Uncovering zinc's role in cholera signaling
New findings from MGI reveal how zinc shapes bacterial behavior, offering insight into cholera’s survival strategies.
Cholera is a waterborne disease caused by the bacterium Vibrio cholerae which, if left untreated, can lead to severe dehydration and even death. Although it is preventable, cholera continues to affect hundreds of thousands of people worldwide each year, particularly in regions with limited access to clean water and sanitation. As outbreaks become more frequent due to climate change, conflict, and infrastructure challenges, understanding how V. cholerae survives and spreads remains a key priority for global public health research.
Aathmaja Anandhi Rangarajan, a postdoctoral researcher working in Professor Chris Waters’ lab in MSU’s Department of Microbiology, Genetics, & Immunology is the lead author on a paper published in mBio, which describes new findings about how metal availability influences bacterial behavior, offering fresh insight into the persistence and spread of V. cholerae.
Rangarajan discovered a previously unknown enzyme that helps Vibrio cholerae switch between two important modes: moving freely or forming sticky communities called biofilms. This enzyme, named ZpdA (short for Zinc-inhibited Phosphodiesterase-A), is found in certain strains of the cholera-causing bacterium that are part of the current global pandemic.
ZpdA plays a role in controlling levels of a signaling molecule called cyclic di-GMP, which influences how bacteria move and stick to surfaces.
Rangarajan’s research shows that ZpdA is affected by the amount of zinc in the environment. When zinc is plentiful and many cells are close together, two regulatory proteins—Zur and HapR—turn off the gene that makes ZpdA. Zinc also directly blocks the enzyme’s activity.
In collaboration with Kiwon Ok, a postdoctoral fellow in MSU Foundation Professor Thomas O’Halloran’s group, they measured the metal levels and found that when zinc is scarce, this pathogen takes on high levels of manganese, allowing ZpdA to function. This helps the bacteria adjust their behavior based on the metals around them.
This work is among the first to demonstrate that zinc can directly influence cdG levels in bacteria, affecting behaviors essential to survival and pathogenicity. Since cdG signaling is conserved across many bacterial species, these findings could have broader implications beyond V. cholerae.
“We still know relatively little about the signals that affect cyclic di-GMP in bacteria, which has always intrigued me,” said Rangarajan. “In this work, we discovered that zinc can act as a signal to change the levels of cyclic di-GMP in Vibrio cholerae. This finding opens up exciting new possibilities to explore how different metals shape bacterial lifestyles in the many environments they encounter.”
"Metals are fundamental to life and found in every type of cell, but very few studies have demonstrated how metals impact cyclic di-GMP signaling,” said Waters. “Given the nearly ubiquitous role of cyclic di-GMP in bacteria, Aathmaja's work opens up new understanding of how metals impact bacterial disease and all other aspects of microbiology."
Rangarajan is now investigating whether other enzymes involved in cdG metabolism are also influenced by zinc and other metals in V. cholerae. This next phase of research could further illuminate how environmental signals shape bacterial physiology and pathogenesis.
By linking metal availability to cdG signaling, the study highlights a previously underappreciated layer of complexity in bacterial regulation. Understanding these mechanisms could inform future strategies for controlling cholera outbreaks and managing bacterial biofilms in clinical and environmental settings.
