Wednesday, December 21, 2016

Mycobacterium Tuberculosis CdnP hijacks Immune response


M tuberculosis is a topic that has come up several times in this blog. Tuberculosis is rampant in many developing and underdeveloped countries. The lead problem with combating tuberculosis has been difficulty in laboratory diagnosis, which has been now addressed with new generation cheaper tests which are available worldwide. An equally enormous challenge is treatment, which is due to its long treatment time often ranging to several months. That makes vaccination and exceptionally important tool. Though a universal vaccination campaign is in working order (BCG vaccine), TB is something that has not been eradicated or even controlled.

TB-immunology is a deeply researched topic. As I have explained in multiple earlier blog posts, it is wrongly conveyed by many that TB doesn’t cause an immune response. TB infection does elicit a strong Type IV immune response. This is evident from tests such as Mantoux positivity and granulomatous histopathological findings. What is not achieved is, the immune response is not directed enough to induce pathogen clearance. There are several factors at an independent level which coordinates the immune resistant ability- Intracellular localisation being one among them.

So, give this question a deep thought. Does all intracellular pathogen (Keep the question limited to bacterial pathogens for simplicity) cause chronic infection via resistance to immune attack? The answer is definitely “No”. So mere sitting inside a cell doesn’t help, since intracellular location in itself isn’t a very good defence. Cytosolic surveillance pathway such cGAS-STING pathway can recognise intracellular pathogens and stimulate an innate immune response. These pathways have been well studied for viral infections, but not for bacterial infections. See my earlier post on STING response pathway (Link)

A simple explanation goes something like this. When M tuberculosis infects and internalises into a cell such as a macrophage, the bacterial DNA and c-di-AMP signal is captured in the human cell as the bacterial entry. In response, a molecule called cGAMP is made which signals innate response. In reality, Dey et al;2016 (Paper published in Nature chemical biology) have identified that this signalling never quite happens.
Fig 1: Graphical abstract of the study. Source
The findings of the study are schematically represented in Fig 1. Bacterial cyclic dinucleotide phosphodiesterase (CdnP) action reduces immune detection of bacterial derived c-di-AMP and c-di-GMP and host-derived 2′3′-cGAMP by degrading them into non immunogenic nucleotides. These molecules being danger signals, non detection of these signals leads to numbing of innate response pathways. Host cells possess a control system called ENPP1, which degrades the 2′3′-cGAMP thereby controlling the inflammation. The researchers show that ENPP1 can also degrade bacterial cyclic di-nucleotides. To further look into the evidence, researchers created TB mutants for CdnP and infected a mouse model through aerosol route.

Fig 2: PDEi tested for CdnP inhibitory activity. Source
They showed that indeed there was a significant difference in survival and lack of CdnP was associated with increased survival. This is an indication that CdnP is a possible drug target. So the group tested several phosphodiesterase inhibitors (PDEi) including some FDA approved drugs- Tadalafil, Sildenafil and Cilomilast and Cilostazol. Fig 2 shows commercially available PDEi tested for their ability to inhibit CdnP activity. FDA-approved drugs are marked as *. Though the study shows possible PDEi the authors caution that they are not optimal for development as drugs owing to potential membrane-permeation liability. Further, these PDEi may cross react with ENPP1 which may further impact the outcome.

Herman O Sintim, one of the authors in the paper comments, “The host cGAMP never gets to a high enough concentration to activate the immune response. This is a very effective strategy the bacteria have developed to suppress an immune response.”

  Dey R, Dey B, Zheng Y, Cheung L, Zhou J, Sayre D et al. Inhibition of innate immune cytosolic surveillance by an M. tuberculosis phosphodiesterase. Nature Chemical Biology. 2016. doi:10.1038/nchembio.2254

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