Functional vulnerability of liver macrophages to capsules defines virulence of blood-borne bacteria

An, Haoran; Qian, Chenyun; Huang, Yijia; Tian, Xianbin; Feng, Jiaying; Hu, Jiao; Fang, Yujie; Jiao, Fangfang; Zeng, Yuna; Huang, Xueting; Meng, Xianbin; Liu, Xue; Lin, Xin; Zeng, Zhutian; Guilliams, Martin; Beck, Alain; Chen, Yongwen; Wu, Yuzhang; Wang, Jing; Oggioni, Marco R.; Leong, John M.; Veening, Jan‐Willem; Deng, Haiteng; Zhang, Rong; Wang, Hui; Jiang, Wu; Cui, Yan; Zhang, Jing-Ren

doi:10.1084/jem.20212032

Cited by 25 publications

(62 citation statements)

References 118 publications

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“…inoculation, serotype-4 pneumococci smoothly trafficked through the vasculatures of naïve mice ( Fig. 3F and 3L ; Movie S1 ), a typical feature of high-virulence pneumococci ( 29 ). In sharp contrast, migrating bacteria in the liver sinusoids of PCV13-immunized mice were predominantly accumulated to liver sinusoidal endothelial cells (ECs) (71.8% of total immobilized bacteria) and, to a less extent, to liver resident macrophage Kupffer cells (KCs) (28.2%) ( Fig.…”

Section: Resultsmentioning

confidence: 98%

“…The previous studies have demonstrated that KCs are solely responsible for capturing blood-borne bacteria ( 19–26 ), fungi ( 27 ) and parasites ( 28 ). Our recent study reveals that certain high-virulence bacterial pathogens are able to bypass KC’s surveillance in the liver and thereby cause severe bacteremia and death ( 29 ). Liver ECs are regarded as a sink for viruses in the blood due to their superior capacity to KCs in the clearance of viruses ( 30–33 ) and bacteriophages ( 34 ).…”

Section: Introductionmentioning

confidence: 99%

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Potent Bacterial Vaccines Require FcγRIIB-mediated Pathogen Capture by Liver Sinusoidal Endothelium

Wang

Ding

et al. 2022

Preprint

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Certain vaccines are more effective than others against microbial infections, but the molecular mechanisms separating the two types of vaccines are largely undefined. Here, by comparing two vaccines of Streptococcus pneumoniae with identical antigens but different efficacies (pneumococcal conjugate vaccine – PCV13 and pneumococcal polysaccharide vaccine – PPV23), we reveal that superior vaccine protection against blood-borne bacteria is primarily achieved by activating pathogen capture of the sinusoidal endothelial cells (ECs) in the liver. Consistent with its superior protection in humans, PCV13 confers a more potent protection than PPV23 against pneumococcal infection in mice. In vivo real-time imaging and genetic mutagenesis revealed that PCV13 activates both liver ECs and resident macrophages Kupffer cells (KCs) to capture IgG-coated bacteria via IgG Fc gamma receptor (FcγR). In particular, the FcγRIIB-mediated capture by ECs is responsible for PCV13-induced superior protection. In contrast, PPV23 only activates KCs (but not ECs) to achieve a less effective pathogen capture and protection through complement receptor-mediated recognition of IgM- and C3-coated bacteria. These liver-based vaccine protection mechanisms are also found with the vaccines of Neisseria meningitidis and Klebsiella pneumoniae, another two important invasive human pathogens. Our findings have uncovered a novel EC- and FcγRIIB-mediated mechanism in the liver for more efficacious vaccine protection. These findings can serve as in vivo functional readouts to evaluate vaccine efficacy and guide the future vaccine development.One Sentence SummaryVaccine efficacy is defined by FcγRIIB-mediated capture of antibody-coated bacteria via liver sinusoidal endothelial cells.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Potent Bacterial Vaccines Require FcγRIIB-mediated Pathogen Capture by Liver Sinusoidal Endothelium

Wang

Ding

et al. 2022

Preprint

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“…To assess the direct relationship between the vaccine-elicited pathogen clearance rate and host survival, we compared the PCV13-induced bacterial clearance of different vaccine-covered serotypes of pneumococci from the bloodstream. In particular, we focused on the five high-virulence (HV) serotypes (1, 3, 4, 5 and 6A) covered by PCV13 because the clearance of these serotypes highly depends on PCV13 immunization in mice 19,20 , and the rest of the eight low-virulence (LV) serotypes (6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) are effectively cleared in naïve mice 21 . We first measured CPS-specific IgG antibodies in PCV13-immunized and control mice by enzyme-linked immunosorbent assay (ELISA) because antibody titer has been used as an efficacy marker of pneumococcal polysaccharide conjugate vaccines 22,23 .…”

Section: Resultsmentioning

confidence: 99%

“…Our recent studies have shown that effective clearance of bacteria from the bloodstream in the early phase of septic infections is essential for host survival 21 , and efficient vaccination enhances such the pathogen clearance of certain encapsulated high-virulence bacteria that otherwise persist in the blood circulation 19,20 . To assess the direct relationship between the vaccine-elicited pathogen clearance rate and host survival, we compared the PCV13-induced bacterial clearance of different vaccine-covered serotypes of pneumococci from the bloodstream.…”

Section: The Clearance Rate Of Blood-borne Pneumococci Predicts the P...mentioning

confidence: 99%

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Pathogen Clearance-based Correlates of Immunoprotection Reveal Insightful Features of Vaccine Immunity

Tian

Wang

Chen

et al. 2022

Preprint

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Vaccination has significantly reduced the incidence of invasive infections caused by several bacterial pathogens, including Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. However, no vaccines are available for many other invasive pathogens. A major hurdle in vaccine development is the lack of functional markers to quantify vaccine immunity in eliminating pathogens in the process of infection. Based on our recent discovery of the liver as the major organ of vaccine-induced clearance of blood-borne virulent bacteria, we here describe a new vaccine evaluation system that quantitatively characterize important properties of effective vaccines in shuffling virulent bacteria from the blood circulation to the liver resident macrophage Kupffer cells (KCs) and sinusoidal endothelial cells (LSECs) in animal models. This system consists of three related correlates or assays: pathogen clearance from the bloodstream, pathogen trapping in the liver, and pathogen capture by KCs/LSECs. The readouts of these correlates were consistently associated with the serotype-specific immunoprotection levels of the 13-valent pneumococcal polysaccharide conjugate vaccine (PCV13) against lethal infections of S. pneumoniae, a major invasive pathogen of community-acquired infections in humans. Furthermore, these assays were able to identify a set of functional differences between two licensed PCV13 brands. Finally, the reliability and sensitivity of these correlates in reflecting vaccine efficacy were verified with whole cell vaccines of Klebsiella pneumoniae and Escherichia coli, two major pathogens in hospital-acquired invasive infections. This system may be used as cost effective readouts to evaluate the immunoprotective potential of vaccine candidates in the preclinical phase by filling the current technical gap in vaccine evaluation between the conventional in vitro approaches (e.g., antibody production and pathogen neutralization/opsonophagocytosis) and survival of immunized animals.

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Therapeutic potential of Parabacteroides distasonis in gastrointestinal and hepatic disease

Duan,

Li,

Cheng

et al. 2024

MedComm

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Increasing evidences indicate that the gut microbiota is involved in the development and therapy of gastrointestinal and hepatic disease. Imbalance of gut microbiota occurs in the early stages of diseases, and maintaining the balance of the gut microbiota provides a new strategy for the treatment of diseases. It has been reported that Parabacteroides distasonis is associated with multiple diseases. As the next‐generation probiotics, several studies have demonstrated its positive regulation on the gastrointestinal and hepatic disease, including inflammatory bowel disease, colorectal cancer, hepatic fibrosis, and fatty liver. The function of P. distasonis and its metabolites mainly affect host immune system, intestinal barrier function, and metabolic networks. Manipulation of P. distasonis with natural components lead to the protective effect on enterohepatic disease. In this review, the metabolic pathways regulated by P. distasonis are summarized to illustrate its active metabolites and their impact on host metabolism, the role and action mechanism in gastrointestinal and hepatic disease are discussed. More importantly, the natural components can be used to manipulate P. distasonis as treatment strategies, and the challenges and perspectives of P. distasonis in clinical applications are discussed.

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Functional vulnerability of liver macrophages to capsules defines virulence of blood-borne bacteria

Cited by 25 publications

References 118 publications

Potent Bacterial Vaccines Require FcγRIIB-mediated Pathogen Capture by Liver Sinusoidal Endothelium

Potent Bacterial Vaccines Require FcγRIIB-mediated Pathogen Capture by Liver Sinusoidal Endothelium

Pathogen Clearance-based Correlates of Immunoprotection Reveal Insightful Features of Vaccine Immunity

Therapeutic potential of Parabacteroides distasonis in gastrointestinal and hepatic disease

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