At the intersection of the nervous system and innate immunity

Innate immunity is an important part of the host defence against infections in many organisms along the evolutionary tree. Whilst there is ample evidence that the innate immune system and the nervous system interact, the exact mechanisms linking these two complex networks remain to be revealed. Dr Alejandro Aballay’s research focuses on this intersection. He has gained significant insights into the neural control of immunity by developing an experimental model system that minimises physiological complexity.
Throughout recent years, it has been well documented that household antibiotics are not the reliable cure-all they were once thought to be. Numerous bacteria have mutated to gain resistance against antibiotics, leaving scientists with the question of how to combat this resistance and prevent immune infections.
Dr Alejandro Aballay is one such scientist aiming to tackle this problem. His recent research utilising the Caenorhabditis elegans roundworm model is providing a promising insight into the role that the nervous system has in controlling the immune response to bacterial infections.

The relative simplicity and the wealth of neuronal knowledge about C. elegans make the roundworm a prime model to study neural-immune communications

C. elegans as a model system
Nervous systems in most model organisms are extremely complex and, thus, generally incompletely described. In contrast, each of the 302 neurons within the C. elegans nervous system are well characterised, as are many of their signalling molecules (secreted factors that can act on other cells at a distance). This relative simplicity and wealth of knowledge make the roundworm a prime model to study neural-immune communications using sophisticated laboratory techniques.
Controlling immune reactions
An innate immune reaction to infection involves a rapid and definitive antimicrobial response. This provides protection for the organism, so long as the reaction occurs with the appropriate intensity. Any aberration, i.e., deficient or excessive inflammation, can lead to diseases in humans such as cancer, Crohn’s disease, rheumatoid arthritis or Alzheimer’s disease. Along with the immune system’s self-regulatory mechanisms, the nervous system can act as a perfect ally in fine-tuning the immune response, due to its responsiveness to many types of stimuli.
At the crossroads
Humans are protected by two main strands of the immune system – the innate and the highly specific adaptive immune system. C. elegans lacks the latter. Nevertheless, the roundworm possesses mechanisms to recognise and respond to different pathogens through its inducible innate immune system. In addition, the nervous system of C. elegans uses a variety of signalling pathways in response to infections that do not only impact on immune functions, but also regular housekeeping mechanisms in cells.

Dr Aballay’s group has, for example, determined a key role for certain proteins in nerve cells that are part of the family of G protein-coupled receptors (GPCRs) in controlling a signalling pathway that is as important in humans as it is in C. elegans’ immune system. This pathway elicits a microbicidal response via a conserved p38/PMK-1 mitogen-activated protein kinase (MAPK) that is critical for host resistance against bacterial infection. Dr Aballay’s research suggests that dopamine, a signalling molecule in the nervous system, inhibits the p38/PMK-1 MAPK pathway. Furthermore, sentinel neurons can control the unfolded protein response (UPR). UPR is crucial for the health of a cell and the survival of an infected worm. It ensures that host cells cope with the increased demand for new proteins during the course of an infection. The fact that C. elegans’ neurons can restrain its innate immune response in various ways may give us a glimpse into the causes of poor immunity in stressed humans.
Old drugs, new tricks
In a major undertaking, Dr Aballay’s group has screened an array of marketed drugs capable of activating the p38/PMK-1 MAPK pathway, determining whether these substances can confer protection against bacterial infections. A benefit of working with marketed drugs is that their bioavailability and safety profiles in humans are known and any new insights are therefore very relevant.

Using a simple yet relevant model system, Dr Aballay has provided remarkable insights into host-microbial interactions and, in particular, control mechanisms of the immune system

One of those drugs, the last resort antibiotic colistin, protected the infected C. elegans independently of its antibacterial mechanism of action. What is even more remarkable is that this beneficial effect was associated with increased tolerance to the bacterial burden rather than the intensified killing of the pathogens. In other words, C. elegans was able to withstand the bacterial threat without having to kill it off. It is tempting to speculate that other antibiotics with the ability to modulate the immune response in such a way may improve health conditions of patients with chronic infectious diseases.
What is more, Dr Aballay’s observation that the experimental inhibition of dopamine signalling in the nervous system enhances the immune response, opens up yet another group of drugs that may be tested for their ability to improve aberrant immune functions in humans.
Other research interests
Dr Aballay has taken an interest in mechanisms involved in the recovery from infection. He found factors that lead to the reduction of innate immunity markers and the increase in genes involved in detoxification and other cellular regulation. He also researches how microbial infections can lead to neurodegenerative diseases.
Using a simple yet relevant model system, Dr Aballay has provided remarkable insights into host-microbial interactions and, in particular, control mechanisms of the immune system. Research into its interplay with the nervous system is much needed in a time when our lives are becoming more stressful. This puts our immune defence at risk and renders former household antibiotics useless against antibiotic-resistant pathogenic bacteria.

How well do your research findings translate into humans?
As long as we study conserved signalling pathways, I believe our research has great potential to be translatable. Despite the long evolutionary gulf between nematodes and humans, a number of seminal discoveries made in worms have been translated to humans.
How relevant is C. elegans as a screening tool for drug discovery?
C. elegans is a fantastic tool for drug discovery. Its genetic tractability makes it perfect for target validation. In addition, the entire animal is transparent, making it possible to study the effects of drugs that target single cells in the context of an entire live animal.
What are the chances of finding new applications for old drugs through an improved understanding of the interplay between the nervous and immune systems?
It is too early to be able to tell.

Any potential new approach and discovery […] has the potential to aid and accelerate the discovery of new drugs

Will your discoveries help overcome the increasing threat of bacterial resistance to antibiotics?
Any potential new approach and discovery in terms of mechanisms involved in the control of immune response against infections has the potential to aid and accelerate the discovery of new drugs that should alleviate the problem of bacterial resistance to antibiotics.

What are your future research goals?
We expect to identify targets and drugs capable of regulating signalling pathways that can be used to alleviate infections and conditions that involve a malfunctioning immune system.

Research Objectives
Dr Alejandro Aballay’s early academic research into endocytosis and the intracellular transport of bacteria set him on his research career path. His recent research has focused on the organismal mechanisms of control of immune responses against bacterial pathogens, and the mechanisms involved in the control of recovery after infections.
Funding

• Dana Foundation (Neuroimmunology of Brain Infections and Cancers)
• NIH: NIGMS (GM070977)
• NIH: NIAID (AI117911)

Bio
Dr Alejandro Aballay is a Professor of Molecular Genetics and Microbiology, also serving as the Director of the Duke Center for Host-Microbial Interactions. He has made numerous contributions to the field of host-microbial interactions, focusing historically on bacterial virulence factors and their targets in host cells.
Contact
Alejandro Aballay, Ph.D.
Professor, Department of Molecular Genetics and Microbiology
Duke University Medical Center
207 Research Drive
264-265 Jones Building, Box 3054 DUMC
Durham, NC 27710
USA
T: +1 919 668-1783
F: +1 919 684-2790
E: [email protected]