Hide and Seek: Evasion of Immune Response by Trypanosoma cruzi

By Ben Lueck

            For as long as life has existed on this planet, every organism has been entangled in a fierce competition for survival.  This competition is introduced by the finite amount of nutrients required to support life in any given environment, meaning that whichever organism can obtain and utilize the greatest amount of nutrients can continue living, and ultimately reproduce.  This competition is ruthless, essentially a fight to the death where nothing is off limits.  Common tactics for survival include sequestering all of the resources to starve your competition, directly preying on weaker competition, or even poisoning your competition.  In the face of such brutal battle tactics, a very simple solution is often employed by organisms that cannot compete head on; find a place in which you can live, and hide.  There are no limits to where organisms can hide, and some of the most successful “hiders” are parasites that have found ways to live inside of other organisms.  In response to parasites and other pathogens, higher organisms have evolved ways to fight off these invaders.  Specifically, humans have evolved a complex immune system that is highly capable of coordinating responses to effectively kill invaders.  However, there are still holes in the human immune system, and one parasite in particular, Trypanosoma cruzi, has found ways to exploit these holes.

Romana's sign, a manifestation of
acute Chagas disease.

            Trypanosoma cruzi is a single celled human parasite best known for causing Chagas disease in South America, and the CDC estimates that 8 million people are currently living with Chagas disease.¹ T. cruzi is transmitted to humans from the Triatominae insects, commonly called “kissing bugs.”  These insects are so named because they tend to bite humans on the face, especially around the mouth and eyes.  When these insects bite a human and ingest a blood meal, they engorge to the point that they defecate on the host.  The feces containing the infectious T. cruzi cells can then enter the bite wound passively, but is more often actively smeared into the bite wound by the human host when they itch the bite.  Once inside the host, T. cruzi can enter the bloodstream and cause Chagas disease. 

            Chagas disease is defined by having two major stages of infection; an acute phase and a chronic phase.  The acute phase occurs immediately after T. cruzi infection, and while capable of manifesting as severe disease, is almost always mild, including only non-specific signs and symptoms including swelling, fever, and body aches.²  After the acute phase, the infection moves to the chronic stage, which is a prolonged and persistent infection.  Chronic infection is asymptomatic in 60-80% of individuals³, however 20-40% of chronic infections eventually lead to severe damage of the heart, nervous system, and digestive system.⁴ As previously mentioned, humans have an immune system to kill parasites and other pathogens.  How then, does T. cruzi consistently evade being killed by the immune system to cause a persistent infection?

            Before answering this question we must first explore the human immune system. The human immune system is extremely complex, composed of many branches, each of which contains a multitude of components.  The two major branches of the immune system are the innate immune system and the adaptive immune system.  The innate immune system’s primary job is to create barriers to keep foreign organisms outside of our bodies, and provide an extremely fast response when these barriers to infection break down.  To provide this timely response, the innate immune system is less specific than the adaptive immune system. 

Two branches of the immune system.

            The adaptive immune system on the other hand, is extremely specific for foreign cells, and more effective at killing them.  The adaptive immune system is divided into two main branches, one of which is composed of the B cells in our bodies that produce antibodies in response to pathogens.  The other branch is composed of T cells, of which there are two major types.  The T cells are divided by function into “killer” T cells, cells that are highly efficient at killing their target cell, and “helper” T cells, that function to coordinate the immune response between B cells, T cells, and the innate immune system.  The adaptive immune system is also capable of creating memory for pathogens.  However, this specificity and memory comes at a cost, being that this response takes 3-5 days to prime.⁵ As you can probably appreciate by now, the immune system has many components, and it takes a lot of communication to coordinate action between all of these components.  To do this cells use signaling molecules, called cytokines, to communicate with each other and coordinate action by all of the specialized cells.

            For a pathogen to most effectively break down the immune system, it must interfere with multiple components of the immune system.  This is indeed the strategy employed by T. cruzi, and this allows the infection to exist persistently and evade effective immune response indefinitely.  The first evasion tactic employed by T. cruzi is that it uses a wide range of acquired factors to enter many different types of cells in the human body.  This allows the parasite to hide from the immune system, which sees the host cell as normal, and cannot detect the parasite inside the cell.  Another evasion tactic used by T. cruzi is to interfere with the process of phagocytosis. Phagocytosis is carried out by specialized cells of the innate immune system called phagocytes, and is the process by which cells take up foreign material in a specialized compartment called a phagosome.  The phagosome is then fused with another specialized compartment called a lysosome, which is full of specialized products used to degrade the contents of the now mature phagolysosome.  This process is usually effective at killing foreign cells, but T. cruzi can escape from the compartmentalized phagolysosome, avoiding death, and continue living inside of the cell.⁶ The infected cells attempt to call for help using cytokines when they become infected, but T. cruzi blocks the production of these cytokines, and therefore other cells do not receive the message that the phagocyte is infected.⁶ 

            T. cruzi not only avoids components of the innate immune system, but the adaptive immune system as well.  T. cruzi is capable of altering the process by which T cells are made and activated, preventing the immune system from creating sufficient numbers of killer and helper T cells.⁸ This inhibits killer T cells from killing infected host cells to release the pathogen for killing by other cells, and allows T. cruzi to remain hiding in tissues as a persistent infection.  The absence of helper T cells also inhibits the coordination of immune response.  In addition, T. cruzi alters the process by which antibodies are produced, preventing the immune system from producing a quality antibody response.  This combination of evasion tactics, among others not mentioned, combine to create an environment that allows for T. cruzi to persist in tissues and consistenly evade immune response, making the parasite a formidable opponent for the human immune system.

            After discussing the numerous battle tactics of Trypanosoma cruzi mentioned here, one might ask: “why hasn’t Chagas disease wiped humans off the face of the planet?”  Well, T. cruzi is a hider, not a killer. As a parasite it is more beneficial to live in your host than to kill the host and lose your home. When it comes to facing the human immune system, it seems that Trypanosoma cruzi is more interested in playing hide and seek than going to war.

References

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