Coccidioides: An Evasive and Deceptive Fungal Pathogen

by AD

Coccidioides is the causative agent of San Jaoquin Valley Fever (coccidioidomycosis) which is primarily seen in Central and South America, and the Southwestern Region of the US(10). Coccidioides is an interesting fungal pathogen that is normally spread via spores introduced to hosts through air, associated with dust particles (1). Like other pathogens that ride dust, infection risk might be increased during dry seasons, freeing up the particles to be spread via wind gusts. Due to this factor, many believe that incidences of Valley fever may increase as global climate changes and the Southwest dries further (2).  Coccidioidomycosis has shown a large increase in prevalence in the last thirty years and it could continue to increase in coming years (12).  For this reason more needs to be discovered about Coccidioides and the resulting human illness.

Valley fever presents itself in several common symptoms: fever, a dry cough, rash and flu-like aching (1). Although those infected with coccidioidomycosis don’t usually die (3), many individuals are afflicted by the fungal pathogen in the Americas.  Some people that are at higher risk of infection include those with weakened immune systems and organ donation recipients, but it can infect otherwise healthy hosts (13). By studying Coccidioides, one can learn much about the host immune response to the pathogen and immune evasion methods.  Learning more about this fungus is paramount to our preparation for its continued prevalence.

Think of the immune system as the army of our bodies. We are constantly being introduced to new bacteria, viruses, and fungal pathogens that our body can fend off through war. The immune system is filled with cells devoted to enemy recon (helper T cells, dendritic cells, macrophages), generals that utilize enemy recon to administer an attack against them (B cells, killer T cells), and our soldiers on the frontlines (innate immune cells: neutrophils, endothelial cells secreting antimicrobial peptides, natural killer cells, etc.) that protect our body \everyday against small attacks.

The innate immune response can be thought of as the frontline of our bodies army, protecting us from infection through various cuts, micro-abrasions, dust inhalation, and talented enemy pathogens that can find their way through epithelial tissue. These cells use various ammunition to ward off infectious agents. One of the important molecules they use as ammunition is nitric oxide. Nitric oxide is a precursor to many different molecules that can have broad reaching effects from cell-cell signaling to tumor suppression to antimicrobial activity (8). For antimicrobial defense, many cells release this molecule for various functions including inhibition of DNA and protein synthesis, and hindering the ability of these attackers to perform other normal cellular functions (4).

One of the main cogs in our bodies army that utilizes this important molecule is the macrophage. Macrophages are cells that reside in tissue or can be recruited to sites of infection, and they can eat and degrade (phagocytose) infectious agents. NO can be made by macrophages and it can be used with certain oxygenated molecules like hydrogen peroxide to kill bad microbes (8). Macrophages utilize this molecule as a precursor to deadly ammunition that can be used to destroy foreign invaders. Coccidioides posadasii has found a way to fight back. C. posadasii can suppress this response of macrophages by decreasing production of nitric oxide (NO) (5). Many invading microbes need to be eaten to perform this downregulation of NO production, but this interesting fungus can deplete production of the ammunition without the increased risk of death of phagocytosis (5).

By allowing decrease in production without phagocytosis, the microbe can gain an advantage on the host immune system and is able to thrive in the host. Think of this like an opposing army infiltrating enemy lines, depleting its important stocks of ammo, and being able to multiply within enemy lines, increasing its population of soldiers. But how exactly does it deplete the enemies ammunition? C. posadasii can secrete an unidentified molecule that can inhibit the ability to make nitric oxide (5). To do this, the molecule can inhibit a protein essential to nitric oxide synthesis: inducible nitric oxide synthetase (iNOS) (5). This is analogous to capturing the head of production of an ammunition supply factory in the middle of war to be able to infiltrate enemy lines without getting shot at. By utilizing this ability, C. posadassi can infect individuals with decreased risk of death. To do this, the fungi employs spies that can prevent molecules used by iNOS from being used in the production of NO(6). These molecules are arginine, and the spies are called the Arginase I complex. This complex degrades arginine before it can be used by iNOS for its intended goal (6). By stealing molecules needed to produce NO, kidnapping the production facilities boss, and employing enough spies to perform these functions, the fungi can thrive behind enemy lines.

This modulation of NO production is also common to other pathogens such as Cryptococcus neoformans and Candida albicans, but the former and Coccidioides cannot be transmitted from human to human (dead-end interaction) (9). So why would Coccidioides engage in this challenging battle without the ability to infect more humans? There could be many reasons. Perhaps a mammalian reservoir of Coccidioides (there is no known animal reservoir at this point) has led to adaptations that confer the infectious nature toward humans, but not allow the spread from human-human. Maybe the fungi can get into the GI tract of human hosts and escape, or maybe humans are the home that these fungi have always dreamed of and they don’t want to leave.
 
There is recent evidence that Coccidiodes could be hiding even more efficiently from the immune army than previously hypothesized. There have been multiple cases of Coccidiodes hiding in a healthy organ and the fungi using this tissue as a trojan horse to attack a new host when this organ is used for transplantation (11).

After being transported as a gift, the fungi escape from the tissue and attacks the new host with vengeance. This is a very effective strategy by the fungi for a few reasons. When someone receives an organ donation, one of the primary concerns of this is the recipient rejecting the new tissue, so they must be put on immunosuppressants. This means that the fungi are being introduced to an army that is sleeping at base with depleted ammunition stocks. Also, in many cases the recon cells and generals have never seen these foreign invaders before, so they have no idea what they are up against. This allows the fungal cells to have an advantage against the immune system and thrive in the new environment. This may also allow Coccidioides to escape into different regions of the body and escape into the GI tract to be transported back to the environment.

Reports of coccidioidomycosis in the lower GI tract are rare, but perhaps they’re either underreported or not examined. When individuals admit themselves into the hospital, an examination of their intestinal contents may not be of primary concern. This could lead to an under-reporting of the Coccidioides in the fecal matter of individuals. Maybe these novel fungi are utilizing undiscovered methods to escape into the GI tract and infect other mammals. Some have shown the ability of Coccidioides to traverse into the lower GI tract, but more work needs to confirm this ability (7). Maybe this is an evolutionary behavior of a successful pathogen evolving. This fungal pathogen has adapted to permit an infectious behavior of humans, will it also evolve to infect other humans from human excrement? The novel fungus is certainly adapting to the times, and preparing itself for future battles.

Much can be learned from Coccidioides and its intricate methods of infectivity. The ability of Coccidioides to infect the host by limiting its ammunition supply is an extremely effective tactic and its use of a trojan horse to infect more humans from seemingly healthy tissue is useful. Perhaps, the pathogen is further evolving to overcome a dead-end human interaction. Only time will tell if the fungal pathogen will evolve further to counteract other immune system attacks. Will we continue to see a rise in the prevalence of coccidioidomycosis or will we learn enough about the microbe to thwart its unique battle strategies? Will this thrifty bug continue to evolve successful immune evasion techniques, or will the human immune army prevail? Only time will tell.

References

1. Jin J. Valley Fever (Coccidioidomycosis). JAMA. 2013; 310(22): 2470.

2. Kolivras KN, Comrie AC. Modeling valley fever (coccidioidomycosis) incidence on the basis of climate conditions. Int J Biometeorol. 2003; 47: 87-101.

3. Kirkland TN, Fierer J. Coccidioidomycosis: A Reemerging Infectious Disease. Emerging Infectious Disease. 1996; 3(2): 192-199.

4. Bogdan C. Nitric oxide and the immune response. Nature Review. 2001; 2(10): 907-916.

5. Gonzalez A, Hung CY, Cole GT. Coccidioides releases a soluble factor that suppresses nitric oxide production by murine primary macrophages. Microb Pathog. 2001; 50(2): 100-108.

6. Hung CT, Xue J, Cole GT. Virulence mechanisms of Coccidioides. Ann N Y Acad Sci. 2007; 1111: 225-235.

7. Zhou S, Ma Y, Chandrasoma P. Small Bowel Dissemination of Coccidioidomycosis. Case Reports in Pathology. 2015; 403671: 1-3.

8. MacMicking J, Xie QW, Nathan C. Nitric Oxide and Macrophage Function. Annual Review of Immunology. 1997; 15: 323-350.

9. Collette JR, Lorenz MC. Mechanisms of immune evasion in fungal pathogens. Current Opinion in Microbiology 2011, 14: 668-675.

10. Hung CY, et al. A metalloproteinase of Coccidioides posadasii contributes to evasion of host detection. Infection and Immunity, 2005; 73(10): 6689-6703.

11.  Wright PW, et al. Donor-related coccidioidomycosis in organ transplant recipients. CID 2003; 37: 1265-1269. 

12. Brown J, et al. Coccidioidomycosis: epidemiology. Clinical Epidemiology, 2013; 5: 185-197.

13. Hector RF, Laniado-Laborin R. Coccidioidomycosis- A Fungal Disease of the Americas. PLOS Medicine. 2005, 2(1): 15-18.

14. Pinterest Pictures

15. Scabies Innate Immune Response