Rethinking TB

New observations of the early stages of tuberculosis infection may turn scientists' understanding of the bug's pathogenesis on its head: clumps of immune cells, called granulomas, long thought to protect hosts from the disease instead appear to be launching pads for the bacteria to further invade an infected individual, according to a study published in __Cell__ this week. The insight may spawn new approaches to treating TB, which annually infects and kills millions of people worldwide and is increasingly cropping up in antibiotic-resistant forms.

"[This paper] is essentially showing that an orchestrated immune response that was apparently being found to wall off and restrict the infection is actually being enhanced by the bacteria for their own expansion and dissemination," linkurl:Lalita Ramakrishnan,;http://depts.washington.edu/immunweb/faculty/profiles/ramakrishnan.htm a University of Washington infectious disease researcher and the study's lead author, told __The Scientist__. Working in zebrafish embryos, whose skin is nearly transparent, Ramakrishnan and her coauthor, J. Muse Davis, were able to track granuloma formation and the behavior of bacteria in macrophages recruited to the site. According to Ramakrishnan, being able to observe the dynamics of TB infection sequentially in the same living animal allowed the researchers to study the early stages of the disease in unprecedented detail. "Typically people had used static measurements in adult animals to look at the progress of tuberculosis," she said. "We've been able to study infection from the get go. That may be the reason we've been able to pick up on an event that people hadn't picked up on before." Ramakrishnan and Davis found that when the TB bacterium, __Mycobacterium tuberculosis__, sets up shop inside a hapless host, it calls macrophages to the infection site and co-opts those cells into helping it replicate and spread. Researchers have known that the TB bug uses individual host cells to aid in replication, but such an orchestrated hijacking of cellular machinery on the tissue level had not previously been identified. "We have known for a long time that __Mycobacterium tuberculosis__ subverts the intracellular signal transduction pathways to suit its own design," Johns Hopkins tuberculosis researcher linkurl:William Bishai,;http://www.hopkinsmedicine.org/DOM/TB_Lab/faculty/bishai.html who was not involved in the study, told __The Scientist__. "What [the Davis and Ramakrishnan] study has shown is that beyond subverting the operation of the single cell, the bug is subverting the tissue processes of cell recruitment and tissue immunology of the host for its own design." The two researchers also identified a secretion system locus, ESX-1/RD1, that the bacterium seems to use both in recruiting new macrophages to sites of granuloma formation and to enhance infection within forming granulomas. Mutants lacking the ESX-1/RD1 locus were essentially unable to form granulomas within their hosts and were not as good at infecting new macrophages, the two showed. Ramakrishnan said the work built upon research conducted by Hannah Volkmann, a past graduate student in her lab. "She was the first to discover that if you don't have the [ESX-1/RD1] secretion system, you don't get granulomas," she explained. With Davis, Ramakrishnan elucidated the dynamics involved with this phenomenon. Davis and Ramakrishnan found that TB bacteria were able to coordinate the arrival of new macrophages to granuloma sites and then transfer some of their genetic material to those recruited immune cells. The two also saw bacteria inciting apoptosis in some macrophages that were in turn fed upon by arriving macrophages so that bacterial genetic information was disseminated. Ramakrishnan likened the activities of the TB bacteria to encourage granuloma expansion to home improvement. "If you're a bug sitting inside a macrophage, and you call more macrophages to you and find a way to transfer some of your contents to those cells, then you have more room to grow," Ramakrishnan said. "It's kind of like building an addition onto your house." Bishai instead drew an analogy to public transportation. "The bacterium is using macrophages as ferry boats or taxi cabs to spread itself through the host system," Bishai said. Though TB treatment usually starts much later than the events elucidated by Davis and Ramakrishnan, said Harvard microbiologist linkurl:Eric Rubin,;http://www.hsph.harvard.edu/faculty/eric-rubin/ the researchers' insights open the door to treatments that might modulate early infections by altering host responses to infection. "This [paper] suggests that that's possible," Rubin told __The Scientist__. Bishai agrees. "Virtually all successful antibiotics target the bug," he said. "This paper makes it very clear that the bug is manipulating host responses, and therefore we, as drug developers who want to fight the infection, might need to do the same."
**__Related stories:__***linkurl: Turning Back the Tuberculosis Tide;http://www.the-scientist.com/article/display/15477/
[23 May 2005]*linkurl:Mutant candidate for TB vaccine;http://www.the-scientist.com/article/display/20663/
[9 September 2002]*linkurl:M. Tuberculosis Genome Sequence;http://www.the-scientist.com/article/display/11639/
[10 January 2000]

Rethinking TB

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