The host response to infection in the critically ill

2016 ◽  
Author(s):  
W. Joost Wiersinga ◽  
Tom van der Poll
Keyword(s):  
Critically Ill ◽  
Host Response ◽  
Inflammatory Responses ◽  
Coagulation Cascade ◽  
Microbial Infection ◽  
Pathogen Invasion ◽  
New Therapeutic Approaches ◽  
Microbial Invasion ◽  
Molecular Patterns

Infection continues to be a leading cause of intensive care unit death. The host response to infection can be seen as a pattern recognition receptor (PRR)-mediated dysregulation of the immune system following pathogen invasion in which a careful balance between inflammatory and anti-inflammatory responses is vital. A measured and rapid response to microbial invasion is essential to health. The same immunological and coagulation systems that protect against localized infection can act to our disadvantage when these systems are activated systemically during generalized microbial infection. Toll-like receptors (TLR), the inflammasomes and other PRRs initiate the host response after recognition of pathogen-associated-molecular-patterns (PAMPs) or endogenous danger-associated-molecular-patterns (DAMPs). The systemic host response to infection will result in activation of coagulation, downregulation of physiological anticoagulant mechanisms, and inhibition of fibrinolysis. Further dissection of the role of host–pathogen interactions, the cytokine response, the coagulation cascade and their multidirectional interactions in sepsis should lead towards the development of new therapeutic approaches in the critically ill who are faced with infection.

Clinical Implications of Crosstalk Between Coagulation and Inflammation: The Role of Anticoagulation in Treating Sepsis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2874-2874
Author(s):  
Zhi Xu ◽  
Elizabeth Phillips ◽  
Prasanta Basak ◽  
Stephen Jesmajian
Keyword(s):  
Vitamin K ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Vitamin K Antagonist ◽  
Coagulation Cascade ◽  
Factor Vii ◽  
Clinical Implications ◽  
Factor X ◽  
All Cause Mortality

Abstract BACKGROUND: Despite decades of active investigation, sepsis remains one of the leading causes of mortality worldwide. Multiple lines of evidence have illustrated that up-regulation of the activated Factor VII (FVIIa)/Tissue Factor (TF) complex, and its downstream extrinsic coagulation cascade, are major contributors to coagulopathies and inflammatory response during sepsis. For example, decreased mortality and inflammatory responses during sepsis were observed in mice with significantly reduced FVII expression. Another recent study demonstrated the association of increased mortality with higher levels of FVIIa in septic patients. Similar results have been demonstrated for Factor X (FX) and thrombin. In addition, several studies have been conducted to investigate the role of heparin in treating sepsis and have yielded promising results, however, the exact mechanisms remain elusive, and the clinical implications of crosstalk between coagulation pathways and sepsis are yet to be determined. Furthermore, the role of vitamin-K antagonist in sepsis has not been investigated. OBJECTIVE: To assess the effects of pre-existing anticoagulation with warfarin on the clinical course of septic patient. METHODS: This was a retrospective observational study undertaken in a community-based teaching hospital. Patients who were admitted with a primary diagnosis of sepsis from January 01 to June 30, 2012 were included in the study. The clinical characteristics between patient groups without and with prior anticoagulation were compared and analyzed. The primary outcomes include the severity of sepsis, length of hospitalization, and mortality rate during hospitalization. RESULTS: A total of 134 septic patients were included in the study. Among them, 105 patients were not anticoagulated, while 29 patients were anticoagulated, prior to admission (mean age: 76.0 + 1.2 vs. 77.5 + 2.6, p = 0.603). All of the patients with anticoagulation had been taking warfarin due to either pre-existing atrial fibrillation (79.3%) or deep vein thrombosis/pulmonary embolism (20.7%). There were significant differences in International Normalized Ratio (INR) of prothrombin time between groups without and with anticoagulation at the time of admission (1.28 + 0.04 vs. 4.59 + 0.83, p < 0.001). Septic patients who did not take warfarin prior to admission presented with higher Sepsis Indices (0.93 + 0.03 vs. 0.82 + 0.05, p < 0.05), resulting in longer hospitalizations (11.60 + 1.02 vs. 8.40 + 0.70, p < 0.001). The overall all-cause mortality rates during the hospitalization between patients without anticoagulation and those with anticoagulation were 23% vs. 14%, respectively. CONCLUSION: To our knowledge, this is the first study to demonstrate that septic patients with prior anticoagulation by a vitamin-K antagonist presented with less severity of sepsis, reduced length of hospital stay, and decreased all-cause mortality during hospitalization as compared with those without anticoagulation. In our study, prior administration of anticoagulation with warfarin may have had significant clinical implications in septic patients. This warrants further prospective studies. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Role of Toll-Like Receptors in Skin Host Defense, Psoriasis, and Atopic Dermatitis

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Lixiang Sun ◽  
Wenjie Liu ◽  
Ling-juan Zhang
Keyword(s):  
Atopic Dermatitis ◽  
Human Body ◽  
Lupus Erythematosus ◽  
Mammalian Cells ◽  
Skin Diseases ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Host Responses ◽  
Molecular Patterns

As the key defense molecules originally identified in Drosophila, Toll-like receptor (TLR) superfamily members play a fundamental role in detecting invading pathogens or damage and initiating the innate immune system of mammalian cells. The skin, the largest organ of the human body, protects the human body by providing a critical physical and immunological active multilayered barrier against invading pathogens and environmental factors. At the first line of defense, the skin is constantly exposed to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), and TLRs, expressed in a cell type-specific manner by various skin cells, serve as key molecules to recognize PAMPs and DAMPs and to initiate downstream innate immune host responses. While TLR-initiated inflammatory responses are necessary for pathogen clearance and tissue repair, aberrant activation of TLRs will exaggerate T cell-mediated autoimmune activation, leading to unwanted inflammation, and the development of several skin diseases, including psoriasis, atopic dermatitis, systemic lupus erythematosus, diabetic foot ulcers, fibrotic skin diseases, and skin cancers. Together, TLRs are at the interface between innate immunity and adaptive immunity. In this review, we will describe current understanding of the role of TLRs in skin defense and in the pathogenesis of psoriasis and atopic dermatitis, and we will also discuss the development and therapeutic effect of TLR-targeted therapies.

scholarly journals Cell surface carbohydrates of symbiotic dinoflagellates and their role in the establishment of cnidarian–dinoflagellate symbiosis

2021 ◽  
Author(s):  
Giada Tortorelli ◽  
Carsten Rautengarten ◽  
Antony Bacic ◽  
Gabriela Segal ◽  
Berit Ebert ◽  
...  
Keyword(s):  
Cell Surface ◽  
Algal Cell ◽  
Algal Species ◽  
Microbial Infection ◽  
Array Technology ◽  
Lectin Array ◽  
Symbiotic Dinoflagellates ◽  
Nucleotide Sugars ◽  
Molecular Patterns

AbstractSymbiodiniaceae algae are often photosymbionts of reef-building corals. The establishment of their symbiosis resembles a microbial infection where eukaryotic pattern recognition receptors (e.g. lectins) are thought to recognize a specific range of taxon-specific microbial-associated molecular patterns (e.g. glycans). The present study used the sea anemone, Exaiptasia diaphana and three species of Symbiodiniaceae (the homologous Breviolum minutum, the heterologous-compatible Cladocopium goreaui and the heterologous-incompatible Fugacium kawagutii) to compare the surface glycomes of three symbionts and explore the role of glycan–lectin interactions in host–symbiont recognition and establishment of symbiosis. We identified the nucleotide sugars of the algal cells, then examined glycans on the cell wall of the three symbiont species with monosaccharide analysis, lectin array technology and fluorescence microscopy of the algal cell decorated with fluorescently tagged lectins. Armed with this inventory of possible glycan moieties, we then assayed the ability of the three Symbiodiniaceae to colonize aposymbiotic E. diaphana after modifying the surface of one of the two partners. The Symbiodiniaceae cell-surface glycome varies among algal species. Trypsin treatment of the alga changed the rate of B. minutum and C. goreaui uptake, suggesting that a protein-based moiety is an essential part of compatible symbiont recognition. Our data strongly support the importance of D-galactose (in particular β-D-galactose) residues in the establishment of the cnidarian–dinoflagellate symbiosis, and we propose a potential involvement of L-fucose, D-xylose and D-galacturonic acid in the early steps of this mutualism.

Innate immune receptors in type 1 diabetes: the relationship to cell death-associated inflammation

2020 ◽  
Vol 48 (3) ◽  
pp. 1213-1225 ◽  
Author(s):  
Tae Kang Kim ◽  
Myung-Shik Lee
Keyword(s):  
Innate Immunity ◽  
Type 1 Diabetes ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Innate Immune ◽  
Therapeutic Modalities ◽  
Immune Receptors ◽  
Molecular Patterns

The importance of innate immunity in host defense and inflammatory responses has been clearly demonstrated after the discovery of innate immune receptors such as Toll-like receptors (TLRs) or Nucleotide-binding oligomerization domain-containing protein (Nod)-like receptors (NLRs). Innate immunity also plays a critical role in diverse pathological conditions including autoimmune diseases such as type 1 diabetes (T1D). In particular, the role of a variety of innate immune receptors in T1D has been demonstrated using mice with targeted disruption of such innate immune receptors. Here, we discuss recent findings showing the role of innate immunity in T1D that were obtained mostly from studies of genetic mouse models of innate immune receptors. In addition, the role of innate immune receptors involved in the pathogenesis of T1D in sensing death-associated molecular patterns (DAMPs) released from dead cells or pathogen-associated molecular patterns (PAMPs) will also be covered. Elucidation of the role of innate immune receptors in T1D and the nature of DAMPs sensed by such receptors may lead to the development of new therapeutic modalities against T1D.

The role of pathogen-associated molecular patterns in inflammatory responses against alginate based microcapsules

2013 ◽  
Vol 172 (3) ◽  
pp. 983-992 ◽  
Author(s):  
Genaro A. Paredes-Juarez ◽  
Bart J. de Haan ◽  
Marijke M. Faas ◽  
Paul de Vos
Keyword(s):  
Inflammatory Responses ◽  
Molecular Patterns

scholarly journals Circulating Inflammatory Mediators in Patients with Fever: Predicting Bloodstream Infection

2001 ◽  
Vol 8 (6) ◽  
pp. 1189-1195 ◽  
Author(s):  
A. B. Johan Groeneveld ◽  
Ailko W. J. Bossink ◽  
Gerard J. van Mierlo ◽  
C. Erik Hack
Keyword(s):  
Inflammatory Mediators ◽  
Host Response ◽  
Clinical Signs ◽  
Signs And Symptoms ◽  
Blood Cultures ◽  
Peak Temperature ◽  
Microbial Infection ◽  
Microbial Invasion ◽  
Clinical Signs And Symptoms ◽  
Wbc Count

ABSTRACT The systemic host response to microbial infection involves clinical signs and symptoms of infection, including fever and elevated white blood cell (WBC) counts. In addition, inflammatory mediators are released, including activated complement product C3a, interleukin 6 (IL-6), and the acute-phase reactant secretory phospholipase A2 (sPLA2). To compare the value of the latter with the former in predicting (the degree of) microbial infection at the bedside, we determined clinical variables and took blood samples daily for 3 consecutive days in 300 patients with a new fever (>38.0°C rectally or >38.3°C axillary). Microbiological culture results for 7 days after inclusion were collected. Patients were divided into clinical and microbial categories: those without and with a clinical focus of infection and those with negative cultures, with positive local cultures or specific stains for fungal (n = 13) or tuberculous infections (n = 1), and with positive blood cultures, including one patient with malaria parasitemia. The area under the curve (AUC) of the receiver operating characteristic (ROC) for prediction of positive cultures was 0.60 (P < 0.005) for peak temperature and 0.59 (P < 0.01) for peak WBC count, 0.60 (P < 0.005) for peak C3a, 0.63 (P < 0.001) for peak IL-6, and 0.61 (P < 0.001) for peak sPLA2. The AUC under the ROC curve for prediction of positive blood cultures was 0.68 (P < 0.001) for peak temperature and 0.56 for peak WBC count (P < 0.05). The AUC for peak C3a was 0.69, that for peak IL-6 was 0.70, and that for sPLA2 was 0.67 (for all, P < 0.001). The degree of microbial invasion is thus a major determinant of the clinical and inflammatory host response in patients with fever. Moreover, circulating inflammatory mediators such as C3a and IL-6 may help to predict positive blood cultures, together with clinical signs and symptoms of the host response to microbial infection, even before culture results are available. This may help in the designing of entry criteria for therapeutic intervention studies.

scholarly journals Role of autophagy in the host response to microbial infection and potential for therapy

2011 ◽  
Vol 23 (1) ◽  
pp. 65-70 ◽  
Author(s):  
Mario Fabri ◽  
Susan E Realegeno ◽  
Eun-Kyeong Jo ◽  
Robert L Modlin
Keyword(s):  
Host Response ◽  
Microbial Infection

scholarly journals Caspase-11 regulates lung inflammation in response to house dust mites

2020 ◽  
Author(s):  
Arwa Abu khweek ◽  
Marisa R. Joldrichsen ◽  
Eunsoo Kim ◽  
Zayed Attia ◽  
Kathrin Krause ◽  
...  
Keyword(s):  
House Dust ◽  
Inflammatory Responses ◽  
Allergic Sensitization ◽  
Allergic Inflammation ◽  
House Dust Mites ◽  
Host Responses ◽  
Dust Mites ◽  
Molecular Patterns

Abstract Asthma is an inflammatory lung disorder characterized by mucus hypersecretion, cellular infiltration, and bronchial hyper-responsiveness. House dust mites (HDM) are the most prevalent cause of allergic sensitization. Canonical and noncanonical inflammasomes are multiprotein complexes that assemble in response to pathogen or danger-associated molecular patterns (PAMPs or DAMPs). Murine caspase-11 engages the noncanonical inflammasome. We addressed the role of caspase-11 in mediating host responses to HDM and subsequent allergic inflammation using caspase-11−/− mice, which lack caspase-11 while express caspase-1. We found that HDM induce caspase-11 expression in vitro. The presence of IL-4 and IL-13 promotes caspase-11 expression. Additionally, caspase-11−/− macrophages show reduced release of (KC, IL-6 and IL-12) cytokines, and express lower levels of costimulatory molecules (e.g., CD40, CD86 and MHCII) in response to HDM stimulation. Notably, HDM sensitization of caspase-11−/− mice resulted in similar levels of IgE responses and hypothermia in response to nasal HDM challenge compared to WT. However, analysis of cell numbers and cytokines in bronchiolar alveolar fluid (BALF), as well as histological lung tissue showed altered inflammatory responses and reduced neutrophilia in the airways of the caspase-11−/− mice. These findings indicate that caspase-11 regulates airway inflammation in response to HDM exposure.

Inflammatory outcomes of apoptosis, necrosis and necroptosis

2014 ◽  
Vol 395 (10) ◽  
pp. 1163-1171 ◽  
Author(s):  
Pavel Davidovich ◽  
Conor J. Kearney ◽  
Seamus J. Martin
Keyword(s):  
Cell Death ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Necrotic Cell Death ◽  
Caspase Activation ◽  
Microbial Infection ◽  
Necrotic Cell ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Pro Inflammatory Cytokines

Abstract Microbial infection and tissue injury are well established as the two major drivers of inflammation. However, although it is widely accepted that necrotic cell death can trigger or potentiate inflammation, precisely how this is achieved still remains relatively obscure. Certain molecules, which have been dubbed ‘damage-associated molecular patterns’ (DAMPs) or alarmins, are thought to promote inflammation upon release from necrotic cells. However, the precise nature and relative potency of DAMPs, compared to conventional pro-inflammatory cytokines or pathogen-associated molecular patterns (PAMPs), remains unclear. How different modes of cell death impact on the immune system also requires further clarification. Apoptosis has long been regarded as a non-inflammatory or even anti-inflammatory mode of cell death, but recent studies suggest that this is not always the case. Necroptosis is a programmed form of necrosis that is engaged under certain conditions when caspase activation is blocked. Necroptosis is also regarded as a highly pro-inflammatory mode of cell death but there has been little explicit examination of this issue. Here we discuss the inflammatory implications of necrosis, necroptosis and apoptosis and some of the unresolved questions concerning how dead cells influence inflammatory responses.

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