Activation of IFN-γ/STAT/IRF-1 in Hepatic Responses to Klebsiella pneumoniae Infection

Lin, Yi Chun; Lü, Min; Lin, Chi‐Tsai; Chiang, Ming Ko; Jan, Ming‐Shiou; Tang, Hui Ling; Liu, Hsu Chung; Lin, Wea Lung; Huang, Chih Yang; Chen, Chuan-Mu; Lai, Yi‐Chyi

doi:10.1371/journal.pone.0079961

Cited by 19 publications

(16 citation statements)

References 53 publications

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“…Indeed, in L-78 infection, the levels of procaspase-3 were significantly reduced at the early stages pi indicating activation of caspase-3, whereas in the ATCC 43816 model, procaspase-3 levels decreased less. In agreement with the study of Lin [ 20 ], who also showed that activated caspase-3 was significantly elevated in murine liver lysates upon K. pneumoniae infection, our results suggest that L-78 infection massively induces caspase-3-mediated apoptosis at early stages pi in vivo .…”

Section: Discussionsupporting

confidence: 93%

A fragment of the alarmin prothymosin α as a novel biomarker in murine models of bacteria-induced sepsis

et al. 2017

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Sepsis is a life-threatening condition that requires urgent care. Thus, the identification of specific and sensitive biomarkers for its early diagnosis and management are of clinical importance. The alarmin prothymosin alpha (proTα) and its decapeptide proTα(100-109) are immunostimulatory peptides related to cell death. In this study, we generated bacterial models of sepsis in mice using two Klebsiella pneumoniae strains (L-78 and ATCC 43816) and monitored sepsis progression using proTα(100-109) as a biomarker. Serum concentration of proTα(100-109) gradually increased as sepsis progressed in mice infected with L-78, a strain which, unlike ATCC 43816, was phagocytosed by monocytes/macrophages. Analysis of splenocytes from L-78-infected animals revealed that post-infection spleen monocytes/macrophages were gradually driven to caspase-3-mediated apoptosis. These results were verified in vitro in L-78-infected human monocytes/macrophages. Efficient phagocytosis of L-78 by monocytes stimulated their apoptosis and the concentration of proTα(100-109) in culture supernatants increased. Human macrophages strongly phagocytosed L-78, but resisted cell death. This is the first report suggesting that high levels of proTα(100-109) correlate, both in vitro and in vivo, with increased percentages of cell apoptosis. Moreover, we showed that low levels of proTα(100-109) early post-infection likely correlate with sepsis resolution and thus, the decapeptide could eventually serve as an early surrogate biomarker for predicting bacteria-induced sepsis outcome.

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Section: Discussionsupporting

confidence: 93%

A fragment of the alarmin prothymosin α as a novel biomarker in murine models of bacteria-induced sepsis

et al. 2017

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“…Similarly, we detected greater production of inflammatory cytokines TNF-␣ and IL-6 in Kupffer cells infected with hvKp strain SGH4. A previous study in an oral infection mouse model to simulate KLA also found a proinflammatory response in the liver (34).…”

Section: Discussionmentioning

confidence: 75%

Protective Role of Kupffer Cells and Macrophages in Klebsiella pneumoniae-Induced Liver Abscess Disease

2019

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Klebsiella pneumoniae-induced liver abscess (KLA) is emerging as a leading cause of pyogenic liver abscess worldwide. In recent years, the emergence of hypervirulent K. pneumoniae (hvKp) has been strongly associated with KLA. Unlike classical K. pneumoniae, which generally infects the immunocompromised population, hvKp can cause serious and invasive infections in young and healthy individuals. hvKp isolates are often associated with the K1/K2 capsular types and possess hypermucoviscous capsules. KLA is believed to be caused by K. pneumoniae colonizing the gastrointestinal tract of the host and translocating across the intestinal barrier via the hepatic portal vein into the liver to cause liver abscess. We optimized the isolation of the liver-resident macrophages called Kupffer cells in mice and examined their importance in controlling bacterial loads during hvKp infection in healthy mice. Our study reveals the high capability of Kupffer cells to kill hvKp in vitro despite the presence of the bacterial hypermucoviscous capsule, in contrast to other macrophages, which were unable to phagocytose the bacteria efficiently. Depletion of Kupffer cells and macrophages with liposome-encapsulated clodronate (liposomal clodronate) in both an intraperitoneal and an oral mouse infection model resulted in increased bacterial loads in the livers, spleens, and lungs and increased mortality of the infected mice. Thus, Kupffer cells and macrophages are critical for the control of hvKp infection.

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“…An intestinal portal of entry has been suggested for the development of invasive infections, such as liver abscess and meningitis, by hypervirulent K. pneumoniae strains (Tu et al, 2009 ; Fung et al, 2012 ; Lin et al, 2013 ; Hsu et al, 2015 ). To examine whether colibactin contributed to the development of invasive infections caused by K. pneumoniae 1084 via the intestinal route, we used 1 × 10 9 CFU of K. pneumoniae 1084S, ΔClbA (the clbA deletion mutant of 1084S), and ΔClbA_pC (ΔClbA complemented with pYC502, the clbA -containing plasmid) to challenge groups of BALB/c mice via an orogastric inoculation route.…”

Section: Resultsmentioning

confidence: 99%

Colibactin Contributes to the Hypervirulence of pks+ K1 CC23 Klebsiella pneumoniae in Mouse Meningitis Infections

Chen

Chiang

et al. 2017

Front. Cell. Infect. Microbiol.

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Klebsiella pneumoniae is the most common pathogen of community-acquired meningitis in Taiwan. However, the lack of a physiologically relevant meningitis model for K. pneumoniae has impeded research into its pathogenesis mechanism. Based on the core genome MLST analyses, the hypervirulent K1 K. pneumoniae strains, which are etiologically implicated in adult meningitis, mostly belong to a single clonal complex, CC23. Some K1 CC23 K. pneumoniae strains carry a gene cluster responsible for colibactin production. Colibactin is a small genotoxic molecule biosynthesized by an NRPS-PKS complex, which is encoded by genes located on the pks island. Compared to other hypervirulent K. pneumoniae which primarily infect the liver, the colibactin-producing (pks+) K1 CC23 strains had significant tropism toward the brain of BALB/c mice. We aimed in this study to develop a physiologically relevant meningitis model with the use of pks+ K1 CC23 K. pneumoniae. Acute meningitis was successfully induced in adult BALB/c male mice through orogastric, intranasal, and intravenous inoculation of pks+ K1 CC23 K. pneumoniae. Besides the typical symptoms of bacterial meningitis, severe DNA damages, and caspase 3-independent cell death were elicited by the colibactin-producing K1 CC23 K. pneumoniae strain. The deletion of clbA, which abolished the production of colibactin, substantially hindered K. pneumoniae hypervirulence in the key pathogenic steps toward the development of meningitis. Our findings collectively demonstrated that colibactin was necessary but not sufficient for the meningeal tropism of pks+ K1 CC23 K. pneumoniae, and the mouse model established in this study can be applied to identify other virulence factors participating in the development of this life-threatening disease.

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Activation of IFN-γ/STAT/IRF-1 in Hepatic Responses to Klebsiella pneumoniae Infection

Cited by 19 publications

References 53 publications

A fragment of the alarmin prothymosin α as a novel biomarker in murine models of bacteria-induced sepsis

A fragment of the alarmin prothymosin α as a novel biomarker in murine models of bacteria-induced sepsis

Protective Role of Kupffer Cells and Macrophages in Klebsiella pneumoniae-Induced Liver Abscess Disease

Colibactin Contributes to the Hypervirulence of pks+ K1 CC23 Klebsiella pneumoniae in Mouse Meningitis Infections

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