Despite being classified as distinct entities, the nervous and immune systems work interdependently. In the brain, skin, and gastrointestinal tract, the interplay between the nervous and immune systems, known as the neuro-immune axis, orchestrates a variety of physiological processes. 

“It fascinated me how cells in these two systems talk to each other,” said Isaac Chiu, an immunobiologist at Harvard Medical School who spent graduate school investigating the crosstalk between T cells and microglia in neurodegeneration. 

Further research led him to an even more complex situation. During his postdoctoral research on bacterial skin infections, Chiu discovered that bacteria could directly interact with sensory neurons, causing pain and suppressing immune responses. This unexpected finding introduced a third player, microbes, into the mix. 

“The finding that nerves can directly sense microbes opens up so many question,” Chiu said, “How do neurons sense microbes? How do neurons participate in an infection? Does pain affect host defense against pathogens? How do neurons, microbes, and immune cells interact altogether?” 

To answer these questions, Chiu launched his lab combining immunology, neurobiology, and microbiology in 2014. Recently, Chiu and his team uncovered novel mechanisms of pain and inflammation in various microbial infections such as meningitis, anthrax, and colitis. By establishing the link between neurons, immune cells, and microbes, Chiu’s research may inspire new therapeutic strategies to treat these infections. 

What are the biological mechanisms underlying pain?

As an unpleasant sensation, pain is the body’s fundamental ability to sense danger. Pain is mediated by neurons called nociceptors, which have long branches going from the spinal cord all the way to tissues such as the skin, the gut, and the joints. Once nociceptors activate, they send signals to the brain, and the brain processes that information. Different pain-mediating neurons sense cold, heat, and mechanical force in different ways. Pain is intimately associated with the immune system. Inflammation involves pain, redness, heat, and swelling. When tissues are full of inflammatory mediators and immune cells, pain occurs. 

How do nociceptors interact with the immune system?

There is bidirectional crosstalk between immune cells and nociceptors. Immune cells produce cytokines, prostaglandins, and other lipid mediators that can act directly on the nerves to make them fire more easily. Immune cells also sense neuronal mediators from nociceptors. In their nerve terminals, nociceptors store neuropeptides such as calcitonin gene-related peptide (CGRP), and many different types of immune cells express receptors for these neuropeptides. 

Our research team has focused a lot on CGRP and its interaction with receptor activity-modifying protein 1 (RAMP1) and the calcitonin receptor-like receptor, which are highly expressed in macrophages, neutrophils, monocytes, T cells, and B cells. We recently found that their interactions could suppress cytokine production or polarize macrophages to a more wound-repair and less proinflammatory phenotype. The interaction also regulates neutrophil recruitment into tissues and acts on dendritic cells to affect downstream T cell responses. These neuropeptides are powerful regulators of immunity.

What roles do microbes play in neuro-immune interactions during pain?

Pain fibers can be hijacked by bacteria in a clever way. We recently studied meningitis, where bacteria invade the brain through the cerebrospinal fluid. We found that nociceptor neurons were exploited by two bacterial pathogens, Streptococcus pneumoniae and Streptococcus agalactiae, which are the leading causes of meningitis in humans. These bacteria induce pain directly by activating nociceptor neurons with a pore-forming toxin, pneumolysin. Pneumolysin induces the neurons to fire and produce CGRP. CGRP then acts on the macrophages next to the nerves, suppressing the production of protective cytokines against the bacteria. By shutting down the immune response, the bacteria survive better in the meninges and more easily invade the brain. 

When we removed the nerves or CGPR in the meninges using genetic or pharmacological approaches, we enhanced the immune system’s ability to fight bacterial pathogens that cause meningitis. The macrophages produced higher levels of cytokines and chemokines, which helped recruit neutrophils and monocytes to kill the bacteria. 

How do you study the crosstalk between microbes, neurons, and immune cells?

We use a combination of in vivo and in vitro approaches, but we prioritize in vivo experimentation because it captures all neuroimmunological factors. 

We use animal models to look at what happens to one system when we manipulate another. For example, we genetically target specific microbial factors to see which microbe toxin causes pain. We also target specific immune cell types to see whether they contribute to pain or host defense against the microbe. Additionally, by using chemogenetic or optogenetic methods, we can temporarily activate or silence neurons and see what happens to the immune system or microbes. 

To study specific molecular interactions, we perform in vitro assays in a dish. For example, we grow nerves in a dish to see how they respond to the microbe or culture immune cells and see if they respond to a neurotransmitter or neuropeptide in a certain way. 

How does neuro-immune crosstalk work in the body?

We study these interactions in the gut and skin, which are two major sites where nerves, immune cells, and microbes closely interact. The situation is different in each context. 

In the gut, mucus forms a barrier and protects the gut from harmful substances. Inadequate mucus production can lead to inflammatory bowel diseases. Last year, we discovered that nociceptors in the gut regulate goblet cells, which produce mucus. The gut microbiome helps this process by stimulating nociceptors to produce CGRP, which triggers mucus production. Meanwhile, mucus keeps the microbiome healthy as well. We found in mice that this mechanism protects against colitis. 

Microbes can silence neurons as well. We studied anthrax, a skin infection in humans and livestock that does not cause any pain. Anthrax bacteria produce a toxin that acts on the nociceptors and blocks pain. It is fascinating that microbes can exploit different pathways not just to survive in the body, like in meningitis, but also to help them spread. 

Can targeting pain pathways help treat infections?

There is a lot of promise there. By blocking CGRP, we can enhance immune responses against microbes. In fact, there are many drugs now on the market that block CGRP or its receptor RAMP1 to treat headaches and migraine. We can repurpose these drugs to treat infections. For example, in bacterial meningitis, we could use CGRP blockers to enhance antibiotic treatment. In addition, CGRP also regulates immune responses during invasive skin infections, such as necrotizing fasciitis. Necrotizing fasciitis is a horrible disease caused by aggressive Streptococcus pyogenes infection. We are interested in exploring the potential of using CGRP blockers to treat this infection. 

What is the most exciting aspect of this research?

I'm excited about how microbes affect neurons. The interaction between microbes and neurons plays a role in pain and in the gut-brain axis, where gut microbes affect the brain. We think it affects many different neurological diseases such as Alzheimer's disease, Parkinson's disease, and depression. Interestingly, some evolutionary biologists working with Caenorhabditis elegans found that neurons might be the most ancient defense against pathogens. Microbe-neuro-immune circuits may have evolved to protect us or to activate when we're sick. These circuits are essential to gaining insights into the underlying causes of neurodegeneration and infection. 

This interview has been condensed and edited for clarity.