Following Olfactory Cues to Detect the Activation of Innate Immune Responses

Thanks to their keen sense of smell, African giant pouched rats can be trained to detect landmines and tuberculosis. Two weeks ago, Maarten Boersema reported in The Scientist that “It takes about nine months to fully train a tuberculosis-detection rat. But once trained, the rat can screen thousands of patients every month.”

Rats are not the only disease-sniffing animals. Results from a study published in 2006 (Diagnostic accuracy of canine scent detection in early- and late-stage lung and breast cancers) show that, in just a few weeks, ordinary household dogs can be trained to accurately distinguish the scent of different breath samples — breath samples from lung and breast cancer patients and breath samples from healthy controls.

Photo credit: Mark Watson, licensed under the Creative Commons Attribution 2.0 Generic license.

Results from another study (Human ovarian carcinomas detected by specific odor) published a few years later, demonstrate that trained dogs can distinguish different types and grades of ovarian carcinomas from healthy control samples, with 100% sensitivity and 97.5% specificity. Interestingly, the study also shows that most common ovarian carcinomas are characterized by a single specific odor, an odor different from those of cervical, endometrial, and vulvar carcinomas.

The disease-sniffing ability of dogs is not limited to cancers. Dogs for Diabetics (D4D) trains dogs to recognize the scent associated with chemical changes in blood sugar, so they can provide an alert prior to the onset of hypoglycemia  (low blood sugar), which develops as a side-effect of insulin therapy. D4D then places the trained dogs with insulin-dependent diabetic patients.  

Now, a new study shows that humans are capable of similar feats — they can recognize the scent of an activated innate immune response. The study (The Scent of Disease: Human Body Odor Contains an Early Chemosensory Cue of Sickness), published a few days ago (January 22, 2014) in the journal Psychological Science, was carried out by an international team of researchers based in Sweden and the U.S.

The researchers recruited 8 volunteers for “donation of body odor”. The donors received injections of either LPS or saline. LPS — or bacterial lipopolysaccharides — are major components of the outer surface membrane present in almost all Gram-negative bacteria and are efficient stimulators of the innate (inflammatory) immune response, our first line of defense. Saline is a salt water solution that was used as a control. The donors wore tight T-shirts to allow for the sampling of body odor.

Four hours after injection of either LPS or saline, the researchers measured the body temperature of the donors as well as the levels, in the donors’ blood, of proinflammatory cytokines — proteins that indicate the presence of an inflammatory response. The researchers found that the donors injected with LPS had increased body temperature and increased levels of proinflammatory cytokines — thus, these donors developed an inflammatory response similar to that induced by a bacterial infection. In contrast, body temperature and levels of proinfammatory cytokines were unchanged in the donors injected with saline (the control donors).

Next, the researchers recruited 40 participants to evaluate the body odor of the donors. Each T-shirt worn by the donors during and after injections of LPS or saline was placed separately in a squeeze bottle. The 40 evaluators were asked to squeeze the bottles, smell the headspace, and rate the intensity, pleasantness, and health of the body odor. The results of the study indicate that humans can recognize and differentiate the odors of sick and healthy individuals.

The researchers conclude that humans are able to detect sickness on the basis of body odor alone, which can be triggered by the innate immune response, observable just a few hours after activation induced by injection of LPS (as in the study) or by bacteria (as in natural infections). Thus, the ability to sense body odors may provide a “behavioral immune response” that protects healthy individuals from infection by changing their patterns of interaction with infected individuals.   

Copyright © 2014 Immunity Tales.

15 Responses

  1. mashim331
    mashim331 at | | Reply

    I would love to call those rats and dogs mentioned in the post “Diseases Police” as they are able to catch diseases by sniffing. However, I have mix feelings on the odor detection experiment on human. Although human can differentiate a lot of odors, our sense of smell is nowhere near that of a dog or a rat. So I wonder how accurate the result of the experiment is, especially when it was performed with only a small group of testers. Maybe a future experiment can prove this claim more effective. Nevertheless, this post provides a very interesting perspective of the immune system is that our body avoids sickness based on odor. A defense mechanism by odor is not new in the animal world. For example, spoiled foods produce an unpleasant odor that lets us knows not to eat those. However, the sense released by immune system is a fairly new approach. While the odors made by spoiled food are very strong and can be detected easily, the odor of sickness is much more subtle. People might “feel” the sickness odor around but they might not smell it and name it. Anyway, that would be so awesome if each disease has an odor tag for us to differentiate. No more lab work, no more blood sample will be needed if this comes true.

    1. sarah
      sarah at | | Reply

      I agree with your opinion about improving the accuracy and efficacy of the experiment. I do not think that a small group of people can represent the ability of the olfactory system for the world. Every person has olfactory receptors in their nostrils that send signals to the brain telling us what a certain molecule smells like. I believe that not everyone can smell the exact same odor as the person next to them. So how do all of the participants in the experiment can identify the smell of “disease” and associate it with a similar odor? I think that since all (or most) humans have an immune system that consist of different types of white blood cells and their functions are all very similar compare to the next person, the smell of “sickness” can be identified from the tagging of LPS to the degradation of LPS via our immune system. The process of our immune system can produce a product of something that all (or most) humans have in their body and can probably be identified by every single person with olfactory receptors. There is an endless possibility as of what type of molecule that a person’s nose can identify as a “disease”. This means that there are many ways a person can smell sickness and can probably identify what type of sickness it is just base on the process of our immune system. I find this very interesting and I hope they have a more in-depth experiment that may interest us furthermore.

  2. cns2392
    cns2392 at | | Reply

    It is not surprising to me that humans can detect illness in other humans just on the basis of smell. Were you to only use touch, you may detect side effects such as chills or heat, dryness or clamminess, and even frailness. Using just eye sight, one might see tiredness, weariness, paleness and more. Using just hearing, one may hear struggled cough, restlessness, sniffling, and even heavy or shortness or breath. So why would the sense of smell be any different? Granted, our sense of smell is likely our weakest sense, and therefore the most underestimated. In isolation, the sense of smell must differentiate between healthy and unhealthy, and using the innate immune response is brilliant of our bodies to do. The innate, or non-specific, immune response is antigen-independent and results in an immediate response. The first line of defense is the skin, which plays a role in tear and saliva production, which often have a noticeable scent. Sweat, which we all know has a very distinct scent, has fatty acid components that inhibit the proliferation of bacteria. Based on scent alone, this article shows that our bodies are capable of amazing things; however, realistically, we are never forced to rely on the one single scent. We use our entire sensory system in every encounter of life. Sensing an unhealthy individual will be noticeable by touch, sight, hearing and olfaction. But, it’s nice to know that I am capable of smelling them before becoming too close or staying too long in their vicinity!

    1. ics100190
      ics100190 at | | Reply

      Although I agree with the fact that our sense of smell is underestimated, it is one of our strongest senses with the capability of memory imprinting stronger that most of our other senses. If isolated there is no telling how amplified our sense of smell could become and how it could lead to “sniffing out” the sickly. I think as you mentioned above we already can detect certain bodily scents and odors that help us understand particular characteristics of the body and how it is functioning. For example like you mentioned sweat. If one is sweating, there are certain deductions that can be made: they have an elevated heart rate (exercise) the body temperature could be elevated (fever) or they simply didn’t wear deodorant that morning. Regardless of the situation the smell of sweat is a clue that can help you to determine something about a person. I would be interested to see if certain scents could be developed to indicate a particular disease or illness, almost like a pathogen perfume, and would like to see if after exposure one could differentiate different illnesses based upon their designated scent. If our body is naturally secreting these hormones it shouldn’t be too difficult to synthetically compose a scent that mimicked the one that we are naturally producing.

  3. Z. Haqqani
    Z. Haqqani at | | Reply

    It’s not too surprising to me that the participants were able to distinguish between an ill patient and one in good health, as I’ve noticed for myself that people who are sick tend to smell a bit different than they do when they are well. However, like Mashim331, I am kind of iffy about this study. Body odor varies from person to person. Some people have a naturally strong body odor, while others don’t. Would this not affect results?

    Also, would this method only be effective for bacterial infections? Because I’ve learned in my microbiology class that the body reacts differently to bacterial infections than it does to viral infections. If this method works for diagnosing bacterial infections specifically, maybe we could utilize it in areas where patients can’t afford for certain tests to be performed, like those that distinguish between viral and bacterial infections.

    1. Samantha Deochand
      Samantha Deochand at | | Reply

      As far as the body reacting differently towards different types of pathogens, the innate immune response towards both bacterial and viral infections is the same. For the adaptive immune response, the same steps will occur as far as eliminating lymphocytes that attack healthy human cells and lymphocytes that do not attack the pathogen. I think the only real difference would be the receptors and antibodies that are used to neutralize and opsonize the pathogen for phagocytosis by the macrophages.

  4. Samantha Deochand
    Samantha Deochand at | | Reply

    The idea of a “behavioral immune response” is quite a valid concept. Before small pox was eradicated, people know to stay away from people who showed symptoms of small pox like the rash and blisters. It would not surprise me that we have evolved to be able to detect sickness by the sense of smell. While our sense of smell is not as strong as a dog, our sense of smell is our strongest of our five sense because it does not get processed by the thalamus before it is stored in the brain. Everyone knows that when they smell their mom’s cooking or significant other’s cologne, memories are instantly remembered without thought. So why not apply this to disease and sickness? Many people cannot stand the smell of hospitals because they claim to smell the sickness. They might be smelling the disinfects used in hospitals, but it can also very well be “sickness”. Ultimately, evolution could still be working on developing our sense of smelling and accurately distinguishing different disease.

  5. ankovalli
    ankovalli at | | Reply

    Human sense of smell might not be as strong as the mammalian sense of smell but humans do have a pretty good sense of smell. When someone walks into a house or restaurant they can immediately pick the smell that is in there and depending on whether its pleasant or not, they may stay or leave. The same concept can be used towards sick people or places like hospitals that harbor sick people; we normally stay away or avoid these people or places. Humans don’t want to be near people that are sick because we can smell the odor of their body while they are sick and it’s something that we don’t want to be near and try to move away from. For example, people don’t want to marry their siblings or cousins because they have similar MHC genes like themselves. We tend to go get attracted to people whom have different MHC genes compared to ours and whose pheromones we are attracted towards. Our MHC is what presents pathogen peptides to TCR’s that aid the overall adaptive immune response. Similarly, we don’t like staying near sick people because we know they are hosting pathogens that can easily transfer to our bodies and cause us to get sick.

  6. Amina Bouhamed
    Amina Bouhamed at | | Reply

    I do believe that it would be beneficial for us to be able to sense sickness in individuals with infectious diseases. It can protect us from contracting these diseases by keeping away from those infected. But I doubt that it can serve as a benefit to us since we can’t sense the development of chronic diseases like cancer and diabetes. That’s why it’s actually more important to do research on animals like dogs and rats, that can sense emerging sicknesses, giving doctors the ability to be one step ahead of illnesses. There is actually a recent study done this year on fruit flies, where they are modified to sense cancer cells. Apparently cancer cells emit an odor due to their metabolic differences, that can be sensed by sensitive creature like the fruit fly. They tried to modify their antennas to glow when they detect healthy cells from different kinds of cancerous cells. This is possible due to the fly’s ability to differentiate responses in receptor neurons. All the scientists had to do was genetically alter the relevant neurons to trigger a response due to a cancerous odor, and thereby emitting a glow in the intended fluorescent protein. This sort of scientific progress, where neurons in animals can be manipulated to detect odor of diseases, can eventually help scientists produce a more helpful way to create devices that can do the same. This can make detection easier, cheaper and more effective.

    Martin Strauch, Alja Lüdke, Daniel Münch, Thomas Laudes, C. Giovanni Galizia, Eugenio Martinelli, Luca Lavra, Roberto Paolesse, Alessandra Ulivieri, Alexandro Catini, Rosamaria Capuano, Corrado Di Natale. More than apples and oranges – Detecting cancer with a fruit fly’s antenna. Scientific Reports, 2014; 4 DOI: 10.1038/srep03576

  7. dpitts5
    dpitts5 at | | Reply

    Wow this is one of the coolest articles I’ve read so far. I was always aware that dogs had a very keen sense of smell, however I never knew that dogs and rats were able to detect diseases based on breath samples and body odors. The article states that this is not only something animals are capable of but humans as well. This statement I thought was a little far fetched because like mashim331 stated humans sense of smell are nowhere as good as a dogs sense of smell so this makes me question the validity of the humans results. I am unaware if the use of dogs and rats for medical purposes is occurring in the United States, if not I think this would be a great thing for modern medicine. The use of dogs and rats in medicine would be advantageous economically. I can personally attest to receiving a PPD test, which is the test used to test for tuberculosis. I had to get a shot intradermally (between the skin) which caused an induration under this skin. After this I had to return to the facility approximately 48-72 hours later for them to be sure the induration had went down, confirming I was tuberculosis free. With the use of rats we can avoid the use of needles, save time and money, and in turn screen thousands more patients than we would via the old fashion ppd test.

  8. tbrown110
    tbrown110 at | | Reply

    I heard about dogs being able to detect cancer via their olfactory sense, but I believed it to be a myth. This is a rather amazing feat and testament to the strength of their sense of smell. To realize that such slight shifts in the human body can be detected, such as changes in the chemicals in blood, by the nose brings a rather “out-of-the-box” approach into light that can be used in the diagnosis process. This may be a stretch, but since dogs can detect cancer in the lungs and breast both in/on the chest cavity they may be able to detect the build-up of arterial plaque, which can occur in the chest cavity, via their noses. This could help with the diagnosis of chest pains to help prevent arterial disease and possibly other heart conditions. Also the African giant pouch rat being able to detect tuberculosis is phenomenal. This could help expedite diagnosis because the PPD test which is currently used requires a couple of days to complete. To specify it would more helpful to know how early the rats can detect tuberculosis because it is a caused by a slow growing bacteria that takes weeks to manifest itself. As far humans being able to smell when an individual I have to align myself with the consensus that it not that difficult to smell the different in a sick individual and a healthy one.

  9. Maria Mbugua
    Maria Mbugua at | | Reply

    When reading this article I remember an article I read last year that talked about the Giant African Pouched Rats (1). I was very fascinated by them but I was not very certain until I read the article in the blog. It is very interesting that rats detect tuberculosis since the infectious agent mycobacterium tuberculosis causes many problems especially in people which HIV. Another important fact about mycobacterium tuberculosis is that phagocytes cannot degrade and it replicates in the phagocytes. If the rats or trained dogs can detect them it may help the individual from dying. The dogs that can detect cancer at early stages will save many peoples lives. The rats and the dogs are very smart animals. Many experiments should be performed to see how the rats and the dogs detect the diseases.
    Mahoney, A., Edwards, T. L., Weetjens, B. J., Cox, C., Beyene, N., Jubitana, M., & … Poling, A. (2013). GIANT AFRICAN POUCHED RATS (CRICETOMYS GAMBIANUS) AS DETECTORS OF TUBERCULOSIS IN HUMAN SPUTUM: TWO OPERATIONAL IMPROVEMENTS. Psychological Record, 63(3), 583-593. doi:10.11133/j.tpr.2013.63.3.012

  10. Aaron Peaslee
    Aaron Peaslee at | | Reply

    It’s absolutely astounding, although not too surprising, to me that given all the time, money, and effort focused on developing technology to detect disease that dogs, rats, and even humans, to a lesser extent, can perform the same task by way of natural development. Personally I would like to see a more in depth studies on these mechanisms. As our technology develops it will become increasing similar to organic processes, and at some point the bridge will be made between modern computing as we understand it and organic computing. Better understanding of these mechanisms could help us in making that bridge. It could allow us to incorporate the organic process with computers to create a detection method (similar to the type of innovation that Mina previously mentioned) that would both be simple and accurate and possibly more time and cost effective.

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    Sacs Longchamps Rose at | | Reply

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  12. kennybob1
    kennybob1 at | | Reply

    i have theorized that the human immune system can be affected by another’s immune system through olfaction. (by means of MHC). This would be beneficial to the evolution of humans, especially since virus and bacteria are capable of evolving more quickly than humans, and that this sense may be a driver of prejudious via the flight or fight mechanism

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