Host-parasite interactions

Once Leishmania enters the human host, macrophages try to attack Leishmania with reactive oxygen and nitrogen molecules. Leishmania parasite produces prote­ase with increased activity which considerably lowers macrophage activity.

Protective immune response to leishmaniasis mainly depends on the T-cell subset response accompanied with the specific cytokines, transcription factors, presenting of antigen, and production of various interleukins having direct or indirect effect on the main immune system. However, it is important to note that susceptibility or resistance to leishmaniasis is possible in individuals with altered genetics or depending on the environmental conditions as well as parasite strain starting the infection [26].

Immune response starts with the cells of innate immune system. Neutrophils are the first immune system cells responding to the sandfly bite starting the leishmani­asis infection [27]. Neutrophils are capable of producing microbicidal factors effec­tive against Leishmania such as nitric oxide (NO) and neutrophil extracellular traps [27, 28]. Neutrophils are effective protective agent in most forms of the leishmaniasis, but this is usually affected by the host genetics and Leishmania strain effecting the host [27]. Neutral killers are also recruited to the site of infection after neutrophils, and their cytotoxic activity is effective against parasite by mediating lysis [29, 30]. Organ-specific protection during the early stages of infection is the case for natural killer T cells [31]. Increased natural killer T-cell concentration during the disease progress and decreased concentration following treatment indicates importance in early response [32].

Leishmania parasites have developed their own way in order to reduce the effec­tiveness of immune system. Modifying toll-like receptors’ pathogen recognition ability, delaying phagosomes ability to terminate parasite once consumed, altering macrophage antigen presentation, and modifying host signaling in order to effect production or inhibition of certain cytokines or chemokines such as IL-10 and IL-12 are some of the examples of immune evasion mechanisms used by parasites [27]. Being a progressive disease, increased concentrations of IFN-γ and TNF-α cytokines indicate immunosuppressive mechanism for leishmaniasis especially in VL [34-37]. IL-10, which is produced by many immune system cells such as B cells, T-cell sub­sets, and innate cells, is a regulatory cytokine responsible from immune suppression and reducing the effectiveness of antigen-presenting cells like macrophages and dendritic cells where initial response mainly depends on this process [34]. For VL, IL-10 was found to be majorly produced by CD4 + CD25-Foxp3- cells in the spleen suggesting that suppression of antileishmanial immunity in effected individuals depends on the expression of IL-10 by T cells. In addition, experiments done with mouse models have shown that IL-12 signaling and presence of high antigen dose can lead to the activation of Th1 cells which coexpresses IL-10 [38]. IL-27 is another immune system regulator which promotes T cells to produce IL-10 following an infection [39]. Furthermore, upregulation of IL-21 by T cells in order to reach elevated levels of IL-10 is thought to be the role of IL-27 [40].

IFN-γ is another important immune system molecule produced by parasite­dependent Th1 CD4+ lymphocytes and is related to intracellular control of para­sites upon infection. On the other hand, Th2 CD4+ cells are responsible from the progression of the disease. This difference in Th1 and Th2 cell line responses was further confirmed by Holaday et al.'s study done on mouse models carrying specific mutations. The study showed that in the presence of antigen, Th1-like cell line response was to produce IL-2 and IFN-γ, whereas Th2-like cell line response was to produce IL-4 and IL-5 upon stimulation [42].

In another study, Th1, Th2, and Th17 CD4+ T-cell subsets were found to induce production of IL-10 despite having different signaling pathways and transcription route. ERK1 and ERK2 transcriptional activation was common in all these Th cell subsets. c-Maf is an important transcription factor in macrophages for the process of IL-10 expression and was also found to be common for the previously mentioned three different T-cell subsets. c-Maf expression was also found to be dependent on ERK activation in Th1 and Th17 cells [38].

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