Trypanosoma cruzi is the causal agent of Chagas disease that affects 6–7 million people around the world, principally in Latin America. This disease is characterized for the presence of an acute phase in which the host immune response plays a central role in the elimination of the parasite. If the parasite is not efficiently eliminated, patients can remain asymptomatic or develop a chronic infection. One of the cells that are primarily infected with this intracellular parasite is macrophages (Mϕ). Mϕ present a wide array of activation states with classically activated macrophages in one pole (CAMϕ) and alternatively activated macrophages (AAMϕ) in the other. One of the most important differences between these two activation states is the presence of the inducible nitric oxide synthase (iNOS or NOS2) in CAMϕ and arginase 1 (Arg-1) in AAMϕ; both enzymes share the same substrate, l-arginine, and are reciprocally regulated by the action of Th1 cytokines in the case of NOS2 and Th2 cytokines in the case of Arg-1. The activation of CAMϕ permits the production of nitric oxide (NO), highly trypanotoxic, while the activation of AAMϕ allows the synthesis of polyamines, necessary for parasite duplication. l-arginine is a very important metabolite situated in the center between the elimination and perpetuation of T. cruzi.
- inducible nitric oxide synthase
- trypanosoma cruzi
Trypanosoma cruzi is the causal agent of Chagas disease that affects 6–7 million people around the world, mainly in Latin America , although in the last years it has also become a potential public health problem in developed countries due to the constant migrations with cases reported in the USA, Canada, Europe, Japan, and Australia .
This intracellular obligate parasite enters the human host in the form of metacyclic promastigotes that are released from the triatomine feces during the blood meal, through damaged skin or mucosae. Alternatively, infection can occur through other routes such as oral, congenital, blood transfusions, or organ transplants. After entering the host, trypomastigotes are phagocytized mainly by macrophages, where they transform to amastigotes, the intracellular form that has the ability to replicate. In order to evade the host immune response and ensure its persistence inside macrophages, Trypanosoma has developed multiple strategies. One of these has as a target
2. Phases of the infection with Trypanosoma cruzi
The infection with T. cruzi presents an acute phase that is auto-limiting and can go unnoticed in many infected individuals. During this phase, parasites actively duplicate in different cells and tissues such as macrophages; muscular cells of smooth, striated, and cardiac muscles; adipocytes; and cells of the central nervous system . While some patients succumb during the acute phase of the disease, the development of an adaptive immune generally permits the control of infection with T. cruzi. If the parasite is not completely eradicated, individuals remain infected for life, and a dynamic equilibrium is established with the parasite that results in different clinical outcomes. In this way, while many individuals chronically infected remain in an asymptomatic intermediate phase, a significant proportion (30–35%) of patients develop cardiac or digestive manifestations that can drive them to congestive cardiac failure, arrhythmias, and eventually death or develop colon or esophageal megasyndromes. All of these are irreversible pathologic changes that occur even though the presence of the parasite is scarce. One experimental model that recapitulates chagasic myocarditis is present in infected mice for long periods with different T. cruzi strains that develop chronic lesion in the myocardium [4, 5].
3. Generalities of
ʟ-arginine is one of the most versatile amino acids at the metabolic level. Besides serving as a precursor for protein synthesis, it is also a precursor of multiple compounds of great biologic importance such as urea, nitric oxide, polyamines,
In adult mammals, ʟ-arginine is a nonessential amino acid; nevertheless, during childhood and certain physiologic or pathologic conditions (e.g., pregnancy, sepsis, trauma, catabolic stress, intestinal or renal damage), it is considered as a semi-essential amino acid or conditioned nonessential, due to the fact that its consumption exceeds the capacity of being synthesized by the organism and has to be supplied exogenously [8, 9, 10]. In mammals, the provision of
l-arginine metabolism in the immune response: special emphasis in macrophages
In the immune response, ʟ-arginine metabolism through NOS2 and Arg-1 has a pivotal role in the regulation of the effector capabilities of macrophages, dendritic cells, and neutrophils [17, 18, 19, 20] during infectious processes caused by a great variety of microorganisms: different species of Mycobacterium, Leishmania, Trypanosoma, Schistosoma, and Salmonella, among others [21, 22].
NOS2 or iNOS is an oxide-reductase responsible for the synthesis of
5. Immune response to Trypanosoma cruzi
Inside the mammalian host, macrophages represent an important site for the duplication of T. cruzi. One of the most important mechanisms in the protective immunity against T. cruzi is the activation of macrophages in order to achieve the elimination of parasites (Figure 3). CAMϕ are able eliminate T. cruzi thanks to NOS2 and RONS that kill intracellular parasites by the modification of structural properties of T. cruzi molecules. On the other hand, the different forms of AAMϕ present high levels of mannose receptor (MR) and an overregulation of Arginase 1 . Arg-1 hydrolyzes ʟ-arginine in urea and ʟ-ornithine; the latter is the principal intracellular source for the synthesis of polyamines and trypanothione. Polyamines are small cationic molecules required for cellular proliferation and macrophage homeostatic processes, besides being vital for the intracellular growth of Trypanosoma [19, 31]. Both inducible enzymes share ʟ-arginine as substrate, and the expression and function of both enzymes are reciprocally regulated by the action of Th1 and Th2 cytokines. Thus, ʟ-arginine is situated as a frontier between the elimination and survival of Trypanosoma in host cells, and its metabolism is a determinant factor in the evolution of the disease.
In response to the defense mechanisms of the host, parasites have developed several strategies in order to escape host immune response and take advantage of some host’s molecules. In this way, parasites must reduce the production of toxic molecules, including nitric oxide and its derivatives, that are synthesized by the immune system, in particular by macrophages [32, 33, 34]. In addition, internalized parasites of different T. cruzi strains are able to escape from the parasitophorous vacuole of resident macrophages , a strategy that utilizes a variety of molecules with antioxidant properties [36, 37]. Nevertheless, as the infection progresses, the evasion strategies displayed by T. cruzi are widely surpassed by the development of a humoral specific immune response and the activation of macrophages by IFN-𝛾 and other cytokines. As has been previously mentioned, the infection with T. cruzi can have an acute or a chronic phase. One of the possible causes of the passage from one phase to another is the fact that the effector immune response against the parasite is insufficient or inappropriate due to a deficient activation of the specific immune response or an excessive regulation of this response.
6. Role of Arg-1 in the infection with Trypanosoma
The induction of Arg-1 in macrophages promotes the infection of parasites of the genus Trypanosoma by providing nutrients derived from polyamines, since Trypanosoma parasites cannot generate their own source of ornithine through the activity of a functional arginase [38, 39]. The increase in arginase activity counteracts the host’s immune response and favors parasite growth. It has been shown that in African trypanosomiasis caused by Trypanosoma gambiense, there is an increase in the serum level of Arg-1 that returns to basal values after the treatment . Similarly, in experimental murine trypanosomiasis caused by Trypanosoma brucei, macrophage Arg-1 activity represents a disease susceptibility marker . In T. brucei Arg-1 activity is induced by excretion/secretion factors, particularly TbKHC1, kinesin H chain, and has been identified as an inductor factor of Arg-1 . Other studies have demonstrated that the addition of an Arg-1 inhibitor reduces parasite growth, which is restored with
Trypanosoma cruzi is the causal agent of Chagas disease that affects 6–8 million people primarily in Latin America. It is an intracellular parasite that infects a variety of cells, among which macrophages are a very important target and thus transcendental for the immune response against the parasite. Macrophages can traverse through a gradient of stages of activation with classically activated macrophages in one end and alternatively activated macrophages in the other. These two phases of activation are characterized by the expression of two enzymes that are reciprocally regulated and share the same substrate:
This work was funded by project number IN218119 from Papiit, DGAPA, UNAM, to LGK.
Conflict of interest
Authors declare no conflict of interests.