scholarly journals MODIFICATION OF HOST RESPONSES TO BACTERIAL ENDOTOXINS

1965 ◽  
Vol 121 (5) ◽  
pp. 751-759 ◽  
Author(s):  
Yoon Berm Kim ◽  
Dennis W. Watson
Keyword(s):  
Standard Dose ◽  
Endotoxin Tolerance ◽  
Immunologic Tolerance ◽  
Host Responses ◽  
Immune Mechanism ◽  
Immunoelectrophoretic Analysis ◽  
Specific Antibodies ◽  
Bacterial Endotoxins ◽  
Exclusion Chromatography

Serum from rabbits rendered tolerant or immune to 100 MPD-3/kg of endotoxin when passively transferred to normal rabbits gave partial tolerance to the standard dose of endotoxin. The same serum was fractionated by DEAE chromatography into 4 major fractions. Immunoelectrophoretic analysis indicated that the 7S γ2-and the 19S γ1-immunoglobulins were separated into two distinct fractions. Of the four fractions tested, only fraction IV containing 19S γ1-immunoglobulm conferred complete pyrogenic tolerance to 100 MPD-3/kg of endotoxin. Additional fractionation of DEAE fraction IV by exclusion chromatography on sephadex G-200 gave 3 fractions. Of these only the first, containing 19S γ1-immunoglobulin conferred complete pyrogenic and lethal tolerance to normal rabbits. There was no correlation between the quantity of O-specific antibodies and the ability to transfer tolerance. It is concluded that endotoxin tolerance involves a classical immune mechanism which includes both 19S γ1-immunoglobulin specific for toxophore groups common to many endotoxins and a normally functioning RES. To avoid confusion with immunologic tolerance, it is suggested that the term endotoxin immunity be substituted for endotoxin tolerance.

scholarly journals MODIFICATION OF HOST RESPONSES TO BACTERIAL ENDOTOXINS

1963 ◽  
Vol 118 (3) ◽  
pp. 425-446 ◽  
Author(s):  
Dennis W. Watson ◽  
Yoon Berm Kim
Keyword(s):  
Lipid A ◽  
Biological Activities ◽  
Endotoxin Tolerance ◽  
Host Responses ◽  
Antigenic Determinants ◽  
Cross Tolerance ◽  
Anamnestic Response ◽  
Immunological Mechanism ◽  
Bacterial Endotoxins ◽  
Highly Sensitive

Evidence is presented suggesting that the apparent non-specificity of pyrogenic tolerance observed with Gram-negative bacterial endotoxins is due to related antigenic determinants associated with the macromolecular toxins. This is based on results obtained in rabbits from pyrogenic cross-tolerance tests with selected endotoxins. In these tests, purified endotoxins from Escherichia coli (COO8) and Chromobacterium violaceum (CV) gave results one might expect with non-reciprocal cross-reacting antigens in classical immune systems. Additional evidence for an immune mechanism in tolerance is suggested by the highly significant anamnestic response observed. Lipid A, a toxic derivative of the purified COO8 endotoxin, failed to induce pyrogenic tolerance against the parent toxin. These results are explained by assuming that endotoxins have two interdependent activities associated with different portions of the macromolecule; one is assumed to be responsible for the primary toxicity, and the other is involved in secondary toxicity. The latter is dependent on the hypersensitive state of the host. Additional evidence for the role of hypersensitivity in secondary toxicity is based on the observation that adult rabbits are highly sensitive to the pyrogenic, lethal, and skin-reacting activities of endotoxin in contrast to young animals which are more resistant to all of these attributes of toxicity. In adults, the host responses to pyrogenicity, lethality, and skin reactivity could be partially inhibited by the early exposure of the animals to massive doses of endotoxin equivalent to a LD50. The pyrogenic tolerance shown in these animals was specific indicating that the inhibition of the hypersusceptibility to endotoxin involved an immunological mechanism. A mechanism of endotoxin tolerance is proposed and discussed based on the induction of specific antibodies capable of assisting the RES in the clearance and destruction of endotoxin. It is suggested that the present inconsistencies relative to the chemical nature and biological activities of endotoxins might be explained on the basis of these two activities and the failure to recognize the importance of the immunological state of the host in which the toxins are tested.

scholarly journals Biofilm Growth Increases Phosphorylcholine Content and Decreases Potency of Nontypeable Haemophilus influenzae Endotoxins

2006 ◽  
Vol 74 (3) ◽  
pp. 1828-1836 ◽  
Author(s):  
Shayla West-Barnette ◽  
Andrea Rockel ◽  
W. Edward Swords
Keyword(s):  
Haemophilus Influenzae ◽  
Inflammatory Responses ◽  
Opportunistic Pathogen ◽  
Host Responses ◽  
Toll Like Receptor ◽  
Nontypeable Haemophilus Influenzae ◽  
Toll Like Receptor 4 ◽  
Biofilm Growth ◽  
Bacterial Endotoxins ◽  
Cell Layers

ABSTRACT Nontypeable Haemophilus influenzae (NTHI) is a common respiratory commensal and opportunistic pathogen. NTHI is normally contained within the airways by host innate defenses that include recognition of bacterial endotoxins by Toll-like receptor 4 (TLR4). NTHI produces lipooligosaccharide (LOS) endotoxins which lack polymeric O side chains and which may contain host glycolipids. We recently showed that NTHI biofilms contain variants with sialylated LOS glycoforms that are essential to biofilm formation. In this study, we show that NTHI forms biofilms on epithelial cell layers. Confocal analysis revealed that sialylated variants were distributed throughout the biofilm, while variants expressing phosphorylcholine (PCho) were found within the biofilm. Consistent with this observation, PCho content of LOS purified from NTHI biofilms was increased compared to LOS from planktonic cultures. Hypothesizing that the observed changes in endotoxin composition could affect bioactivity, we compared inflammatory responses to NTHI LOS purified from biofilm and planktonic cultures. Our results show that endotoxins from biofilms induced weaker host innate responses. While we observed a minimal effect of sialylation on LOS bioactivity, there was a significant decrease in bioactivity associated with PCho substitutions. We thus conclude that biofilm growth increases the proportion of PCho+ variants in an NTHI population, resulting in a net decrease in LOS bioactivity. Thus, in addition to their well-documented resistance phenotypes, our data show that biofilm communities of NTHI bacteria contain variants that evoke less potent host responses.

scholarly journals SIMILARITY OF HOST RESPONSES ELICITED BY POLYSACCHARIDES OF ANIMAL AND PLANT ORIGIN AND BY BACTERIAL ENDOTOXINS

1957 ◽  
Vol 106 (1) ◽  
pp. 77-97 ◽  
Author(s):  
Maurice Landy ◽  
Murray J. Shear ◽  
Keyword(s):  
Host Responses ◽  
Mouse Tissue ◽  
Rabbit Skin ◽  
Biological Phenomena ◽  
Hemorrhagic Necrosis ◽  
Bacterial Endotoxins ◽  
Shwartzman Reaction ◽  
Sarcoma 37 ◽  
Kidney Liver ◽  
Plant Sources

Ten polysaccharides, isolated from various animal and plant sources, were selected for comparison with 2 bacterial polysaccharides, typical of Gram-negative endotoxins. The tissue sources were: mouse (kidney, liver, lung, stomach, Sarcoma 37, and Carcinoma 241-6); rabbit skin and chick embryo skin; and tangerine and Bryonia root. The bacterial endotoxins were those of S. typhosa and Serr. marcescens. Their relative potency was determined in inducing the following host effects: fever, tolerance to pyrogenic action, leucocytic changes, the Shwartzman reaction, damage to Sarcoma 37, dermal hemorrhagic-necrosis by epinephrine, enhancement of antibody production, and lethality. Some of the polysaccharides were consistently active in all the host reactions studied; except for pyrogenic activity at high dosage, the other polysaccharides were consistently negative throughout. The mouse tissue polysaccharides elicited all the effects studied; in some instances their potency approached those of the bacterial polysaccharides. It is pointed out that elicitation of the above array of biological phenomena, hitherto considered characteristic of bacterial endotoxins, can be obtained with polysaccharides from animal and plant tissues.

Hybridization by Deoxycholate Treatment or by Biological Degradation of Bacterial Endotoxins Extracted from Smooth and Rough Strains

1970 ◽  
Vol 1 (1) ◽  
pp. 15-20
Author(s):  
L. Chedid ◽  
M. Parant ◽  
F. Parant ◽  
F. Peroux ◽  
J. J. Perez
Keyword(s):  
Sodium Deoxycholate ◽  
Salmonella Typhi ◽  
Side Chains ◽  
Biological Degradation ◽  
Specific Antibodies ◽  
Electrophoretic Migration ◽  
Bacterial Endotoxins ◽  
Phenol Water ◽  
Smooth Strain

An endotoxin extracted with phenol-water from a rough microorganism ( Salmonella typhi strain R 2 ) was hybridized with an endotoxin obtained by the Boivin technique from a smooth strain ( S. enteritidis Danysz) when they were mixed in the presence of sodium deoxycholate. These two toxic antigens could also be hybridized by incubation in citrated serum. With this new composite molecule, the presence of the hydrophilic side chains on the smooth moiety influenced the electrophoretic migration of the R antigen and greatly hindered the reactivity of the R sites with their specific antibodies.

Role of bacterial endotoxins of intestinal origin in rat heat stress mortality

1983 ◽  
Vol 54 (1) ◽  
pp. 31-36 ◽  
Author(s):  
D. A. DuBose ◽  
K. Basamania ◽  
L. Maglione ◽  
J. Rowlands
Keyword(s):  
Heat Stress ◽  
Bacterial Count ◽  
Endotoxin Tolerance ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Bacterial Endotoxins ◽  
Intestinal Origin ◽  
Heat Stress Resistance ◽  
Resistance To Heat

Using unanesthetized rats, the effect on heat stress mortality of endotoxin tolerance or zymosan treatment was determined. In addition, the incidence of invasion by gram-negative bacteria and their endotoxins was studied to evaluate the role of gut-derived bacterial endotoxins after heat stress. Endotoxin tolerance resulted in heat stress resistance. The estimated mean total thermal area, which induced an LD50 in endotoxin-tolerant rats (61.85 degrees C . min) was significantly greater (P less than 0.001) than that for non-tolerant rats (44.03 degrees C . min). Rats were significantly (P less than 0.005) more sensitive to endotoxin after zymosan treatment, but this treatment did not alter the heat stress mortality rate. The Limulus amoebocyte lysate test indicated that endotoxemia did not occur as a result of heat stress. Though a significantly increased incidence of high gram-negative bacterial count in the duodenum was noted, extraintestinal invasion was not found. It was concluded that resistance to heat stress may not be due to protection from gut-derived bacterial endotoxins, but resistance may possibly be associated with the ability of endotoxin tolerance to protect from shock syndromes. Thus bacterial endotoxins of intestinal origin did not appear to have a significant role in rat heat stress mortality.

scholarly journals Opsonization by non-neutralizing antibodies can confer protection to SARS-CoV-2 despite Spike-dependent modulation of phagocytosis

2021 ◽  
Author(s):  
Wael Bahnan ◽  
Sebastian Wrighton ◽  
Martin Sundwall ◽  
Anna Bläckberg ◽  
Olivia Larsson ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Antibody Binding ◽  
Spike Protein ◽  
Infection Model ◽  
Immune Functions ◽  
Immune Mechanism ◽  
Neutralization Potential ◽  
Specific Antibodies ◽  
Low Levels

Spike-specific antibodies are central to effective COVID19 immunity. Research efforts have focused on antibodies that neutralize the ACE2-Spike interaction but not on non-neutralizing antibodies. Antibody-dependent phagocytosis is an immune mechanism enhanced by opsonization, where typically, more bound antibodies trigger a stronger phagocyte response. Here, we show that Spike-specific antibodies, dependent on concentration, can either enhance or reduce Spike-bead phagocytosis by monocytes independently of the antibody neutralization potential. Surprisingly, we find that both convalescent patient plasma and patient-derived monoclonal antibodies lead to maximum opsonization already at low levels of bound antibodies and is reduced as antibody binding to Spike protein increases. Moreover, we show that this Spike-dependent modulation of opsonization seems to affect the outcome in an experimental SARS-CoV-2 infection model. These results suggest that the levels of anti-Spike antibodies could influence monocyte-mediated immune functions and propose that non-neutralizing antibodies could confer protection to SARS-CoV-2 infection by mediating phagocytosis.

scholarly journals Immunologic perturbations in severe COVID-19/SARS-CoV-2 infection

2020 ◽  
Author(s):  
Leticia Kuri-Cervantes ◽  
M. Betina Pampena ◽  
Wenzhao Meng ◽  
Aaron M. Rosenfeld ◽  
Caroline A.G. Ittner ◽  
...  
Keyword(s):  
B Cells ◽  
Critical Illness ◽  
B Cell ◽  
Nk Cells ◽  
Peripheral Blood ◽  
Host Responses ◽  
Cell Populations ◽  
T And B Cells ◽  
Specific Antibodies ◽  
Immune Correlates

AbstractAlthough critical illness has been associated with SARS-CoV-2-induced hyperinflammation, the immune correlates of severe COVID-19 remain unclear. Here, we comprehensively analyzed peripheral blood immune perturbations in 42 SARS-CoV-2 infected and recovered individuals. We identified broad changes in neutrophils, NK cells, and monocytes during severe COVID-19, suggesting excessive mobilization of innate lineages. We found marked activation within T and B cells, highly oligoclonal B cell populations, profound plasmablast expansion, and SARS-CoV-2-specific antibodies in many, but not all, severe COVID-19 cases. Despite this heterogeneity, we found selective clustering of severe COVID-19 cases through unbiased analysis of the aggregated immunological phenotypes. Our findings demonstrate broad immune perturbations spanning both innate and adaptive leukocytes that distinguish dysregulated host responses in severe SARS-CoV-2 infection and warrant therapeutic investigation.One Sentence SummaryBroad immune perturbations in severe COVID-19

Oxacillin-Induced Agranulocytosis

1977 ◽  
Vol 11 (7) ◽  
pp. 420-423
Author(s):  
Robert D. Scalley ◽  
Richard D. Roark
Keyword(s):  
Oral Mucosa ◽  
Causative Agent ◽  
Immune Mechanism ◽  
Drug Reactions ◽  
Specific Antibodies ◽  
Threatening Condition ◽  
Life Threatening ◽  
Clinical Responses ◽  
Sudden Decrease

Schultz's Disease — Drug allergic agranulocytosis — Is a syndrome characterized by a sudden decrease in circulating granulocytes, necrotic lesions of the oral mucosa, and general symptoms of severe prostration. This is a life threatening condition which is thought to be caused by an immune mechanism. Although identification of specific antibodies has not been successful in all cases, clinical responses in many reports also suggest an allergic basis for this syndrome. The appearance of agranulocytosis is reported in a 79-year-old woman receiving three drugs associated with this dyscrasia. Identification of the most likely causative agent is discussed, and the importance of allergic drug reactions is demonstrated.

scholarly journals Spike-Dependent Opsonization Indicates Both Dose-Dependent Inhibition of Phagocytosis and That Non-Neutralizing Antibodies Can Confer Protection to SARS-CoV-2

2022 ◽  
Vol 12 ◽  
Author(s):  
Wael Bahnan ◽  
Sebastian Wrighton ◽  
Martin Sundwall ◽  
Anna Bläckberg ◽  
Olivia Larsson ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Infection Model ◽  
Immune Functions ◽  
Immune Mechanism ◽  
Neutralization Potential ◽  
Specific Antibodies ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Low Levels ◽  
Dose Dependent

Spike-specific antibodies are central to effective COVID19 immunity. Research efforts have focused on antibodies that neutralize the ACE2-Spike interaction but not on non-neutralizing antibodies. Antibody-dependent phagocytosis is an immune mechanism enhanced by opsonization, where typically, more bound antibodies trigger a stronger phagocyte response. Here, we show that Spike-specific antibodies, dependent on concentration, can either enhance or reduce Spike-bead phagocytosis by monocytes independently of the antibody neutralization potential. Surprisingly, we find that both convalescent patient plasma and patient-derived monoclonal antibodies lead to maximum opsonization already at low levels of bound antibodies and is reduced as antibody binding to Spike protein increases. Moreover, we show that this Spike-dependent modulation of opsonization correlate with the outcome in an experimental SARS-CoV-2 infection model. These results suggest that the levels of anti-Spike antibodies could influence monocyte-mediated immune functions and propose that non-neutralizing antibodies could confer protection to SARS-CoV-2 infection by mediating phagocytosis.

scholarly journals JAK2-STAT Epigenetically Regulates Tolerized Genes in Monocytes in the First Encounter With Gram-Negative Bacterial Endotoxins in Sepsis

2021 ◽  
Vol 12 ◽  
Author(s):  
Octavio Morante-Palacios ◽  
Clara Lorente-Sorolla ◽  
Laura Ciudad ◽  
Josep Calafell-Segura ◽  
Antonio Garcia-Gomez ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Transcriptional Activation ◽  
Ex Vivo ◽  
Initial Response ◽  
Endotoxin Tolerance ◽  
Integrated Analysis ◽  
Gram Negative ◽  
Bacterial Endotoxins ◽  
Stat Pathway

Microbial challenges, such as widespread bacterial infection in sepsis, induce endotoxin tolerance, a state of hyporesponsiveness to subsequent infections. The participation of DNA methylation in this process is poorly known. In this study, we perform integrated analysis of DNA methylation and transcriptional changes following in vitro exposure to gram-negative bacterial lipopolysaccharide, together with analysis of ex vivo monocytes from septic patients. We identify TET2-mediated demethylation and transcriptional activation of inflammation-related genes that is specific to toll-like receptor stimulation. Changes also involve phosphorylation of STAT1, STAT3 and STAT5, elements of the JAK2 pathway. JAK2 pathway inhibition impairs the activation of tolerized genes on the first encounter with lipopolysaccharide. We then confirm the implication of the JAK2-STAT pathway in the aberrant DNA methylome of patients with sepsis caused by gram-negative bacteria. Finally, JAK2 inhibition in monocytes partially recapitulates the expression changes produced in the immunosuppressive cellular state acquired by monocytes from gram-negative sepsis, as described by single cell-RNA-sequencing. Our study evidences both the crucial role the JAK2-STAT pathway in epigenetic regulation and initial response of the tolerized genes to gram-negative bacterial endotoxins and provides a pharmacological target to prevent exacerbated responses.

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