History

Historical researches on endotoxin and sepsis at Institut Pasteur

Endotoxin


Pasteurians were very active in conducting research on endotoxins (lipopolysaccharide, LPS), a membrane compound of Gram-negative bacteria that alone can initiate most of the pathophysiological disorders observed during sepsis.

In 1904-1905, Alexandre Besredka (1870-1940), who succeeded Elie Metchnikoff (1845-1916), was the first scientist to obtain, and to characterize anti-endotoxin antibodies (Rietschel E. T., Cavaillon J-M: Richard Pfeiffer and Alexandre Besredka : creator of the concept of endotoxin and anti-endotoxin. Microbes and Infection 2003, 5, 1407-1414).


In 1935, André Boivin (1895-1945) joined the Institut Pasteur, after being the first to characterize the biochemical nature of endotoxin ("l’antigène glucido-lipidique") together with Lydia Mesrobeanu (1908-1978) at the Cantacuzene Institute in Bucharest.





Anne-Marie Staub
In 1960-1970, Anne-Marie Staub (born 1914) further characterized the nature of the O-antigens of various LPS, and made important immunochemical characterizations. She identified the subtle modifications of the O-antigen after infection of Salmonella by bacteriophages. With Prof. Otto Lüderitz and Otto Westphal, the leaders in the field, she further identified the biochemical and immunochemical properties of tyvelose, a new sugaridentified as part of the O-antigen of Salmonella typhi.



In 1970-1980, Louis Chedid, before studying muramyl dipeptide (MDP), made major contributions to the analysis of the polyclonal activation of B cells by LPS as well as its adjuvant properties. He also worked on the role of corticoids in animal models, and was the
first to propose the concept of an universal antibody Louis Chedid (Chedid L et al. A proposed mechanism for natural immunity to enterobacterial pathogens. J. Immunol. 1968; 100 : 292-306), which could neutralize endotoxin during sepsis. In the Institute, Robert Girard, Richard Chaby and Jean-Marc Cavaillon perpetuate the interest of scientists at Institut Pasteur for endotoxins and made important contributions in the fields of B cell activation, cytokine production, and endotoxin tolerance.

In 2000, the Institut Pasteur hosted the the 6th conference of the "International Endotoxin Society" (IES).

 





Some of the presidents of the International Endotoxin Society:
from left to right: Robert Munford (USA, 2000-2002), Takashi Yokochi (Japan, 2002-2004), Jean-Marc Cavaillon (France, 1998-2000), Stephanie Vogel (USA, 2004-2006), David Morrison (USA, 1996-1998), Ernst Rietschel (Germany, 1990-1992).



Sepsis

In 1879 -1880, Louis Pasteur was called by physicians to study puerperal septicemia. For the first time he identified the presence of bacteria in the blood stream of the patients. When Pasteur reported his observations in front of the Academies of Sciences and of Medicine, for the only woman who survived, he mentioned "Natura medicatrix won the victory". It is this Natura medicatrix that we need to better understand to help the body to fight sepsis. (Séance Acad. Sci., Paris, March 18, 1879; Séance Acad. Sci., Paris, May, 3rd, 1880).
Since Louis Pasteur, no further work on human septicemia was undertaken in this Institute before Jean-Marc Cavaillon initiated his work in the field. This has only been possible thanks to two other people, Dr. Carlos Muñoz, a Chilean scientist who joined Cavaillon’s team for a post doctoral stay after he had worked with Prof. Charles Dinarello and brought the specific radio-immunoassays that allowed the measurements of IL-1ß and TNF in patients, and Dr. Jean Carlet, head of the intensive care unit at Saint Joseph hospital (Paris), who was a rare French medical doctor at that time ready to collaborate with scientists.
 
This fruitful collaboration resulted in a highly cited paper that demonstrated the altered capacity of monocytes from sepsis patients to release cytokines in response to endotoxin [*]. Sepsis remains a major problem in intensive care units [**]. Since then, Cavaillon has never stopped working with the most brilliant Parisians critical care doctors. In addition to saving lives, these critical care doctors’ scientific knowledge contributes to make progress when addressing the diseases. The collaborative works have been achieved with Prof. D. Payen (Hosp. Lariboisère), Prof J-F. Dhainaut (Hosp. Cochin), Dr. P. Moine (Hosp. Kremlin-Bicêtre), Prof. Annane (Hosp. H. Poincaré) and C. Adrie (Hosp. Delafontaine).

[*] Muñoz C., Carlet J., Fitting C, Misset B, Bleriot J-P., Cavaillon J-M. Disregulation of in vitro cytokine production by monocytes during sepsis. J. Clin. Invest. 1991, 88, 1747-1754
[**] Annane D., Bellissant E., Cavaillon J-M. Septic Shock The Lancet, 2005, 365, 63-78


Dr J. Carlet


Dr. Carlos Muñoz


Elie Metchnikoff, the father of cellular innate immunity
 

Cavaillon JM. The historical milestones in the understanding of leukocyte biology initiated by Elie Metchnikoff. J Leukoc Biol. 2011 Sep;90(3):413-24. 

Starting his career as a zoologist and an embryologist, Elie Metchnikoff became a pathologist, beautifully defining the role of monocytes, macrophages, and neutrophils during inflammation and innate immunity. Elie Metchnikoff was born in the Russian Empire near Kharkoff, present-day Ukraine. After his major discovery about phagocytosis in Sicily, he went looking for a permanent position. After his first meeting in 1887 with Louis Pasteur, Metchnikoff decided to join the Institut Pasteur, which was newly created. Metchnikoff was offered a director position of one of five units created when the institute was opened in 1888. Later, he was appointed deputy-director of Institut Pasteur from 1904 to 1916. From Paris, Metchnikoff was an active defender of the role of phagocytosis in inflammation and innate immunity. The controversy was mainly about the respective roles played by humoral immunity and cellular immunity in fighting infection. Among his most famous pupils, let’s mention Jean Cantacuzène (1863–1934), a Romanian medical doctor who opened an institute that bears his name, similar to Institut Pasteur - The Cantacuzino Institute, and Jules Bordet (1870–1961), a medical doctor from Belgium who was awarded the Nobel Prize in 1919 for his discovery on the complement system. During the end of his career, Metchnikoff worked on aging and particularly on intestinal flora and initiated the concept of probiotics.

 

 
Portrait of Metchnikoff painted by his wife Olga