Microbes and Molecules
Jon-Emile Kenny MD
Faculty Peer Reviewed
With the recent sensory overload regarding swine flu, I’ve spent considerable time pondering our immune system – and what an amazing system it is! From minor respiratory tract infections, to chronic viral replication and overwhelming bacterial sepsis, the immune system mobilizes a myriad of macromolecules to maintain our health.
In the Journal of the American Medical Association this week, Cruz et al. reported on the use of Polymyxin Hemoperfusion in septic shock. Recall that plasma endotoxin activates certain innate proteins and leads to a massive cytokine release and the syndrome of septic shock. Since Polymyxin binds to gram negative endotoxin, it has been postulated that filtering blood through columns containing the antibiotic may benefit patients with severe gram negative sepsis. The authors reported that polymyxin B hemoperfusion added to conventional therapy significantly improved hemodynamics and organ dysfunction and reduced 28-day mortality in a targeted population with severe sepsis and/or septic shock from intra-abdominal gram-negative infections.
In Science this week, Johnson and Jameson report on the importance of interleukin 21. Chronic viral infections are taxing to the immune system, especially CD8+ cytotoxic T cells. Over time, these cells can become ‘exhausted’ and viruses like hepatitis win the war of attrition. However, CD4+ helper T cells prevent ‘exhaustion’ with the release of interleukin 21. The clinical implications are obvious in patients co-infected with both HIV and hepatitis. I direct you also to Dr. Sarwar’s excellent clinicalcorrelations entry on this very topic.
The innate immune response is crucial during infection by superantigen-producing staphylococci. In Nature Medicine, Chau et al. showed that human toll-like receptors activated by peptidoglycan in the cell wall of staphylococci species induce apoptosis of antigen presenting cells, therefore nullifying the adaptive immune response. This evasion of the adaptive immune system makes overwhelming toxic-shock syndrome less likely by staphylococcal species. Clinically, this explains why bacteriostatic antibiotics are more effective than bacteriocidal antibiotics when treating staphylococcal bacteremia. Bacteriostasis preserves microbial architecture and maintains inhibition of a devastating immune response.
What about medicine’s wonder drugs? In the last 10 years statins have been reported to modify the immune system by modulating cytokine production, neutrophil chemotaxis, and various other mechanisms of anti-inflammation. Indeed, human observational studies have reported that statins can improve outcomes in sepsis and pneumonia. This week Dublin et al. reported in the British Medical Journal that previously reported pneumonia protection with statins may have suffered from the ‘healthy user bias.’ In other words, compared to people who don’t take statins, those who do may be healthier and have habits that lower their risks of unrelated diseases such as pneumonia. Thus, the improvement in protection from pneumonia seen with statins is not a true cause and effect. Only a large randomized controlled trial would be able to adequately answer this question.
Now, I turn to a venerable Bellevue Hospital concern. Multi-drug resistant tuberculosis is becoming a prominent worldwide concern and cases are becoming common in New York City. Additional molecular targets are needed to combat this public health threat. Streibel et al. in Nature Structural and Molecular Biology identified an analogous ubiqutin-proteasome pathway in mycobacterium. Nobel Prize winning work in the 1980s identified that proteins within eukaryotic cells are degraded within molecular ‘shredders’ (i.e. proteasomes) after being marked for destruction with ubiquitin protein. Indeed manipulation of this system has been used to treat human disease (e.g. multiple myeloma). Only recently has a similar mechanism been found in bacteria – called the pup system. Streibel et al detailed this pathway in mycobacterium tuberculosis with potential for treatment of multidrug resistant strains.
Finally, a novel method of HIV eradication has been described. For years it has been thought that the latent phase of HIV infection (i.e. integration of the HIV genome into human immune cells) precludes its cure. However, inventive biochemical strategies are being proposed. Recently, Savarino et al. described a novel means of ‘smoking out’ HIV as an adjunct to the ‘shock and kill’ technique, in the journal of Retrovirology. Normally, the HIV genome remains quietly coiled around histone proteins within human DNA. However, histone deacetylase inhibitors promote DNA unwinding and the expression of HIV genome. This ‘shock phase’ induces HIV expression, and in combination with drugs aimed at destroying these cells (i.e. the ‘kill phase’) HIV could, theoretically, be eliminated.
Dr. Kenny is a 2nd year internal medicine resident at NYU Medical Center