Wednesday, December 4, 2013

It’s a Fungus-Eat-Dog World: Blastomycosis

By LN

            It’s a summer evening, and the skies are finally clear. The rain all week has kept your outdoor activities to a minimum, but at last you now have the time to take a proper romp in the forest with your dog. The damp from the debris on the forest floor soaks into your shoes, and you smile as your dog pulls at their leash, eager to keep going. Following the peaceful babble of the swollen stream, you and your dog enjoy an evening out. You watch the sunset, and your dog digs in the mulch. After heading back home, you are satisfied with a relaxing evening.
            Fast forward a few weeks. You and your dog are sick with what feels like the flu. Being the superb pet owner you are, you decide to take your dog to the vet, because the poor pup is having difficulty breathing, hasn’t been eating, and now has a fever. The vet screens for first for common ailments like cancer and bacterial infections. Upon taking x-rays of your dog’s lungs, the vet gives you a diagnosis of blastomycosis, a fungal infection, and suggests you get yourself checked out for the same thing. After your own checkup, you find that you and your dog are infected with the same disease. How did this happen?
Figure 1: Left side shows the microbe's morphology when it lives
in the environment and the areas to which it's endemic.
Right side shows the stages of infection in humans.
            Blastomyces dermatitidis, the cause of blastomycosis, is a widespread fungal pathogen found in the U.S. and Canada. In the U.S. it is most often found in the central and eastern parts of the country. Generally found in river valleys and areas near bodies of water, B. dermatitidis is thought to favor damp organic matter, such as decaying leaves and wood, as a habitat (1). It’s a dimorphic fungus, living as a filamentous mold in the environment and transforming into a round yeast when inside a host. This is triggered simply by temperature change. At 25˚C, B. dermatitidis takes its filamentous form, but at body temperature (37˚C), it takes its yeast form (2). Blastomyces is an ascomycete, so it forms conidiospores when it reproduces. These conidiospores are the infectious agents. Blastomycosis begins as a pulmonary infection caused by inhalation of disturbed spores, which could be caused by something like a dog digging in the dirt. It can infect healthy as well as immunocompromised humans, as well as a variety of other large mammals such as dogs and horses. Once the infection has taken hold, it could spread to other areas of the body, potentially resulting in something as severe as meningoencephalitis, an infection of the brain and surrounding tissue. If a disseminated infection is misdiagnosed or left untreated, the infected person or animal could die. Overall, dogs are infected more often than humans are. Outbreaks in kennels are sadly rather common; in Minnesota, there are at least 50 reported canine infections per year (3). This does not include the instances of misdiagnosis. It can be easily mistaken for a bacterial lung infection, and treatment with antibiotics only makes the dog more susceptible to the fungal infection.
Figure 2: The number of canine infections due to B. dermatitisin the state of Minnesota from 1999-2012.
             Proteins present on the cell surface can play a large role in how a pathogen interacts with the host that it infects. In Blastomyces dermatitis, the surface protein BAD1 has been found to be an essential factor in its ability to infect a host (4). It interacts with the host’s complement system, specifically the C3 molecules, and prevents them from binding to the infectious cell. The complement system is part of what is called “innate immunity”, which is the part of your immune system that reacts and fights the infection nonspecifically, and won’t remember a pathogen if you get reinfected. For clarification, this is not the part of the immune system that allows vaccines to work. Complement C3 molecules are incredibly important to the human immune system. They act like big neon sign that says ‘DANGER, THIS DOES NOT BELONG HERE’ to the other immune cells on patrol. When they are bound to a foreign cell surface, leukocytes (white blood cells) phagocytose and destroy them. BAD1 doesn’t allow this process to even begin, because it prevents the C3 molecules from binding at all. Other surface molecules, such as α- and β-glucan, have also been found to be important for B. dermatitidis pathogenicity in establishing an infection for similar reasons. If we can figure out how this organism lives outside of a host, this would give us additional insight as to how it succeeds when it invades.
            There is not a lot known about how this mysterious microbe lives in the environment. Attempts to culture it from environmental samples and even to recover it from inoculated animals have overwhelmingly failed. Success has only been achieved 20 times in the lab since its discovery, and each success could not be repeated (5). However, thanks to the advances in technology in recent years, molecular methods have been used to detect B. dermatitidis from samples of soil. Using the polymerase chain reaction (PCR), researchers at the University of Wisconsin – La Crosse developed a method to detect B. dermatitidis DNA by amplifying it and then visualizing it using gel electrophoresis (6). This method is cheap, effective, and has potential to be used as a detection system that can help identify areas where the fungus is endemic so that instances of infection can be avoided.
             Let’s return to the scenario where you’re walking your dog in a damp forest, but set in the (hopefully near) future where testing for B. dermatitidis is a regular occurrence. If the infrastructure was in place, the areas near your waterways would have been sampled and tested for Blastomyces. You would have run into a warning sign as soon as you neared the wooded area warning you about the potential to contract blastomycosis. As we’ve already established, you are a superb pet owner, and seeing this warning, unwilling to risk the health and safety of your best friend, you promptly turn around and seek out another place to watch the sunset, knowing that you both will be safe.

References
1.            CDC - Fungal Diseases - Blastomycosis.
2.            Medoff G, Painter A, Kobayashi GS. 1987. Mycelial- to yeast-phase transitions of the dimorphic fungi Blastomyces dermatitidis and Paracoccidioides brasiliensis. J. Bacteriol. 169:4055–60.
3.            Blastomycosis Statistics and Maps - Minnesota Dept. of Health.
4.            Zhang MX, Brandhorst TT, Kozel TR, Klein BS. 2001. Role of glucan and surface protein BAD1 in complement activation by Blastomyces dermatitidis yeast. Infect. Immun. 69:7559–64.
5.            BAUMGARDNER DJ, PARETSKY DP. 2008. The in vitro isolation of Blastomyces dermatitidis from a woodpile in north central Wisconsin, USA. Med. Mycol. 37:163–168.
6.            Burgess JW, Schwan WR, Volk TJ. 2006. PCR-based detection of DNA from the human pathogen Blastomyces dermatitidis from natural soil samples. Med. Mycol. 44:741–8.

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