Neutralization of macrophage migration inhibitory factor improves host survival after Clostridium difficile infection

Jose, Shinsmon; Mukherjee, Avijit; Abhyankar, Mayuresh M.; Leng, Lin; Bucala, Richard; Sharma, Divya; Madan, Rajat

doi:10.1016/j.anaerobe.2018.06.014

Cited by 24 publications

(14 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MIF promotes secretion of inflammatory mediators leading to severe pathology (31). Recently, it was shown that MIF levels were increased after CDI both in humans and mice and that neutralization of MIF could protect mice (32). It was suggested that MIF induced a type 17 response to exaggerate CDI, and our results are consistent with this hypothesis.…”

Section: Discussionsupporting

confidence: 90%

Immune Profiling To Predict Outcome of Clostridioides difficile Infection

Abhyankar

Jennie

Scully

et al. 2020

mBio

Self Cite

View full text Add to dashboard Cite

There is a pressing need for biomarker-based models to predict mortality from and recurrence of Clostridioides difficile infection (CDI). Risk stratification would enable targeted interventions such as fecal microbiota transplant, antitoxin antibodies, and colectomy for those at highest risk. Because severity of CDI is associated with the immune response, we immune profiled patients at the time of diagnosis. The levels of 17 cytokines in plasma were measured in 341 CDI inpatients. The primary outcome of interest was 90-day mortality. Increased tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), C-C motif chemokine ligand 5 (CCL-5), suppression of tumorigenicity 2 receptor (sST-2), IL-8, and IL-15 predicted mortality by univariate analysis. After adjusting for demographics and clinical characteristics, the mortality risk (as indicated by the hazard ratio [HR]) was higher for patients in the top 25th percentile for TNF-α (HR = 8.35, P = 0.005) and IL-8 (HR = 4.45, P = 0.01) and lower for CCL-5 (HR = 0.18, P ≤ 0.008). A logistic regression risk prediction model was developed and had an area under the receiver operating characteristic curve (AUC) of 0.91 for 90-day mortality and 0.77 for 90-day recurrence. While limited by being single site and retrospective, our work resulted in a model with a substantially greater predictive ability than white blood cell count. In conclusion, immune profiling demonstrated differences between patients in their response to CDI, offering the promise for precision medicine individualized treatment. IMPORTANCE Clostridioides difficile infection is the most common health care-associated infection in the United States with more than 20% patients experiencing symptomatic recurrence. The complex nature of host-bacterium interactions makes it difficult to predict the course of the disease based solely on clinical parameters. In the present study, we built a robust prediction model using representative plasma biomarkers and clinical parameters for 90-day all-cause mortality. Risk prediction based on immune biomarkers and clinical variables may contribute to treatment selection for patients as well as provide insight into the role of immune system in C. difficile pathogenesis.

show abstract

Section: Discussionsupporting

confidence: 90%

Immune Profiling To Predict Outcome of Clostridioides difficile Infection

Abhyankar

Jennie

Scully

et al. 2020

mBio

Self Cite

View full text Add to dashboard Cite

show abstract

“…45,46 On the contrary, inhibition of neutrophil recruitment through administration of anti-CD18 (leukocyte adhesion molecule) in rabbits 47 or anti-Minflammatory protein (MIP)-2 in rats 48 leads to reduction of Toxin-Ainduced enterotoxicity. 49 Furthermore, M migration inhibitory factor (MIF) 50 and IL-17A/F 51 mediates disease severity through regulation of neutrophil infiltration and inflammation in infected mice. Hasegawa et al showed that IL-22 enhances the ability of neutrophils to kill commensal bacteria through the induction of C3 expression and deposition on pathobionts.…”

Section: Innate Immune Response During Clostridioides Difficile Infecmentioning

confidence: 99%

The adaptive immune response toClostridioides difficile: A tricky balance between immunoprotection and immunopathogenesis

Pino

Barbero

Español

et al. 2020

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Clostridioides difficile (C. difficile) is the major cause of hospital-acquired gastrointestinal infections in individuals following antibiotics treatment. The pathogenesis of C. difficile infection (CDI) is mediated mainly by the production of toxins that induce tissue damage and host inflammatory responses. While innate immunity is well characterized in human and animal models of CDI, adaptive immune responses remain poorly understood. In this review, the current understanding of adaptive immunity is summarized and its influence on pathogenesis and disease outcome is discussed. The perspectives on what we believe to be the main pending questions and the focus of future research are also provided. There is no doubt that the innate immune response provides a first line of defense to CDI. But, is the adaptive immune response a friend or a foe? Probably it depends on the course of the disease. Adaptive immunity is essential for pathogen eradication, but may also trigger uncontrolled or pathological inflammation. Most of the understanding of the role of T cells is based on findings from experimental models. While they are a very valuable tool for research studies, more studies in human are needed to translate these findings into human disease. Another main challenge is to unravel the role of the different T cell populations on protection or induction of immunopathogenesis.

show abstract

“…All animals were maintained and bred at the Department of Laboratory Animal Medicine, University of Cincinnati, under pathogen-free conditions in individually ventilated cages. In experiments performed to determine the effect of CXCR2 on neutrophil trafficking, C57BL/6 wildtype mice were fed with cefoperazone in drinking water and challenged with purified C. difficile spores (1×10 4 VPI 10463 spores per mouse) by oral gavage as previously described ( Jose et al, 2018b ). CXCR2 signaling was blocked by intraperitoneal injection of SB225002 (1mg/kg/day) for 2 days prior to CDI.…”

Section: Methodsmentioning

confidence: 99%

Leptin Receptor q223r Polymorphism Influences Clostridioides difficile Infection-Induced Neutrophil CXCR2 Expression in an Interleukin-1β Dependent Manner

Horrigan

Jose

Mukherjee

et al. 2021

Front. Cell. Infect. Microbiol.

Self Cite

View full text Add to dashboard Cite

Neutrophils are key first-responders in the innate immune response to C. difficile infection (CDI) and play a central role in disease pathogenesis. Studies have clearly shown that tissue neutrophil numbers need to be tightly regulated for optimal CDI outcomes: while excessive colonic neutrophilia is associated with severe CDI, neutrophil depletion also results in worse outcomes. However, the biological mechanisms that control CDI-induced neutrophilia remain poorly defined. C-X-C chemokine receptor 2 (CXCR2) is a chemotactic receptor that is critical in neutrophil mobilization from bone marrow to blood and tissue sites. We have previously reported that a single nucleotide polymorphism (SNP) in leptin receptor (LEPR), present in up to 50% of people, influenced CDI-induced neutrophil CXCR2 expression and tissue neutrophilia. Homozygosity for mutant LEPR (i.e. RR genotype) was associated with higher CXCR2 expression and more tissue neutrophils. Here, we investigated the biological mechanisms that regulate neutrophil CXCR2 expression after CDI, and the influence of host genetics on this process. Our data reveal that: a) CXCR2 plays a key role in CDI-induced neutrophil extravasation from blood to colonic tissue; b) plasma from C. difficile-infected mice upregulated CXCR2 on bone marrow neutrophils; c) plasma from C. difficile-infected RR mice induced a higher magnitude of CXCR2 upregulation and had more IL-1β; and d) IL-1β neutralization reduced CXCR2 expression on bone marrow and blood neutrophils and their subsequent accrual to colonic tissue. In sum, our data indicate that IL-1β is a key molecular mediator that communicates between gastro-intestinal tract (i.e. site of CDI) and bone marrow (i.e. primary neutrophil reservoir) and regulates the intensity of CDI-induced tissue neutrophilia by modulating CXCR2 expression. Further, our studies highlight the importance of host genetics in affecting these innate immune responses and provide novel insights into the mechanisms by which a common SNP influences CDI-induced neutrophilia.

show abstract

Neutralization of macrophage migration inhibitory factor improves host survival after Clostridium difficile infection

Cited by 24 publications

References 61 publications

Immune Profiling To Predict Outcome of Clostridioides difficile Infection

Immune Profiling To Predict Outcome of Clostridioides difficile Infection

The adaptive immune response toClostridioides difficile: A tricky balance between immunoprotection and immunopathogenesis

Leptin Receptor q223r Polymorphism Influences Clostridioides difficile Infection-Induced Neutrophil CXCR2 Expression in an Interleukin-1β Dependent Manner

Contact Info

Product

Resources

About