Related Research Articles
Sepsis is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is followed by suppression of the immune system. Common signs and symptoms include fever, increased heart rate, increased breathing rate, and confusion. There may also be symptoms related to a specific infection, such as a cough with pneumonia, or painful urination with a kidney infection. The very young, old, and people with a weakened immune system may have no symptoms of a specific infection, and the body temperature may be low or normal instead of having a fever. Severe sepsis causes poor organ function or blood flow. The presence of low blood pressure, high blood lactate, or low urine output may suggest poor blood flow. Septic shock is low blood pressure due to sepsis that does not improve after fluid replacement.
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide composed of O-antigen, outer core and inner core joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria. The term lipooligosaccharide ("LOS") is used to refer to a low-molecular-weight form of bacterial lipopolysaccharides.
Septic shock is a potentially fatal medical condition that occurs when sepsis, which is organ injury or damage in response to infection, leads to dangerously low blood pressure and abnormalities in cellular metabolism. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defines septic shock as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by requiring a vasopressor to maintain a mean arterial pressure of 65 mm Hg or greater and having serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%.
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Humans lack genes for TLR11, TLR12 and TLR13 and mice lack a functional gene for TLR10. TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located on the cell membrane, whereas TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicles.
Lipid A is a lipid component of an endotoxin held responsible for the toxicity of gram-negative bacteria. It is the innermost of the three regions of the lipopolysaccharide (LPS), also called endotoxin molecule, and its hydrophobic nature allows it to anchor the LPS to the outer membrane. While its toxic effects can be damaging, the sensing of lipid A by the immune system may also be critical for the onset of immune responses to gram-negative infection, and for the subsequent successful fight against the infection.
The bacterial outer membrane is found in gram-negative bacteria. Its composition is distinct from that of the inner cytoplasmic cell membrane - among other things, the outer leaflet of the outer membrane of many gram-negative bacteria includes a complex lipopolysaccharide whose lipid portion acts as an endotoxin - and in some bacteria such as E. coli it is linked to the cell's peptidoglycan by Braun's lipoprotein.
C5a is a protein fragment released from cleavage of complement component C5 by protease C5-convertase into C5a and C5b fragments. C5b is important in late events of the complement cascade, an orderly series of reactions which coordinates several basic defense mechanisms, including formation of the Membrane Attack Complex (MAC), one of the most basic weapons of the innate immune system, formed as an automatic response to intrusions from foreign particles and microbial invaders. It essentially pokes microscopic pinholes in these foreign objects, causing loss of water and sometimes death. C5a, the other cleavage product of C5, acts as a highly inflammatory peptide, encouraging complement activation, formation of the MAC, attraction of innate immune cells, and histamine release involved in allergic responses. The origin of C5 is in the hepatocyte, but its synthesis can also be found in macrophages, where it may cause local increase of C5a. C5a is a chemotactic agent and an anaphylatoxin; it is essential in the innate immunity but it is also linked with the adaptive immunity. The increased production of C5a is connected with a number of inflammatory diseases.
Virulence factors are cellular structures, molecules and regulatory systems that enable microbial pathogens to achieve the following:
Collectins (collagen-containing C-type lectins) are a part of the innate immune system. They form a family of collagenous Ca2+-dependent defense lectins, which are found in animals. Collectins are soluble pattern recognition receptors (PRRs). Their function is to bind to oligosaccharide structure or lipids that are on the surface of microorganisms. Like other PRRs they bind pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) of oligosaccharide origin. Binding of collectins to microorganisms may trigger elimination of microorganisms by aggregation, complement activation, opsonization, activation of phagocytosis, or inhibition of microbial growth. Other functions of collectins are modulation of inflammatory, allergic responses, adaptive immune system and clearance of apoptotic cells.
Lipopolysaccharide binding protein (LBP) is a protein that in humans is encoded by the LBP gene.
Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an intracellular signaling pathway NF-κB and inflammatory cytokine production which is responsible for activating the innate immune system.
Lymphocyte antigen 96, also known as "Myeloid Differentiation factor 2 (MD-2)," is a protein that in humans is encoded by the LY96 gene.
Peptidoglycan recognition protein 1, PGLYRP1, also known as TAG7, is an antibacterial and pro-inflammatory innate immunity protein that in humans is encoded by the PGLYRP1 gene.
Clostridium difficile toxin A (TcdA) is a toxin generated by Clostridioides difficile, formerly known as Clostridium difficile. It is similar to Clostridium difficile Toxin B. The toxins are the main virulence factors produced by the gram positive, anaerobic, Clostridioides difficile bacteria. The toxins function by damaging the intestinal mucosa and cause the symptoms of C. difficile infection, including pseudomembranous colitis.
Toll-like receptor 11 (TLR11) is a protein that in mice and rats is encoded by the gene TLR11, whereas in humans it is represented by a pseudogene. TLR11 belongs to the toll-like receptor (TLR) family and the interleukin-1 receptor/toll-like receptor superfamily. In mice, TLR11 has been shown to recognise (bacterial) flagellin and (eukaryotic) profilin present on certain microbes, it helps propagate a host immune response. TLR11 plays a fundamental role in both the innate and adaptive immune responses, through the activation of Tumor necrosis factor-alpha, the Interleukin 12 (IL-12) response, and Interferon-gamma (IFN-gamma) secretion. TLR11 mounts an immune response to multiple microbes, including Toxoplasma gondii, Salmonella species, and uropathogenic E. coli, and likely many other species due to the highly conserved nature of flagellin and profilin.
In molecular biology, the lipid-binding serum glycoproteins family, also known as the BPI/LBP/Plunc family or LBP/BPI/CETP family represents a family which includes mammalian lipid-binding serum glycoproteins. Members of this family include:
Murine caspase-11, and its human homologs caspase-4 and caspase-5, are mammalian intracellular receptor proteases activated by TLR4 and TLR3 signaling during the innate immune response. Caspase-11, also termed the non-canonical inflammasome, is activated by TLR3/TLR4-TRIF signaling and directly binds cytosolic lipopolysaccharide (LPS), a major structural element of Gram-negative bacterial cell walls. Activation of caspase-11 by LPS is known to cause the activation of other caspase proteins, leading to septic shock, pyroptosis, and often organismal death.
Dipshikha Chakravortty is an Indian microbiologist, molecular pathologist and a professor at the department of Microbiology and Cell Biology at the Indian Institute of Science. Known for her studies on Salmonella and antibacterial resistance, Chakravortty is an elected fellow of the National Academy of Sciences, India, the Indian Academy of Sciences and the Indian National Science Academy. The Department of Biotechnology of the Government of India awarded her the National Bioscience Award for Career Development, one of the highest Indian science awards, for her contributions to biosciences, in 2010.
Peptidoglycan recognition protein 4 is an antibacterial and anti-inflammatory innate immunity protein that in humans is encoded by the PGLYRP4 gene.
Roman Dziarski is a Polish-born American immunologist and microbiologist. He is best known for his research on innate immunity and bacterial peptidoglycan, for discovering the family of human peptidoglycan recognition proteins, which comprises PGLYRP1, PGLYRP2, PGLYRP3, and PGLYRP4, and for defining the functions of these proteins.
References
- ↑ Elsbach P (July 1998). "The bactericidal/permeability-increasing protein (BPI) in antibacterial host defense". Journal of Leukocyte Biology. Wiley-Liss. 64 (1): 14–8. doi: 10.1002/jlb.64.1.14 . PMID 9665269. S2CID 36780757.
- ↑ Canny G, Levy O, Furuta GT, Narravula-Alipati S, Sisson RB, Serhan CN, Colgan SP (March 2002). "Lipid mediator-induced expression of bactericidal/ permeability-increasing protein (BPI) in human mucosal epithelia". Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences. 99 (6): 3902–7. Bibcode:2002PNAS...99.3902C. doi: 10.1073/pnas.052533799 . PMC 122621 . PMID 11891303.
- ↑ Levin M, Quint PA, Goldstein B, Barton P, Bradley JS, Shemie SD, Yeh T, Kim SS, Cafaro DP, Scannon PJ, Giroir BP (September 2000). "Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study Group". Lancet. Lancet Publishing Group. 356 (9234): 961–7. doi:10.1016/S0140-6736(00)02712-4. PMID 11041396. S2CID 40877544.
- ↑ Schlag G, Redl H, Davies J, Scannon P (February 1999). "Protective effect of bactericidal/permeability-increasing protein (rBPI21) in baboon sepsis is related to its antibacterial, not antiendotoxin, properties". Annals of Surgery. Lippincott Williams & Wilkins. 229 (2): 262–71. doi:10.1097/00000658-199902000-00015. PMC 1191640 . PMID 10024109.
- ↑ Srivastava A, Casey H, Johnson N, Levy O, Malley R (January 2007). "Recombinant bactericidal/permeability-increasing protein rBPI21 protects against pneumococcal disease". Infection and Immunity. American Society for Microbiology. 75 (1): 342–9. doi:10.1128/IAI.01089-06. PMC 1828387 . PMID 17101667.
- ↑ Khan AA, Lambert LH, Remington JS, Araujo FG (April 1999). "Recombinant bactericidal/permeability-increasing protein (rBPI21) in combination with sulfadiazine is active against Toxoplasma gondii". Antimicrobial Agents and Chemotherapy. American Society for Microbiology. 43 (4): 758–62. doi:10.1128/aac.43.4.758. PMC 89203 . PMID 10103177.
- ↑ Balakrishnan A, DasSarma P, Bhattacharjee O, Kim JM, DasSarma S, Chakravortty D (September 2016). "Halobacterial nano vesicles displaying murine bactericidal permeability-increasing protein rescue mice from lethal endotoxic shock". Scientific Reports. 6: 33679. Bibcode:2016NatSR...633679B. doi:10.1038/srep33679. PMC 5028748 . PMID 27646594.
