How the equine immune system uses inflammation to defend against pathogens

In our anything-but-sterile world, horses are both filled with and surrounded by microscopic organisms—bacteria, viruses, and protozoa—as well as more complex parasites. Some, especially those that make up the normal microbiome, are beneficial and support horse health. However, the environment is also filled with pathogenic microbes that put horses at risk of disease. If those microbes enter the body successfully, the horse becomes a host to invaders that set up shop, churning out replicates of themselves in massive numbers and eventually spreading to new hosts.  

To fight that scenario the body comes equipped with a multipart defense plan: Recognize invaders and sound the alert; send out first-line defense mechanisms; crush the enemy with tailor-made attacks for that specific invader; and get the body back to “normal”—a state known as homeostasis, says Caroline Chauché, DVM, MSc, PhD, a research fellow at the University of Edinburgh, in Scotland.

It’s a system that works well—keeping horses living for decades rather than months or years, she says. But it’s not perfect. In particular, inflammation resulting from immune responses, while it represents “an essential step in the battle against a pathogen’s progression and its related disease processes,” can also undermine the general health and welfare of the host itself.

Inflammation: At the Center of the Defense Plan

When a pathogen slips into the body—through the lungs, the gastrointestinal tract, or the skin, for example—the immune system sends out alerts to all its components. “It’s saying, ‘There’s something foreign, and you should do something about it,’ ” says Christiane Schnabel, DVM, a researcher in equine immunology at the University of Leipzig, in Germany.

It next initiates an immediate general kind of attack by producing cytokine (special messaging protein) and other types of immune mediators, which attracts and activates local and peripheral (blood) innate immune cells, says Chauché. That attack isn’t very precise, but it gives the body a fighting chance while it configures a more specific strategy for that pathogen.

“After 12 hours or so, you have (even) more leukocytes and inflammatory cells that get attracted there, to take care of the foreign material,” Schnabel explains. This next step of the defense is a more customized battle called the adaptive immune response, which uses pathogen-specific antigens that, ideally, destroy the invaders, she says. “Usually, this results in the body eventually clearing the pathogen through a cascade of first-defense cells and then some other (adaptive) cells.”

The Inflammatory Response: Swelling, Secretions, Redness, Pain, Heat

The second part of the immune system response—the general attack, also known as the innate response—spurs inflammation, Schnabel says. Cytokines have just signaled alerts in the brain and throughout the body, calling for extensive shipments of combat supplies to the affected region.

In the lungs and other organs, much of that process happens at a microscopic level or in other ways that are invisible to the observer, says Alicia Long, DVM, an emergency and critical care fellow at the University of Pennsylvania School of Veterinary Medicine’s New Bolton Center, in Kennett Square. It’s a process that’s very similar to what happens visibly on skin (e.g., with a wound), where you might see redness, swelling, pain, and sometimes oozing, she says.

As the body flushes large amounts of fluids into the affected area, swelling naturally occurs, says Chauché. “It’s actually necessary because you are bringing into the wound basically all the necessary cells and nutrients and cytokines that are needed for the repair process,” she explains.

If there’s bleeding, clotting materials also flow into the wound, Long adds.

Meanwhile, cytokines call different types of cells to action to heal and repair tissue damage, says Chauché. In the respiratory system, for example, basal epithelial cells must multiply and differentiate to replace what pathogens destroy—especially viruses that take over the host’s cell “machinery” to pump out their own viral proteins, which eventually kill the cell. “In the end it creates a real wound in the lung that needs to be repaired,” she says. 

Plus, fluids are a quick fix for filling gaps that unbalance the body’s osmotic pressure, adds Chauché. “The whole body’s interconnected, and it doesn’t like emptiness,” she says. “So if you create a wound, then some part of your body needs to be filled up. The first way the body does that is by bringing fluids.”

To clear the invaders, the tissue “gets a bit leaky,” says Schnabel. That’s especially true with mucosal surfaces such as upper airways. “They increase their secretions, so maybe there’s a very runny nose or more mucus than you’d usually have,” she says. “That’s a first line of defense to get out the stuff that’s not supposed to be in there.”

Increased blood perfusion causes the tissue to redden, she explains. “And then that inflammatory signaling is also entailed with pain,” she adds.

Heat usually accompanies inflammation, too—either locally, in the affected tissues, or generally, as a fever, says Long. In fact, it’s part of the cytokines’ role when they detect immunocompromise: Turn on the heaters.

“There are actually direct molecules whose job it is to cause that response,” she says.

The idea, Long explains, is to make it too hot for invaders to survive. “Basically, the body is trying to make it an unfavorable environment,” she says. “So to a certain extent, that is a good thing.”

Inflammation’s Balancing Act in the Horse

The great irony about the immune response and resulting inflammation, of course, is while it’s fighting disease processes, it’s also using up a lot of energy and making the horse feel sick and weak, our sources say. In other words, both the pathogens and the body’s reactions to the pathogens can create illness.

If the immune response is effective, the pathogens lose the battle before the inflammatory process overcomes the horse, Chauché says. But it doesn’t always work that way.

Sometimes inflammation ends up being as great a threat to the horse’s health as the pathogen itself—if not more, Long says. High fevers can cause permanent tissue damage and eventually death. Swelling and mucous secretions can block normal organ function. Prolonged pain can not only be detrimental to welfare but also cause a catabolic state that interferes with healing, and it could give way to neuropathic pain, in which horses become permanently oversensitive to stimuli that shouldn’t be painful.

“A lot of these severe pathologies are excessive inflammation,” Schnabel says.

Age, general health status, genetics, and environmental conditions probably make some horses more susceptible than others. But many other factors likely lead to such a wide variety of individual reactions, says Chauché. “It’s like with COVID-19,” she says. “Some people get very sick, because the immune system reacts too strongly to the virus, and some people just cope with it.”

The pathogen itself could also be the cause, Chauché adds. Herpesviruses and influenza viruses, for example, have evolved to trick the immune system as they replicate and/or—in the case of herpesviruses—hide quietly in their hosts for years.

“They’re excellent at this; they know how to do it,” she says. “They’re totally hidden so that the body thinks, ‘There’s no flu here,’ and it doesn’t react. And meanwhile, the flu is replicating and spreading really well.”

It’s when inflammatory responses become uncontrolled that they’re deadly, says Chauché. Her team’s been studying a cytokine that seems to keep signaling an immune response to repair lung tissue damaged by viruses, for longer than is necessary. “That’s going to harm the body, and you basically keep destroying whatever you’re trying to repair,” she explains.

So if the pathogen makes the horse sick, but so does the inflammation meant to kill the pathogen, what are caretakers to do?

For Long, it’s all about balance. Veterinarians must let the horse’s immune system fight its fight but in a controlled manner, she says.

“We’ve got medications that effectively reduce swelling and fever, and they make the horse feel better,” says Long. “But actually, we’re reducing the body’s ability to fight. It’s something we discuss in a hospital setting a lot, because we don’t want to respond too aggressively with anti-fever and anti-inflammatory medications because those processes are probably a little beneficial to the horse’s response to whatever’s going on.”

Medications can also mask important information about the disease, she says. A fever that resolves on its own suggests the disease is resolving—which would be impossible to know if the horse is on fever-reducing or anti-inflammatory drugs. Plus, medications can come with side effects, often affecting the gastrointestinal tract or the kidneys.

If fever and inflammation are preventing the horse from eating, drinking, and resting, though, they require treatment, Long says. “You need to not have them suffer or be in pain,” she says. “I think it’s better to not give them too much. But at the same time, you have to balance that out with the horse being comfortable.”

Chauché agrees. “You don’t want to suppress the inflammation; you want to prevent the uncontrolled inflammation that’s not good for you,” she says. “You want to keep the inflammation that’s helping the body fight against viral replication and ­transmission.”

“Inflammation … is obviously really necessary to fight disease, but it can really become detrimental when it goes into overdrive,” Long says.

The Effects of Vaccines

Vaccines include a deactivated virus or bacterium, or portions thereof, to cause the immune system to react and provide a customized, adaptive immune response—which will be ready to go when the horse encounters the real virus in the environment, says Schnabel.

This generally provokes a slight but necessary innate response with inflammation at the time of vaccination, she says.

But the idea is that during real exposure to the pathogen, the body will “skip” the prolonged reliance on just the innate response and, hence, detrimental inflammation, Schnabel explains. “The specific antibodies recognize the virus and then ideally neutralize it,” she says. “However, the adaptive immune system is not always perfect, and vaccination is usually designed to prevent severe disease.”

Viral vaccine research will probably lead to more efficient vaccines based on live, attenuated viruses administered locally—at the site where the pathogen invades—says Chauché. For example, an intranasal vaccine offers protection in the respiratory mucosa. “You want to stay as close to the real situation and help the body make a natural response to the virus vaccine,” she explains.

Schnabel notes pregnancy can dampen immune responses due to a weakened natural reaction to invaders. “You don’t want to get rid of the foreign thing growing inside your body, because it’s a baby,” she says.

The Effects of the Microbiome

As researchers investigate various body system microbiomes—the ecosystems of microbes living there—they’re starting to understand more of their functions. One of them, says Long, could be immunity.

“Something that we’re learning, actually, is that not only are our own immune cells involved in fighting off invading pathogens, but the normal bacteria that inhabit (each system) are, as well,” she says.

Healthy microbiomes appear to “kind of overgrow and take over” invaders, she says, just by living there. The good bacteria don’t necessarily take on a direct battle; rather, they take up space or resources, and they might produce byproducts that are toxic to pathogens. “Basically, it’s like a competition, right?” she says. “And as long as the environment is pretty healthy, things can work out pretty well.”

For this reason, disruptions in the microbiome—for example, through a sudden change in diet or the administration of antibiotics—could interfere with its natural immune functions, Long says.

The Effects of Existing ­Inflammation

When inflammation is already present, the body is susceptible to opportunistic bacterial infections in the inflamed area, Schnabel says. That’s because the immune system has been weakened by the first fight, she says.

Asthmatic horses, for example, sometimes have low-level pneumonia, Long says.

Some researchers believe inflammation due to smoke, dust, or other environmental factors could make horses more susceptible to viral infections, says Chauché. Even excess ammonia in stalls, for example, might lead to airway inflammation that increases the risk of reactions to pathogens. “You reduce your chances of fighting a virus,” she says. “There’s definitely a link.”

Some have hinted at such a link with the deadly 2022 influenza outbreak in Colorado mustangs following a nearby wildfire or the Streptococcus zooepidemicus outbreak in Iceland just after the 2010 eruption of the Eyjafjallajokull volcano (TheHorse.com/160009).

Our sources, however, are less convinced. “You can have wildfires and volcanic eruptions without outbreaks, and you can have outbreaks without these events,” Schnabel explains. “So it’s very difficult to pinpoint.”

Take-Home Message

Inflammation is—in many senses—a necessary evil, our sources say. An effective pathogen-killer, the first-line defense mechanism also can drain horses’ energy. While researchers are still learning about secondary effects and long-term consequences, they already know it’s important to control inflammation so its benefits continue to outweigh the risks. Ongoing studies will provide greater insight into the role of uncontrolled inflammation in equine asthma and other diseases.