dendritic cells (DCs) strongly enhances MCMV clearance by boosting natural killer (NK) cell CD69 expression and IFN-γ production. In addition, we show that in the absence of plasmacytoid DCs (pDCs), conventional DCs (cDCs) promote robust NK cell effector function and MCMV clearance in a TLR9/MyD88-dependent manner. Simultaneously, cDC-derived IL-15 regulates NK cell degranulation by TLR9/MyD88-independent mechanisms. Overall, we compartmentalize the cellular contribution of TLR9 and MyD88 signaling in individual DC subsets and evaluate the mechanism by which cDCs control MCMV immunity.

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“…In order to study the specific role of MyD88 in the epithelium as well as DCs and macrophages, we used the MyD ON mouse model for Cre-mediated activation of functional MyD88. We and others have shown that this model allows the precise study of direct consequences of cell type-specific TLR-mediated signaling on the immune response [27,30,[36][37][38][39]. This gain-offunction model enabled us, as demonstrated previously, to restrict functional MyD88 signaling to the intestinal epithelium or CD11c + MNPs, encompassing both DCs and macrophages in intestinal tissues, while all other cells and tissues of the body remain deficient for MyD88 [30].…”

Section: Discussionmentioning

confidence: 66%

Epithelium‐specific MyD88 signaling, but not DCs or macrophages, control acute intestinal infection with Clostridium difficile

et al. 2019

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Infection with Clostridium difficile is one of the major causes of health care acquired diarrhea and colitis. Signaling though MyD88 downstream of TLRs is critical for initiating the early protective host response in mouse models of C. difficile infection (CDI). In the intestine, MyD88 is expressed in various tissues and cell types, such as the intestinal epithelium and mononuclear phagocytes (MNP), including DC or macrophages. Using a genetic gain‐of‐function system, we demonstrate here that restricting functional MyD88 signaling to the intestinal epithelium, but also to MNPs is sufficient to protect mice during acute CDI by upregulation of the intestinal barrier function and recruitment of neutrophils. Nevertheless, we also show that mice depleted for CD11c‐expressing MNPs in the intestine display no major defects in mounting an effective inflammatory response, indicating that the absence of these cells is irrelevant for inducing host protection during acute infection. Together, our results highlight the importance of epithelial‐specific MyD88 signaling and demonstrate that although functional MyD88 signaling in DC and macrophages alone is sufficient to correct the phenotype of MyD88‐deficiency, these cells do not seem to be essential for host protection in MyD88‐sufficient animals during acute infection with C. difficile.

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Lung epithelium and myeloid cells cooperate to clear acute pneumococcal infection

Cited by 25 publications

References 62 publications

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

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

Conventional Dendritic Cells Confer Protection against Mouse Cytomegalovirus Infection via TLR9 and MyD88 Signaling

Epithelium‐specific MyD88 signaling, but not DCs or macrophages, control acute intestinal infection with Clostridium difficile

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