Monday, March 11, 2013

Vibiro strikes, pseudomonas counter strike

Greetings,

    For the past few weeks, I have been attending conferences in Microbiology, and the topic that was invariably discussed at great lengths was that of antibiotic resistance. How are we going to treat the infections? Of course, antibiotics are not the only weapon that we can think of (But it is a major one). Researchers are trying variety of techniques such as new classes of antibiotics, phage therapy, quorum sensing inhibitors and use of bacteria against bacteria. I have talked about many aspects, in my previous posts. One thing that I haven't talked much about is bacteria vs bacteria. I have written one post on possible use of S epidermidis against the S aureus (Link). In the same post I highlighted that this can be attributed to epidermidis serine protease (ESP).

    Let me try and give u some important ideas in this realm of combat strategy. The key understanding here is competition. When it comes to human body (The angle of clinical thinking), there is a limited space and nutrition source for the microbe to take advantage of. Any site you can think of is occupied by highly competitive microbes, what we commonly refer as "Normal Flora". The invading pathogen has to overcome the competition, to establish a territory. Only when they establish can they be capable of causing infection. So you can now easily see, why normal flora is important and forms a part of our defense system.

   As always, even the best defense system have loop holes. The invading pathogen specializes in certain equipments (Virulence factors), that can breach the floral defense and gain access. The sensible idea here is that if you have a microbe flora that can counter attack the invader, then probably you got a great defense system. Mind you, this is all at the level of microbes. There is no active participation of the human body. We just need to support our microbial flora.

Fig 1: Pathogen Sensing and Killing’ system. Source
    Synthetic biology is the technology of the day. We can specifically engineer a bacterial cell, at its genetic level and ask it to perform anything. Form getting a bacteria to synthesize a pharmacological compound to diesel (Reference), microbes have given us fantastic support!!!. Similarly, E coli has been engineered to sense and attack pathogenic Pseudomonas aeruginosa (Reference).

   The engineered E coli produces LasR, which can detect the presence of P aeruginosa. The detection triggers two genes- The first produces pyocin and the second a lysin. The lysin causes bursting of E coli releasing massive quantities of pyocin. Pyocin can drill out holes on P aeruginosa and lyse the cell. The method could kill almost 99% of targets in open and 90% if there is a biofilm. Though still far from actual clinical use, this method for the first time emphasized that bacteria can be really useful against other bacteria.Considering that the organisms like pseudomonas are too difficult to treat and specificity of treating is low in current settings the option seems fantastic.

      That leads me to a more interesting recent paper. This paper concentrates on the Pseudomonas vs Vibrio. To get into this, I want to digress a bit and talk about bacterial secretion systems.

Fig 2: Bacterial secretion systems. Source
    Gram negative bacteria have a complex cell cover structure and hence transporting proteins requires specialized system. These are called as bacterial secretion systems. The secretions are mediated by a set of proteins and mostly involves a pili component. The use of such appendages sometimes allows very precise, syringe like delivery system useful in bacterial combats. The delivered protein is usually and enzyme or a specialized toxin that helps in virulence. There are different secretion systems- Type I to Type VI and probably more. They are designated for example as TISS (Type I secretion system), T6SS (Type 6 secretion system) etc. Based on their pathway, they are classified into 2 groups- Sec dependent and Sec independent.

     T6SS are found in several pathogens such as P. aeruginosa, enteroaggregative E. coli, S. Typhimurium, Vibrio cholerae, Yersinia pestis etc. They are multi-component systems composed of about 12 to 25 subunits. The T6SS functions as a virulence factor capable of attacking both eukaryotic and prokaryotic targets that involves protein transport through a contractile bacteriophage tail-like structure. Reference.

      So what did the researchers do? They tagged a fluorescent signal to Pseudomonas (Green) and Vibrio (Red). The study was able to show that the Vibrio attacks the Pseudomonas. As a counter attack the Pseudomonas throws up effector proteins (Tse 1) through a T6SS that effectively neutralize the Vibrio. This is a perfect demonstration of T6SS of Pseudomonas attacking the T6SS of Vibrio.

Fig 3: P aeruginosa targets T6SS. Source
The paper states "Repeated firing of the newly assembled T6SS organelle results in a counterattack aimed precisely at the point of initial attack by the heterologous T6SS+ cell. If no further attacks are sensed, then dephosphorylation of Fha1 would allow the T6SS organelle to be disassembled and thus primed (by establishing a pool of T6SS organelle precursors) for a quick response".

    The entire scenario makes a lot of sense. The Vibrio is a reluctant pathogen that wants to attack whatever it encounters, to establish itself. Pseudomonas was basically minding its own business, and when attacked responded by neutralizing the invader. The counter attack in this case was induced. My interest in this paper comes from application. Just as the previous idea of engineered suicidal bomber E coli, to attack Pseudomonas, we can possibly use some engineered Pseudomonas to attack Vibrio.

ResearchBlogging.org
Saeidi N, Wong CK, Lo TM, Nguyen HX, Ling H, Leong SS, Poh CL, & Chang MW (2011). Engineering microbes to sense and eradicate Pseudomonas aeruginosa, a human pathogen. Molecular systems biology, 7 PMID: 21847113

Basler M, Ho BT, & Mekalanos JJ (2013). Tit-for-Tat: Type VI Secretion System Counterattack during Bacterial Cell-Cell Interactions. Cell, 152 (4), 884-94 PMID: 23415234

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