Pathogen Recognition and Innate Immunity

At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

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Free Radicals in the Physiological Control of Cell Function

▪ Abstract The innate immune system is a universal and ancient form of host defense against infection. Innate immune recognition relies on a limited number of germline-encoded receptors. These receptors evolved to recognize conserved products of microbial metabolism produced by microbial pathogens, but not by the host. Recognition of these molecular structures allows the immune system to distinguish infectious nonself from noninfectious self. Toll-like receptors play a major role in pathogen recognition and initiation of inflammatory and immune responses. Stimulation of Toll-like receptors by microbial products leads to the activation of signaling pathways that result in the induction of antimicrobial genes and inflammatory cytokines. In addition, stimulation of Toll-like receptors triggers dendritic cell maturation and results in the induction of costimulatory molecules and increased antigen-presenting capacity. Thus, microbial recognition by Toll-like receptors helps to direct adaptive immune responses ...

/pdf/innate-immune-recognition-3eedeqyq83.pdf

Innate Immune Recognition

One of the mechanisms by which the innate immune system senses the invasion of pathogenic microorganisms is through the Toll-like receptors (TLRs), which recognize specific molecular patterns that are present in microbial components. Stimulation of different TLRs induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also instructs the development of antigen-specific acquired immunity. Here, we review the rapid progress that has recently improved our understanding of the molecular mechanisms that mediate TLR signalling.

Toll-like receptor signalling

ObjectiveTo determine the incidence, cost, and outcome of severe sepsis in the United States.DesignObservational cohort study.SettingAll nonfederal hospitals (n = 847) in seven U.S. states.PatientsAll patients (n = 192,980) meeting criteria for severe sepsis based on the International Classification

Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.

Leukocytes respond to lipopolysaccharide (LPS) at nanogram per milliliter concentrations with secretion of cytokines such as tumor necrosis factor-alpha (TNF-alpha). Excess secretion of TNF-alpha causes endotoxic shock, an often fatal complication of infection. LPS in the bloodstream rapidly binds to the serum protein, lipopolysaccharide binding protein (LBP), and cellular responses to physiological levels of LPS are dependent on LBP. CD14, a differentiation antigen of monocytes, was found to bind complexes of LPS and LBP, and blockade of CD14 with monoclonal antibodies prevented synthesis of TNF-alpha by whole blood incubated with LPS. Thus, LPS may induce responses by interacting with a soluble binding protein in serum that then binds the cell surface protein CD14.

https://science.sciencemag.org/content/sci/249/4975/1431.full.pdf

CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein.

The innate immune response is the first line of defence against infectious disease. The principal challenge for the host is to detect the pathogen and mount a rapid defensive response. A group of proteins that comprise the Toll or Toll-like family of receptors perform this role in vertebrate and invertebrate organisms. This reflects a remarkable conservation of function and it is therefore not surprising that studies of the mechanism by which they act has revealed new and important insights into host defence.

Toll-like receptors in the induction of the innate immune response

Mammalian cells respond to endotoxic lipopolysaccharide (LPS) by activation of protein kinase cascades that lead to new gene expression. A protein kinase, p38, that was tyrosine phosphorylated in response to LPS, was cloned. The p38 enzyme and the product of the Saccharomyces cerevisiae HOG1 gene, which are both members of the mitogen-activated protein (MAP) kinase family, have sequences at and adjacent to critical phosphorylation sites that distinguish these proteins from most other MAP kinase family members. Both HOG1 and p38 are tyrosine phosphorylated after extracellular changes in osmolarity. These findings link a signaling pathway in mammalian cells with a pathway in yeast that is responsive to physiological stress.

https://science.sciencemag.org/content/sci/265/5173/808.full.pdf

A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells

Pro-inflammatory Cytokines and Environmental Stress Cause p38 Mitogen-activated Protein Kinase Activation by Dual Phosphorylation on Tyrosine and Threonine (∗)

The primary structure of lipopolysaccharide binding protein (LBP), a trace plasma protein that binds to the lipid A moiety of bacterial lipopolysaccharides (LPSs), was deduced by sequencing cloned complementary DNA. LBP shares sequence identity with another LPS binding protein found in granulocytes, bactericidal/permeability-increasing protein, and with cholesterol ester transport protein of the plasma. LBP may control the response to LPS under physiologic conditions by forming high-affinity complexes with LPS that bind to monocytes and macrophages, which then secrete tumor necrosis factor. The identification of this pathway for LPS-induced monocyte stimulation may aid in the development of treatments for diseases in which Gram-negative sepsis or endotoxemia are involved.

https://science.sciencemag.org/content/sci/249/4975/1429.full.pdf

Richard J. Ulevitch

Papers

CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein.

Toll-like receptors in the induction of the innate immune response

A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells

Pro-inflammatory Cytokines and Environmental Stress Cause p38 Mitogen-activated Protein Kinase Activation by Dual Phosphorylation on Tyrosine and Threonine (∗)

Structure and function of lipopolysaccharide binding protein