Monday, December 08, 2014

Salmonella- survival Inside Macrophage; How?


Isn't it interesting to know that that there are several regions of interest in research, that I have never talked about? Well considering that there is so much of information out there, this blog timeline is too short to have even covered the part of any. Often I get communications from readers, asking opinion on certain topics and ends with a "You need to blog it". Well the list is growing up, but I enjoy those discussions. Here is one such topic that I felt needs a share- Salmonella Typhi, etiological agent of typhoid fever.

More than the biology of Salmonella, it is the story behind it that seems to be popular. So popular that almost everyone has heard "Typhoid Mary". Perhaps only there is a handful of names where patient / carrier is famous as much as the disease. Mary Mallon ( Irish immigrant) was the first documented "healthy carrier" working as a cook in North America. She was banned from the cooking industry twice having infected more than 50 people. There is a radiolab podcast which you must listen to (Link) Salmonella is a mega group of organism, with more than 3000 members in it. Salmonella Typhi (Note, I wrote Typhi and not "typhi"). S Typhi, is in fact a serovariety. Its complete name is Salmonella enterica subsp enterica serovar typhi. You see why we should stick to the short name.

Pathogenesis of typhoid is one of the most fascinating research question. Salmonella Typhi needs to infect in a large dose (ID50 > 105). Most of the organisms are destroyed by gastric acidity. Once into intestine, Salmonella calls up macrophages near it an enjoy a free ride. In addition salmonella can use anaerobic respiration with tetrathionate as a terminal electron acceptor, which gives it a competitive advantage over other members of flora. The details are covered in splendid detail in a post by Elio (Link), in small things considered.

Fig 1: Salmonella inside host. Source

Once inside the macrophage, the bacteria can simply inject different proteins (Nearly 20 effector proteins) into host cell, two distinct type three secretion systems (T3SSs) located on Salmonella pathogenicity islands- 2. These proteins interfere with antigen presentation, Cytokine secretion and cell survival. Moreover, there is an ability to survive inside macrophages as a dormant, non replicating persister. In a earlier paper, it was shown that something stimulates PPARĪ“ (Peroxisome proliferator-activated receptor- delta), a eukaryotic transcription factor involved in sustaining fatty acid metabolism, which increases glucose availability and enhances bacterial replication in macrophage model, and increases persistence. Another important point is once salmonella is inside a macrophage vacoule it probably messes with the pH through a mgtCBR leader sequence which senses cytosolic ATP levels, interacts with mgtCBR operon and is important in virulence.

This discussion came up when someone asked me how does salmonella survive inside a macrophage. As most of the times, as is true in science, it is very difficult to throw a complete definitive answer. That said, it makes an interesting question which I'm sure scientists are exploring.

There is a probable outbreak of salmonella in North Cumbria, with 10 laboratory confirmed cases and five probable cases. It is suspected that the origin is a food source from Penrith.
Forest CG, Ferraro E, Sabbagh SC, & Daigle F (2010). Intracellular survival of Salmonella enterica serovar Typhi in human macrophages is independent of Salmonella pathogenicity island (SPI)-2. Microbiology, 156 (Pt 12), 3689-98 PMID: 20817644

Helaine S, Cheverton AM, Watson KG, Faure LM, Matthews SA, & Holden DW (2014). Internalization of Salmonella by macrophages induces formation of nonreplicating persisters. Science, 343 (6167), 204-8 PMID: 24408438

Haraga A, Ohlson MB, & Miller SI (2008). Salmonellae interplay with host cells. Nature reviews Microbiology, 6 (1), 53-66 PMID: 18026123

Eisele NA, Ruby T, Jacobson A, Manzanillo PS, Cox JS, Lam L, Mukundan L, Chawla A, & Monack DM (2013). Salmonella require the fatty acid regulator PPARĪ“ for the establishment of a metabolic environment essential for long-term persistence. Cell host & microbe, 14 (2), 171-82 PMID: 23954156

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