You’ve survived the first half of the day and finally it’s time to eat. Your stomach is threatening to growl if you do not find a meal, and find it fast. As you walk the street, a plethora of aromas caress your nose but none seem to entice you despite your hunger. Then it hits you…the scent of a double cheeseburger: juicy meat, fresh vegetables and your favorite condiments (fries included). All other senses go numb and you’re like an animal on the prowl. Your only objective now is to find, capture and devour that delicious double cheeseburger. (P.S. Don’t feel left out if you’re not an omnivore, I’m sure it is the same sensation).
The scenario above not only perfectly explains how many of us feel when it’s time to eat, but also relates to our white blood cells which fight invading bacteria. They work in a similar manner by patrolling the veins of the body and interacting with a variety of chemicals and chemoattractants from nearby cell bodies. These are not your typical white blood cells but neutrophils. Neutrophils are a type of white blood cell that are especially attracted to the scent of Acinetobacter baumannii, just as you are attracted to the double cheeseburger. The scent is strong and irresistible and their only “thought” is to find, capture and devour.
This juicy cheeseburger, specifically Acinetobacter baumannii, is the invading bacteria that the neutrophils want to capture. Acinetobacter baumannii is a Gram-negative bacterium currently threatening the microbial environment in our hospitals. Though Acinetobacter species have low virulence, they are one of the most common and serious multidrug resistant (MDR) pathogens encompassed within the acronym “ESKAPE,”: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. It is found in hospitals where it dwells among immunocompromised patients causing pneumonia, meningitis, urinary tract infections (UTI) and a whole host of other complications and has the added benefit of being able to survive for prolonged periods in this environment. Although an opportunistic bacterial pathogen, A. baumannii can be detected by our immune system leading to bacterial-mediated attractants of neutrophils that migrate toward the infected site, clearing away the infection.
Just as you are able to add or take out ingredients from the delicious double cheeseburger in order to change its tastes and smells which affects the amount of customers, microbiologists are able to alter the genome of A. baumannii by altering specific genes that encode for specific functions. For instance, A. baumannii has genes that encode for its phenylacetic acid catabolism pathway that is fundamental for the bacteria to invade an organism. This pathway is a metabolic pathway that degrades the by-product phenylacetate (PA), which acts as a bacterial chemoattractant, similar to the irresistible scent of a burger. When deleting the gacS protein within the paa operon, which is the unit made up of linked genes that is responsible for the PA catabolism pathway, the mutation alters this pathway. This is analogous to changing the meat of the burger to change its scent. The GacS protein is the sensor histidine kinase protein that is encoded from the gacS gene. As a result of the gacS mutation, the severity of the infection becomes decreased as the neutrophils continue to migrate toward the infection and clear it away, increasing the survival of the infected organism. Complementation was used to confirm that gacS was actually responsible for the altered pathway. Complementation is a process that confirms that when a specific gene is deleted, like when an ingredient is taken out of a burger, it’s that particular gene that’s responsible for the new outcome that is observed, like more customers coming to eat the burger from this change. Nearby genes also undergo complementation to confirm that the gene that was originally deleted was responsible for the outcome observed. From this process, it was found that ∆gacS was responsible for the altered PA catabolic pathway.
Furthermore, when the neutrophils are depleted, A. baumannii ∆gacS shows similar results to that of the wild-type because there is a decreased immune response against the bacteria (Fig 1 A and B). Similarly, the number of burgers being made continues to increase or remain the same because there are no customers to eat the burgers. Therefore, it can be concluded that neutrophils are extremely important for an organism’s immune system response against these bacterial infections, specifically when gacS is mutated.
So what makes these neutrophils so attracted to A. baumannii? Just as how you’re attracted to the smell of a burger, the neutrophils are lured to the “smell” A. baumannii gives off, the chemoattractant. This chemoattractant is phenylacetate (PA), which is a bacterial chemoattractant that is degraded by the PA catabolism pathway in the wild-type A. baumannii. However, in A. baumannii ∆gacS the PA catabolism pathway is disrupted, so there is no degradation of the PA, allowing for the accumulation of the chemoattractants. Neutrophil chemotaxis, which is the movement of the neutrophils in response to a chemoattractant, occurs as a result of the build-up of these stimuli. In wild-type A. baumannii, neutrophil chemotaxis leads to migration of the neutrophils toward the infection and migrates away after the infection is cleared, but in A. baumannii ∆gacS, the neutrophils continue to dwell at the site of the infection (Fig 1C). The neutrophils continue to dwell because they’re attracted to the lingering PA present, whereas in the wild-type, the PA is able to be broken down through the nonmutated PA catabolism pathway, allowing the neutrophils to migrate away. Therefore, it can be concluded that A. baumannii ∆gacS affects neutrophil migration patterns.
How do we know that it’s the smell of the burger that people are attracted to? When varying concentrations of PA are injected into an organism, higher concentrations of PA leads to greater neutrophil concentrations to clear away infections. Thus, higher PA levels result in greater survival rates. This determines that PA is the chemoattractant that neutrophils require in order to migrate to the infected area. In the same way that the concentration of PA can influence neutrophil chemotaxis, the distance to which the aroma of the burger can spread will influence the number of customers who will stop by.
Just as the delicious scent of burgers attract hungry customers to devour them, the phenylacetate acid (PA) acts as the “scent” A. baumannii gives off attracting hungry neutrophils to devour them. Altering the ingredients used is similar to the way the mutation, ∆gacS, changes the PA pathway involved in A. baumannii affecting the neutrophil response. The stronger the scent of the burger, the more people will be attracted to it’s location and be able to enjoy the deliciousness of that double cheeseburger. In the same way, increasing PA concentration leads to greater neutrophil migration and dwelling, clearing away of the A. baumannii infection and allowing for survival. We hope you can now appreciate the urgency of such experiments as researchers develop new antibiotics to eradicate the bacteria allowing for safer extended (>90 days) hospital stays. Bon appetit!
Sources:
Bhuiyan, M. S., Ellett, F., Murray, G. L., Kostoulias, X., Cerqueira, G. M., Schulze, K. E., . . . Peleg, A. Y. (2016). Acinetobacter baumannii phenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis. Proceedings of the National Academy of Sciences, 113(34), 9599-9604. doi:10.1073/pnas.1523116113
[Digital image]. (2017). Retrieved from http://www.bioquell.com/files/4814/1113/2103/Microbiology_420x420_Neisseria_meningitidis_41183311.jpg
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