How the Cholera bacteria resist viruses that attack them

A new icddr,b study has shown how a proportion of the epidemic cholera bacteria survive attack by viruses that kill bacteria, after an epidemic to cause the subsequent epidemic in the next season–insight that might be useful to prevent and control the disease.

The infamous Vibrio cholerae bacterium causes severe diarrhoea and vomiting leading to rapid dehydration and death if left untreated, and is responsible for a yearly death toll between 21,000 and 143,000 worldwide, according to the World Health Organization (WHO).

Cholera has survived for centuries with the status of a ‘haunting ancient disease’ that has challenged all efforts to curb it.

Nature seems to have its own mercenaries against V. cholerae. These are viruses called vibriophages that attack the cholera bacteria in the patients’ intestines and also in the aquatic environment where the bacteria circulate.

(left) Vibrio Cholerae and (right) virus known as phage. Image: icddr,b

 

Following every epidemic, these vibriophages or simply phages rise in number and subdue the outbreak of cholera bacteria. “This is a natural process that causes cholera epidemics to collapse after reaching a peak,” says Dr Shah M Faruque, director of the genomics centre and senior author of the study* published in the Scientific Reports, a journal maintained by the Nature Publishing Group.

However, a fraction of the epidemic bacterial population survives to sow the seeds for the next epidemic season. Until recently, it was not completely understood how the surviving bacteria defended themselves against the phages.

Patients at icddr,b Dhaka hospital. Cholera epidemics peak during August-September & March-April in Bangladesh. Photo: Shehzad Noorani / icddr,b

 

According to the icddr,b study, when the cholera bacterial population grow to a high density,  they can communicate with each other using a mechanism called ‘quorum sensing’. Quorum sensing is used by a number of bacterial species to communicate with each other on a community-level. In V. cholerae, quorum sensing activates certain regulatory mechanisms that alter a number of physiological processes including enhancement of phage resistance, as now shown in this study.

“The presence of certain chemicals called ‘autoinducers’ secreted by a bacterium is sensed by other bacteria and that is how they know that they are part of a large group in order to be able to defend themselves against the viruses that kill them,explains Dr Faruque.

In plain English, using the Quorum Sensing technique, the bacteria interact as though they ‘discuss’ amongst themselves which adaptation technique might lead to their survival under unfavourable conditions. “Presumably, this is one of the ways how the cholera bacteria survive the attack by phages until the next peak season,” says Dr Faruque.

 

Infographic: icddr,b

 

Since maintaining constantly elevated defence is energy consuming, bacteria choose to use this system only when they are at high cell density and hence more likely to be found by invading phages.

Earlier research has shown that the cholera bacteria found in the environment and also from infected patients’ stool are densely clumped, which indicates that a similar mechanism of phage defence may be active inside the bodies of cholera patients as well.

This original research done in icddr,b was funded primarily  by the Wellcome Trust grant awarded to Dr Shah Faruque and in part by National Institutes of Health (NIH) grant sub-award by the Harvard Medical School and with core support from the Governments of Bangladesh, Canada, Sweden and the UK.

 

Insights for preventing Cholera in the environment

The icddr,b study also looked at the biological effects of autoinducers, chemicals that the bacteria secrete to communicate with each other during quorum sensing. The study shows that certain of these molecules enhance the bacteria’s resistance against vibriophages in a number of ways.

Using Quorum Sensing, the bacteria can inactivate the vibriophages and at the same time enhance the development of phage-resistant cholera bacteria.

How is this insight useful?

Dr Faruque explains, “As we now know what induces the defence created by the bacteria in the environment and in cholera patients, future research could focus on using this knowledge as a leverage to weaken the defence and hopefully control or tone down cholera outbreaks.”

 

Insights for Phage therapy

Using naturally occurring phages against bacterial infections is known as ‘phage-therapy'. Given the evergrowing problem of antibiotic resistance, phage therapy offers a potential alternative to antibiotics for treating bacterial infections. “Since the phages are enemies of bacteria, earlier researches have tried to investigate whether phages could be used as a treatment for bacterial infections but these did not always prove to be sufficiently effective.”

“With the new insight, we know which of these signalling chemicals strengthen the defence created by the bacteria,” notes Dr Faruque. It may have future implications for research. “Chemicals that can neutralize the quorum sensing signal molecules could be coupled with phages while treating bacterial infections in patient and this might lead to better cure for bacterial infections,” anticipates Dr Faruque.

* Citation: Hoque MM, Naser IB, Bari SM, Zhu J, Mekalanos  JJ, Faruque SM. quorum regulated resistance of Vibrio cholerae against environmental bacteriophages. Sci. Rep. 2016; 6:37956. doi: 10.1038/srep37956.

Muhammad Nabil

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