Differential Roles of MyD88 and TRIF in Hematopoietic and Resident Cells During Murine Gram-Negative Pneumonia

Lieshout, Miriam H. P. van; Blok, Dana C.; Wieland, Catharina W.; Vos, Alex F. de; Veer, Cornelis van ’t; Poll, Tom van der

doi:10.1093/infdis/jis505

Cited by 20 publications

(40 citation statements)

References 28 publications

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“…As with many bacterial infections, MyD88 plays a more significant role than TRIF (170,173,174). Furthermore, the protective role of MyD88 during infection seems to be mediated through expression in both bone-marrow-derived cells and non-bone-marrow-de-rived cells, while that of TRIF is mediated through expression in bone-marrow-derived cells only (175). Mice with defective TLR4 signaling have higher K. pneumoniae CFU and greater mortality during K. pneumoniae pneumonia, indicating that TLR4 prevents mouse mortality and high bacterial loads (176)(177)(178).…”

Section: K Pneumoniae and Host Immune Defensesmentioning

confidence: 99%

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

Paczosa

Mecsas

2016

Microbiol Mol Biol Rev

1,295

1,345

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SUMMARYKlebsiella pneumoniaecauses a wide range of infections, including pneumonias, urinary tract infections, bacteremias, and liver abscesses. Historically,K. pneumoniaehas caused serious infection primarily in immunocompromised individuals, but the recent emergence and spread of hypervirulent strains have broadened the number of people susceptible to infections to include those who are healthy and immunosufficient. Furthermore,K. pneumoniaestrains have become increasingly resistant to antibiotics, rendering infection by these strains very challenging to treat. The emergence of hypervirulent and antibiotic-resistant strains has driven a number of recent studies. Work has described the worldwide spread of one drug-resistant strain and a host defense axis, interleukin-17 (IL-17), that is important for controlling infection. Four factors, capsule, lipopolysaccharide, fimbriae, and siderophores, have been well studied and are important for virulence in at least one infection model. Several other factors have been less well characterized but are also important in at least one infection model. However, there is a significant amount of heterogeneity inK. pneumoniaestrains, and not every factor plays the same critical role in all virulentKlebsiellastrains. Recent studies have identified additionalK. pneumoniaevirulence factors and led to more insights about factors important for the growth of this pathogen at a variety of tissue sites. Many of these genes encode proteins that function in metabolism and the regulation of transcription. However, much work is left to be done in characterizing these newly discovered factors, understanding how infections differ between healthy and immunocompromised patients, and identifying attractive bacterial or host targets for treating these infections.

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Section: K Pneumoniae and Host Immune Defensesmentioning

confidence: 99%

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

Paczosa

Mecsas

2016

Microbiol Mol Biol Rev

1,295

1,345

View full text Add to dashboard Cite

show abstract

“…In our previous studies on the role of TRIF during K. pneumoniae airway infection, we demonstrated that TRIF mutant mice have an impaired antibacterial defense, illustrated by a significantly higher bacterial load in the lungs, blood and spleen [8] . In these investigations, we also observed higher bacterial loads in the livers of TRIF mutant mice and TRIF bone marrow chimeras lacking TRIF in hematopoietic cells (online suppl.…”

Section: Ifn-γ Production Is Impaired In Trif Mutant Mice During Klebmentioning

confidence: 88%

“…Animals TRIF mutant mice, generated on a C57Bl/6 genetic background [22] [8,9] . The mice were sacrificed at the indicated time points after infection and their organs were harvested and processed exactly as described [8,25] .…”

Section: Methodsmentioning

confidence: 99%

“…The mice were sacrificed at the indicated time points after infection and their organs were harvested and processed exactly as described [8,25] . In the reconstitution experiment, the mice were administered 50 ng of rIFN-γ (R&D Systems, Abbington, UK) or vehicle (0.1% human serum albumin in sterile saline) intranasally 30 min before and 24 h after inoculation; they were euthanized after 48 h of infection.…”

Section: Methodsmentioning

confidence: 99%

“…We previously reported the crucial role of the TLR adaptors MyD88 and TRIF during K. pneumoniae infection and their differential contribution to the host response in different body compartments [8,9] . In these studies, we noted that mice deficient for TRIF were incapable of IFN-γ production at the primary site of infection (unpubl.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

TIR-Domain-Containing Adaptor-Inducing Interferon-β (TRIF) Mediates Antibacterial Defense during Gram-Negative Pneumonia by Inducing Interferon-γ

Lieshout

Florquin²,

Veer³

et al. 2015

J Innate Immun

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Klebsiella pneumoniae is an important cause of Gram-negative pneumonia and sepsis. Mice deficient for TIR-domain-containing adaptor-inducing interferon-β (TRIF) demonstrate enhanced bacterial growth and dissemination during Klebsiella pneumonia. We show here that the impaired antibacterial defense of TRIF mutant mice is associated with absent interferon (IFN)-γ production in the lungs. IFN-γ production by splenocytes in response to K. pneumoniae in vitro was critically dependent on Toll-like receptor 4 (TLR4), the common TLR adaptor myeloid differentiation primary response gene (MyD88) and TRIF. Reconstitution of TRIF mutant mice with recombinant IFN-γ via the airways reduced bacterial loads in lungs and distant body sites to levels measured in wild-type mice, and partially restored pulmonary cytokine levels. The IFN-γ-induced, improved, enhanced antibacterial response in TRIF mutant mice occurred at the expense of increased hepatocellular injury. These data indicate that TRIF mediates antibacterial defense during Gram-negative pneumonia, at least in part, by inducing IFN-γ at the primary site of infection.

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ASC and NLRP3 impair host defense during lethal pneumonia caused by serotype 3 Streptococcus pneumoniae in mice

et al. 2017

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Streptococcus (S.) pneumoniae is the most common cause of community-acquired pneumonia. The Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, consisting of NLRP3, ASC (the adaptor apoptosis-associated speck-like protein containing a CARD) and caspase-1, has been implicated in protective immunity during pneumonia induced by high doses of S. pneumoniae serotype 2. Here we investigated the role of the NLRP3 inflammasome in the host response during lethal airway infection with a low dose of serotype 3 S. pneumoniae. Mice were euthanized at predefined endpoints for analysis or observed in survival studies. In additional studies, Tlr2 −/− /Tlr4 −/− mice and Myd88 −/− mice incapable of Toll-like receptor signaling were studied. In stark contrast with existing literature, both Nlrp3 −/− and Asc −/− mice showed a strongly improved host defense, as reflected by a markedly reduced mortality rate accompanied by diminished bacterial growth and dissemination. Host defense was unaltered in Tlr2 −/− /Tlr4 −/− mice and Myd88 −/− mice. These results show that the NLRP3 inflammasome impairs host defense during lethal pneumonia caused by serotype 3 S. pneumoniae. Our findings challenge the current paradigm that proximal innate detection systems are indispensable for an adequate host immune response against bacteria.

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Differential Roles of MyD88 and TRIF in Hematopoietic and Resident Cells During Murine Gram-Negative Pneumonia

Abstract: MyD88- and TRIF-dependent signaling has a differential contribution to host defense in different cell types that changes from early- to late-stage gram-negative pneumonia.

Cited by 20 publications

References 28 publications

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

TIR-Domain-Containing Adaptor-Inducing Interferon-β (TRIF) Mediates Antibacterial Defense during Gram-Negative Pneumonia by Inducing Interferon-γ

ASC and NLRP3 impair host defense during lethal pneumonia caused by serotype 3 Streptococcus pneumoniae in mice

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Differential Roles of MyD88 and TRIF in Hematopoietic and Resident Cells During Murine Gram-Negative Pneumonia

Abstract: MyD88- and TRIF-dependent signaling has a differential contribution to host defense in different cell types that changes from early- to late-stage gram-negative pneumonia.

Cited by 20 publications

References 28 publications

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

TIR-Domain-Containing Adaptor-Inducing Interferon-β (TRIF) Mediates Antibacterial Defense during Gram-Negative Pneumonia by Inducing Interferon-&#947;

ASC and NLRP3 impair host defense during lethal pneumonia caused by serotype 3 Streptococcus pneumoniae in mice

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TIR-Domain-Containing Adaptor-Inducing Interferon-β (TRIF) Mediates Antibacterial Defense during Gram-Negative Pneumonia by Inducing Interferon-γ