How Do Protozoan Parasites Survive Inside Macrophages?

First of all, it is important to define what is a macrophage. Actually, it is a specialized kind of white blood cell playing a major role in the immune system. In fact, macrophages are mainly responsible to clean up the body. As such, they patrol the body engulfing and digesting all kind of debris and foreign matters, such as cancer cells, dying cells and microorganisms. They are therefore a great line of defense against microorganisms, including parasites.

However, even though it is very unusual, some protozoan parasites are able to live and replicate inside macrophages without being digested. They include the protozoan parasites Leishmania species, Trypanosoma cruzi and, at a lesser extend, Toxoplasma gondii. It is interesting to note that, even if it is quite rare, some bacteria, like the causative agent of tuberculosis, and viruses are also able to live and replicate themselves inside macrophages.

Leishmania is considered as the best example of parasites living inside macrophages because it must infect this type of cells in order to fulfill its life cycle. On the contrary, Trypanosoma cruzi is able to stay in the bloodstream or infect a wide range of different cell types. Furthermore, Toxoplasma gondii is an obligate intracellular parasite able to infect a wide range of cell types including macrophages. As such, the latter two parasites are able to invade a macrophage but it is not a strict requirement to the fulfillment of their life cycle.

The survival mechanisms of Leishmania inside macrophages are the most extensively studied. It is still not clear how exactly this parasite enters inside macrophages, but there are currently many relevant hypotheses. At this point, it is important to mention that all type of cells show many signalling molecules at their surface. When a cell is dying, it expresses a specific molecule called phosphatidylserine usually known by the acronym PS. This molecule is a kind of «eat me» signal for the macrophages. As cell expressing PS are dying anyway and are supposed to be harmless, they are engulfed by the macrophage silently without activating it. It is though that infectious Leishmania establish a mixed population with some of them exhibiting PS and others perfectly viable. The viable ones can then enter silently within the macrophage at the same time then PS-expressing dying ones.

Furthermore, it is relevant to mention that Leishmania is also able to enter another type of immune system cells called neutrophils. However, the parasite is not able to proliferate and live within this cell type and infected neutrophils will slowly die within two or three days. As neutrophils are generally recruited at the site of infection before macrophages, Leishmania can enter neutrophils in order to shelter and wait for the arrival of macrophages. After that, they can enter the macrophages when it engulfs dying PS-expressing neutrophils containing living Leishmania. This is commonly known as the Trojan Horse strategy. Furthermore, it is also thought that this parasite could also express a wide range of other molecules at its cell surface helping him to be able to enter macrophages silently.

The relationship established between Leishmania and the macrophage is very complex. Once inside the macrophage, Leishmania is transformed in a smaller immobile form called amastigote and takes the control of the macrophage’s functions in order to promote its own survival and replication. It is interesting to note that amastigotes within macrophages uses many molecules present inside the macrophage to feed themselves. Furthermore, within the macrophage, Leishmania can successfully hide itself in order to avoid being destroyed by other immune system mechanisms. In fact, the parasite greatly modulates the expression of the macrophage’s genes, which induce the deactivation of the digestion function of the macrophage. Moreover, the parasite secretes many molecules and enzymes to prevent being digested by the macrophage.

Leishmania also induces an overexpression of the genes coding for the macrophage’s surface proteins responsible for recruiting other macrophages at the site of infection. This is a key step in the infectious process of this parasite because it proliferates within the macrophage until it bursts because of the high parasite load. If other macrophages are already present at the site, it is easier for the parasite to infect new macrophages.

Finally, Trypanosoma cruzi and Toxoplasma gondii are thought to enter macrophages more actively than Leishmania by direct interaction using their cell surface molecules. After that, Trypanosoma cruzi and Toxoplasma gondii also hijack the macrophage’s functions, or in these cases of any other cell types, in order to promote their own survival and replication.

Source: Merck Manual

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