All Stings Considered

snake1The subject of the next lecture 9/22/08 will be evolutionary considerations of venoms, toxins, and antibodies to these molecules.

What is the difference between a venom and a toxin? Are biologic toxins different from organic toxins? Who benefits from a toxin?  (not including Phillip Morris :) )

What if a “toxin” actually can be good for you, and what if the “toxin” does not benefit the organism that produces it? Is it still a toxin? Or something else entirely? Much work on intensive care patients relates to dramatic reaction to “endotoxin”, otherwise known as lipopolysaccharide. Endotoxin is a basic component of the cell wall of certain bacteria. Endotoxin can result in a drop in blood pressure, widespread inflammation in the body, fever, and leaking capillaries. When severe, these symptoms can kill.

Endotoxin has these effects when it appears in the human bloodstream. It also occurs in huge quantities in the intestines and colon, a result of the vast numbers of E. coli and other bacteria that reside there. Clearly endotoxin has different effects depending on where it occurs. Why might endotoxin have inflammatory effects in the blood? Do you suppose that the bacterium makes endotoxin because it has these inflammatory effects? Alternatively, perhaps bloodstream endotoxin is a signal that bacteria have left the location where they are tolerated (the gut) and have entered the circulation.

Lets think of toxins the way we think of fever. (There is good evidence that in many animals, fever is a host defense that helps destroy pathogens!). Which party does a toxin benefit, the pathogen or the host? Streptococcus is a bacterium that causes strep throat. Streptococcus toxins kill host cells by puncturing holes in their membranes. Strep “perforins” allow bacteria to escape after they have been phagocytosed. These toxins that create conditions favorable to bacterial reproduction and transmission and are harmful to the host.

Endotoxin might be different. Endotoxin initiates an inflammatory response that puts immune cells on high alert to kill invading pathogens. Is it in the bacteria’s best interest to advertise its presence in the blood? Or would the bacteria do better if they were not detected?

If the reaction to endotoxin benefits the host and not the pathogen, we would expect that antobodies to endotoxin would be harmful during bloodstream infections. This proposition has been tested! Which way do you think it turned out?

The following is an excerpt from: “Targeting the lipopolysaccharides: still a matter of debate? Curr Opin Anaesthesiol. 2008 Apr;21(2):98-104.”:

Antiendotoxin antibodies

“A clinical study with antiendotoxin antibodies using nonspecific intravenous immunoglobulins failed to show survival benefit [14]. Clinical studies with the more specific human antiserum applied to heat-killed Escherichia coli (E5) and humanized (HA1A) antibodies against lipid A were nonconclusive [15,16]. Some clinical studies seemed promising [17,18]; however, the results were not universally reproducible [15,16,19,20]. The lack of success may have been due to the inability of the agent used to appropriately neutralize lipopolysaccharide [16,18]. A more recent study [21] supports the benefit of antisera from healthy patients immunized against lipopolysaccharide from E. coli. Lipopolysaccharides extracted from E. coli O111:B4 (E. coli J5) have been noncovalently combined with outer membrane protein of Neisseria meningitides and proven to be protective against fulminant Gram-negative sepsis in animal models [22–24]. The proposed mechanism of this benefit is production of antibodies against core lipopolysaccharide [25]. One limitation is the inability to determine the fraction of antibody required to show benefits [15,26,27]. Clinical studies suggest a correlation between the presence of anticore lipopolysaccharide antibody and onset and survival in sepsis [28–30]. Patients who survived severe sepsis secondary to Gram-negative bacilli were found to have higher levels of anticore lipopolysaccharide immunoglobulin G (IgG) [28–30]. The potential beneficial effect of antiendotoxin antibodies remains unclear and none have been approved for therapy.”

These authors posit that:

“Failure of previous antiendotoxin trials may be for a number of reasons:

1. failure to enroll enough patients with significant amounts of circulating endotoxin;

2. Enrollment of patients too late following release of endotoxin and associated triggering effects, that is the ‘cat is out of the bag’; or
3. ineffectiveness of endotoxin neutralization in general in severe sepsis”
They conclude by saying: “Since endotoxin is the ultimate toxin and is associated with much morbidity and mortality, continued attempts to counter its effects seem warranted.”
Hmmm? What do you think about that?

REQUIRED READINGS (THERE IS ONLY ONE)

1) The one journal article for this week is available here:

endotoxin

THE HANDOUT IS HERE:

All stings considered

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