Lipid A

Lipid A with a reduced number of acyl chains (for example; four) can serve as an inhibitor of immune activation induced by Gram-negative bacteria, and synthetic versions of these inhibitors ([[Eritoran]]) were in clinical trials for the prevention of harmful effects caused by [[gram-negative]] bacterial infections. However, trials were recently discontinued due to lack of efficacy seen in patients with severe sepsis.{{Cite journal |doi = 10.1001/jama.2013.2194|pmid = 23512062|title = Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients with Severe Sepsis|journal = JAMA|volume = 309|issue = 11|pages = 1154–62|year = 2013|last1 = Opal|first1 = Steven M.|last2 = Laterre|first2 = Pierre-Francois|last3 = Francois|first3 = Bruno|last4 = Larosa|first4 = Steven P.|last5 = Angus|first5 = Derek C.|last6 = Mira|first6 = Jean-Paul|last7 = Wittebole|first7 = Xavier|last8 = Dugernier|first8 = Thierry|last9 = Perrotin|first9 = Dominique|last10 = Tidswell|first10 = Mark|last11 = Jauregui|first11 = Luis|last12 = Krell|first12 = Kenneth|last13 = Pachl|first13 = Jan|last14 = Takahashi|first14 = Takeshi|last15 = Peckelsen|first15 = Claus|last16 = Cordasco|first16 = Edward|last17 = Chang|first17 = Chia-Sheng|last18 = Oeyen|first18 = Sandra|last19 = Aikawa|first19 = Naoki|last20 = Maruyama|first20 = Tatsuya|last21 = Schein|first21 = Roland|last22 = Kalil|first22 = Andre C.|last23 = Van Nuffelen|first23 = Marc|last24 = Lynn|first24 = Melvyn|last25 = Rossignol|first25 = Daniel P.|last26 = Gogate|first26 = Jagadish|last27 = Roberts|first27 = Mary B.|last28 = Wheeler|first28 = Janice L.|last29 = Vincent|first29 = Jean-Louis|last30 = Access Study Group|first30 = for the|hdl = 1854/LU-4222072|hdl-access = free}}

Lipid A with a reduced number of acyl chains (for example; four) can serve as an inhibitor of immune activation induced by Gram-negative bacteria, and synthetic versions of these inhibitors ([[Eritoran]]) were in clinical trials for the prevention of harmful effects caused by [[gram-negative]] bacterial infections. However, trials were recently discontinued due to lack of efficacy seen in patients with severe sepsis.{{Cite journal |doi = 10.1001/jama.2013.2194|pmid = 23512062|title = Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients with Severe Sepsis|journal = JAMA|volume = 309|issue = 11|pages = 1154–62|year = 2013|last1 = Opal|first1 = Steven M.|last2 = Laterre|first2 = Pierre-Francois|last3 = Francois|first3 = Bruno|last4 = Larosa|first4 = Steven P.|last5 = Angus|first5 = Derek C.|last6 = Mira|first6 = Jean-Paul|last7 = Wittebole|first7 = Xavier|last8 = Dugernier|first8 = Thierry|last9 = Perrotin|first9 = Dominique|last10 = Tidswell|first10 = Mark|last11 = Jauregui|first11 = Luis|last12 = Krell|first12 = Kenneth|last13 = Pachl|first13 = Jan|last14 = Takahashi|first14 = Takeshi|last15 = Peckelsen|first15 = Claus|last16 = Cordasco|first16 = Edward|last17 = Chang|first17 = Chia-Sheng|last18 = Oeyen|first18 = Sandra|last19 = Aikawa|first19 = Naoki|last20 = Maruyama|first20 = Tatsuya|last21 = Schein|first21 = Roland|last22 = Kalil|first22 = Andre C.|last23 = Van Nuffelen|first23 = Marc|last24 = Lynn|first24 = Melvyn|last25 = Rossignol|first25 = Daniel P.|last26 = Gogate|first26 = Jagadish|last27 = Roberts|first27 = Mary B.|last28 = Wheeler|first28 = Janice L.|last29 = Vincent|first29 = Jean-Louis|last30 = Access Study Group|first30 = for the|hdl = 1854/LU-4222072|hdl-access = free}}

On the other hand, modified versions of lipid A can be used as components of [[vaccine]]s ([[adjuvant]]s) to improve their effect.{{cite journal |author=Coler RN |title= Development and Characterization of Synthetic Glucopyranosyl Lipid Adjuvant System as a Vaccine Adjuvant |journal= PLOS ONE |volume=6 |issue= 1 |article-number= e16333 |year= 2010|pmid= 21298114 |pmc=3027669|doi= 10.1371/journal.pone.0016333 |author2= Bertholet S |author3= Moutaftsi M |author4= Guderian JA |author5= Windish HP |display-authors=etal|bibcode=2011PLoSO...616333C |doi-access= free }} Monophosphorylated lipid A (MPL) is an FDA approved adjuvant that consists of a heterogeneous mixture of lipid A from ''Salmonella minnesota'' R595. The major lipid A species present in MPL lacks one of the two phosphate groups and five acyl chains. Other work has shown that the removal of one or two acyl chains from native lipid A can significantly reduce activation of inflammatory responses.{{Cite journal|last1=Needham|first1=Brittany D.|last2=Carroll|first2=Sean M.|last3=Giles|first3=David K.|last4=Georgiou|first4=George|last5=Whiteley|first5=Marvin|last6=Trent|first6=M. Stephen|date=2013-01-22|title=Modulating the innate immune response by combinatorial engineering of endotoxin|journal=Proceedings of the National Academy of Sciences|language=en|volume=110|issue=4|pages=1464–1469|doi=10.1073/pnas.1218080110|issn=0027-8424|pmc=3557076|pmid=23297218|bibcode=2013PNAS..110.1464N|doi-access=free}}

On the other hand, modified versions of lipid A can be used as components of [[vaccine]]s ([[adjuvant]]s) to improve their effect.{{cite journal |author=Coler RN |title= Development and Characterization of Synthetic Glucopyranosyl Lipid Adjuvant System as a Vaccine Adjuvant |journal= PLOS ONE |volume=6 |issue= 1 |article-number= e16333 |year= 2010|pmid= 21298114 |pmc=3027669|doi= 10.1371/journal.pone.0016333 |author2= Bertholet S |author3= Moutaftsi M |author4= Guderian JA |author5= Windish HP |display-authors=etal|bibcode=2011PLoSO...616333C |doi-access= free }} Monophosphorylated lipid A (MPL) is an FDA approved adjuvant that consists of a heterogeneous mixture of lipid A from ''Salmonella minnesota'' R595. The major lipid A species present in MPL lacks one of the two phosphate groups and five acyl chains. Other work has shown that the removal of one or two acyl chains from native lipid A can significantly reduce activation of inflammatory responses.{{Cite journal|last1=Needham|first1=Brittany D.|last2=Carroll|first2=Sean M.|last3=Giles|first3=David K.|last4=Georgiou|first4=George|author5-link=Marvin Whiteley|last5=Whiteley|first5=Marvin|last6=Trent|first6=M. Stephen|date=2013-01-22|title=Modulating the innate immune response by combinatorial engineering of endotoxin|journal=Proceedings of the National Academy of Sciences|language=en|volume=110|issue=4|pages=1464–1469|doi=10.1073/pnas.1218080110|issn=0027-8424|pmc=3557076|pmid=23297218|bibcode=2013PNAS..110.1464N|doi-access=free}}

The biological activity of [[Lipopolysaccharide|LPS]] depends on the chemical structure of its lipid A. Primarily, [[TLR4]] is required for activation of [[innate immunity]] upon recognition of LPS of [[Gram-negative bacteria]]. The ability of [[TLR4]]/[[MD-2 (immunology)|MD-2]] system to respond to a distinct lipid A species are clinically important. [[Pathogenic bacteria]] may employ LPS with low biological activity of its lipid A to evade proper recognition by the [[TLR4]]/MD-2 complex, dampening the host [[immune response]] and increasing the risk of bacterial dissemination. On the other hand, such lipid A would not be able to induce [[septic shock]] in susceptible patients, rendering septic complications more manageable. Yet, defining and understanding how even the smallest structural differences between the very similar lipid A species may affect the activation of the [[immune response]] may provide the mechanism for the fine tuning of the latter and new insights to immunomodulatory processes.{{cite journal|last1=Korneev|first1=K|last2=Arbatsky|first2=N|last3=Molinaro|first3=A|last4=Palmigiano|first4=A|last5=Shaikhutdinova|first5=R|last6=Shneider|first6=M|last7=Pier|first7=G|last8=Kondakova|first8=A|last9=Sviriaeva|first9=E|last10=Sturiale|first10=L|last11=Garozzo|first11=D|last12=Kruglov|first12=A|last13=Nedospasov|first13=S|last14=Drutskaya|first14=M|last15=Knirel|first15=Y|last16=Kuprash|first16=D|title=Structural Relationship of the Lipid A Acyl Groups to Activation of Murine Toll-Like Receptor 4 by Lipopolysaccharides from Pathogenic Strains of Burkholderia mallei, Acinetobacter baumannii, and Pseudomonas aeruginosa.|journal=Frontiers in Immunology|date=2015|volume=6|page=595|doi=10.3389/fimmu.2015.00595|pmid=26635809|pmc=4655328|doi-access=free}}

The biological activity of [[Lipopolysaccharide|LPS]] depends on the chemical structure of its lipid A. Primarily, [[TLR4]] is required for activation of [[innate immunity]] upon recognition of LPS of [[Gram-negative bacteria]]. The ability of [[TLR4]]/[[MD-2 (immunology)|MD-2]] system to respond to a distinct lipid A species are clinically important. [[Pathogenic bacteria]] may employ LPS with low biological activity of its lipid A to evade proper recognition by the [[TLR4]]/MD-2 complex, dampening the host [[immune response]] and increasing the risk of bacterial dissemination. On the other hand, such lipid A would not be able to induce [[septic shock]] in susceptible patients, rendering septic complications more manageable. Yet, defining and understanding how even the smallest structural differences between the very similar lipid A species may affect the activation of the [[immune response]] may provide the mechanism for the fine tuning of the latter and new insights to immunomodulatory processes.{{cite journal|last1=Korneev|first1=K|last2=Arbatsky|first2=N|last3=Molinaro|first3=A|last4=Palmigiano|first4=A|last5=Shaikhutdinova|first5=R|last6=Shneider|first6=M|last7=Pier|first7=G|last8=Kondakova|first8=A|last9=Sviriaeva|first9=E|last10=Sturiale|first10=L|last11=Garozzo|first11=D|last12=Kruglov|first12=A|last13=Nedospasov|first13=S|last14=Drutskaya|first14=M|last15=Knirel|first15=Y|last16=Kuprash|first16=D|title=Structural Relationship of the Lipid A Acyl Groups to Activation of Murine Toll-Like Receptor 4 by Lipopolysaccharides from Pathogenic Strains of Burkholderia mallei, Acinetobacter baumannii, and Pseudomonas aeruginosa.|journal=Frontiers in Immunology|date=2015|volume=6|page=595|doi=10.3389/fimmu.2015.00595|pmid=26635809|pmc=4655328|doi-access=free}}