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Pathoecology of Vibrio cholerae to better understand cholera index cases in endemic areas

Periodic Reporting for period 2 - CholeraIndex (Pathoecology of Vibrio cholerae to better understand cholera index cases in endemic areas)

Reporting period: 2019-08-01 to 2021-01-31

"Spring 2020. We are in the midst of a pandemic caused by the virus SARS-CoV-2, the likes of which has not been seen since 1918 when the Spanish Flu pandemic killed over 50 million people around the globe. Given the seriousness of the COVID-19 pandemic, people have been asking important questions: “Where does the virus come from?”, “Why does it infect humans?”, “Did it adapt to an animal reservoir (e.g. bats)? If so, why are these animals not severely affected or even dying from it, as humans do?”, “Did genome alterations allow the virus to break the species barrier?”, “Could novel genome alterations make it even more virulent?”, and “Could the virus adapt to humans and be with us infinitively?”.

Though these are common questions normally associated with the emergence of new pathogens, it is important to remember that these questions have not been unambiguously answered for many “old” infectious diseases, which have caused over tens or even hundreds of thousands of deaths annually over the years. Notably, since 1961, humanity has been suffering from the 7th cholera pandemic, which sickens up to 2.9 million people and kills around 95,000 every year and is endemic in more than 47 countries (""Cholera: The Forgotten Pandemic"").

So what have we learnt about cholera and its causative agent Vibrio cholerae over the past century? Cholera is a severe diarrheal disease that can be fatal if left untreated with a case-fatality rate of 50% for untreated severe cases, which is lowered to below 1% for treated patients. It is transmitted primarily through contaminated water wherein a lack of proper sanitation and wastewater treatment can cause large volumes of diarrheal stool to be returned to the aquatic environment, contaminating common water supplies. Consequently, cholera spreads quickly after the infection of one or a few index cases, leading to major outbreaks in endemic areas each year. The ongoing 7th cholera pandemic therefore raised similar questions as those noted above for COVID-19: “Where did the bacterium come from initially?”, “Why does it naturally infect humans but no other known mammals?”, “Are there any animal reservoirs to which the bacterium has adapted?”, “Did the bacterium gain or lose virulence potential through genome alterations?”, “Do environmental non-human hosts serve as a training ground for virulence?”, and “Did the bacterium ultimately adapt to humans?”.

Our project tries to answer some of these questions. To do so, we use a Basic Science approach to decipher the molecular mechanisms used by the bacterium in its primary habitat, the marine/estuarine environment. Hence, we study the pathogen’s evolvability, its interaction partners in aquatic environments, its potential to colonize and form bacterial communities (known as biofilms) on biotic surfaces, and its defense systems against other bacterial species or eukaryotic predators.

Based on these studies, we hope to ultimately decipher the peculiarities of the current 7th pandemic V. cholerae strains and determine how transmission from water sources to the first humans to contract the disease, the so-called index cases, might occur in endemic areas of the world.

Our overall objectives are therefore to better understand (1) the lifestyle in which the pathogen engages in the environment and especially its ability for biofilm formation on the most common biotic surface in the marine habitat (i.e. chitinous surfaces) and (2) the switch the bacterium undertakes from a sessile to a motile lifestyle once it reaches the human intestinal environment; and (3) to decipher how V. cholerae cooperate and compete with other bacteria in the ocean but also upon entry of the human intestinal tract."
(1) Decipher the lifestyle in which the pathogen engages in the environment.
For this aspect of the initial proposal, we have performed and already published several studies. Briefly, we studied the interaction between V. cholerae and a co-habiting aquatic amoebae, which are usually feeding on bacteria. Our data showed that the pathogen uses different strategies to circumvent these bacteriovorus predators: first, V. cholerae can establish a replication niche within aquatic amoebae and take advantage of this niche for efficient growth in a shielded environment. Secondly, the pathogen can defend itself against these predators by using a molecular defense system known as the type VI secretion system, which allows it to kill the grazing amoebae. We also investigated how the bacteria colonize surfaces and distinguish the individuals around them, both of which are fundamental biological problems. In this context, we identified and visualized appendages known as pili that V. cholerae uses to colonize the chitinous surfaces and that enables the bacteria to distinguish between one another.

(2) A switch from sessility to motility.
The switch from a commitment to a certain environment towards an exploratory mode in which the cell seeks new nutrients or escapes danger signals, is a key aspect of bacterial survival. As part of this study, we have identified new regulatory proteins that drive this switch. We also showed that similar regulatory proteins are present in relatives of V. cholerae, including several other human and animal pathogens.

(3) Cooperation and competition with other bacteria.
As part of this last objective, we are currently investigating the ability of V. cholerae to compete with human commensal bacteria. Indeed, this is a very important topic, as our natural microbiota is supposed to protect us from intestinal pathogens such as V. cholerae. Why this isn't always working efficiently, resulting in more than 3 Mio cholera cases every year, is a key question in this field of research.
"So far, we have observed several unexpected behaviors that the pathogen engages in when it colonizes chitinous surfaces or interacts with other bacteria including members of the microbiota.

Until the end of this project, we expect to get a deeper knowledge on the underlying molecular mechanisms, as those might reveal the ""Achilles heel"" of the pathogen, which could be targeted to lower the cholera burden in endemic areas of the world."
Network of bacterial appendages on chitin surfaces