Abstract & Commentary
Synopsis: The bacterium Bacillus anthracis causes the death of macrophages, which may allow it to avoid detection by the innate immune system.
Source: Park JM, et al. Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science. 2002;297:2048-2051.
There is already a good bit known about the pathogenesis of anthrax, interest obviously being piqued by the mini-bioterror epidemic propagated through the US mail just 1 year ago. Now new evidence comes from The Department of Pharmacology at UC San Diego shedding light on the mechanism of a major virulence factor in Bacillus anthracis.
One major question in anthrax research has been what happens to anthrax spores after consumption by pulmonary macrophages? Without an evasion mechanism, the spores would be engulfed and killed. Park and colleagues pick up the story of pathogenesis after protective factor (PA) assists translocation of edema factor and lethal factor (LF). The other existing knowledge is that metalloprotease with ability to cleave mitogen-induced kinases (MAPK), LF combines with PA to produce lethal toxin (LT), which is highly toxic for macrophages.
That macrophage toxicity, some evidence suggests, is due to either necrosis or programmed cell death—apoptosis—of macrophages. Put in a nutshell, this study found that LT produces apoptosis of macrophages but some other factors are needed. The present experiment used classic LPS but also lipoteichoic acid from Staphylococcus aureus and Bacillus subtilis to prime purified macrophages for the apoptotic and necrotic action of LT. Some cell types were more sensitive to the apoptosis effect of LT, some the necrosis effect.
LPS causes signal transduction in macrophages through p38 MKK, glowing, and other kinases. LT was shown to block the activation of p38 map kinase (MAPK) and that blockage allows apoptosis to occur. NFkB and p38 normally act together to inhibit apoptosis. Experimentally produced MKK was cleaved by LF and that LT with either LPS or lipopeptide produced 3-5 times as much apoptosis as LPS or SB alone.
It is important to realize that in order for macrophages to survive LPS, NFkB must be activated. NFkB combined with effects of p38 jointly produce another factor(s) that protect macrophages from apoptosis. In their final experiment Park et al actually tested activation of a number of NFkB targets to show that the activation is p38 dependent. This experiment was performed by measuring total cellular RNA after 4 hours of LT or SB treatment of such NFkB targets as IL-1a, cyclooxygenase, and IKBA.
On a more clinical note, in a late-breaker session at the recent Infectious Diseases Society of America held in Chicago 24-27 in October, the infectious diseases clinical team at the Capitol reported data on the dynamics of spread of anthrax spores from the infamous Senator Daschle letter.1 Dr. Gregory Martin, the infectious diseases physician for the Senate, gave a superb summary of the epidemiology of spore release in October 2001 at the Hart Senate Building. Nasopharyngeal cultures were performed on 58 exposed individuals throughout the building: 28 were positive, 13 of 13 in the immediate vicinity, and 9 of 45 from persons more adjacent and 6 first responders. There were nasopharyngeal cultures of 6000 additional persons with "less definite exposure" and none were positive.
Based on the positive individuals and their location, it was surmised that spores spread very quickly—in 1 to 4 minutes—and could spread quickly also to adjacent floors. Exposed individuals were offered 100 days of antibiotic prophylaxis and anthrax vaccination. There was a higher frequency of symptoms in exposed volunteers compared to nonexposed. No clearcut inhalation anthrax developed, but a milder form of the illness could not be ruled out in culture-positive individuals.
Comment by Joseph F. John, MD
Infectious disease physicians usually think of the deleterious effects of NFkB production including the activation of tumor necrosis factor (TNF), IL-1B, and COX-2. Yet it is known that these lymphokines may have a biphasic cellular response, the first phase often assisting in cell-mediated immune microbial killing. This current work shows with elegance that age-old toxins now revisited on man, like those of B anthracis, inhibit that sentinel system, and, once inhibited, allows programmed cell death to occur that may itself be sufficient for morbidity and mortality in humans or may be combined with the cell necrosis effects of EF and LT. It is the very lack of cytokine expression by macrophages in anthrax that may allow a relative "silent" infection to rage.
Readers may consider the foregoing sequence a space age product, far from the bedside. Analysis of cytokine responses—both supportive and deleterious—may be at hand in severe acute infections. Indeed we have entered an age of use of biological modifiers and we will need to have working knowledge of cytokine perturbation and the fundamentals of the NFkB crosstalk to recommend and evaluate these new therapies.
Anthrax may be a special case because of its ability to produce intense morbidity and mortality. Antibiotic therapy alone, as in LPS induced SIRS, is unlikely to be curative in far-advanced cases. The salvage of many of the 17 recent victims of terroristic anthrax has had one apparent downside. Recent news, yet to be supported in peer-review publications, apparently found that several of the anthrax victims have evolved an illness reminiscent chronic fatigue syndrome, perhaps suggesting that the effects of the toxins of B anthracis are not simply short acting.
The experience in the Hart Senate Building is sobering. As Dr. Martin related on October 27 in Chicago, there were many incorrect assumptions. What was apparent is that weaponized spores can be quickly and easily spread and exposure can be high, certainly for those in the immediate proximity and even adjacent inside locations.
It is my opinion that anthrax remains the ideal bioweapon for many reasons. All physicians led by those experts in infectious diseases need to remain current in their knowledge and skills concerning disease due to B anthracis. The thoughtful response by Dr. Greg Martin and his team at the Capitol demonstrates the versatility and capability of infectious diseases physicians faced with a bewildering problem of microbial exposure. The abstract reported by him and his colleagues provides substantial new information to help other infectious diseases physicians respond to an anthrax attack.
Dr. John, Chief, Medical Subspecialty Services, Ralph H. Johnson Veterans Administration Medical Center; Professor of Medicine, Medical University of South Carolina, Charleston, SC, is Co-Editor of Infectious Disease Alert.
The bacterium Bacillus anthracis causes the death of macrophages, which may allow it to avoid detection by the innate immune system.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content