**1. Introduction**

The leishmaniases are a diverse group of vector-borne diseases resulting from infection with parasites of the genus *Leishmania* (*L*.) (Kinetoplastida: Trypanosomatidae). More than 20 species of *Leishmania* parasites are considered public health threats with the *Leishmania* (*Leishmania*) and *Leishmania* (*Viannia*) subgenera encompassing the medically important human pathogenic *Leishmania* parasites (reviewed in [1]). Leishmaniasis is acquired through the bite of an infected phlebotomine sandfly, with the genera *Phlebotomus* (Old World; OW) and *Lutzomyia* (New World; NW) responsible for human transmission. The *Leishmania* life-cycle (**Figure 1**) is complex as the parasites alternate between a flagellated promastigote form within the insect vector (reviewed in [2]) and an intracellular amastigote form that resides within phagolysosomes of mammalian phagocytic cells (reviewed in [3]). Clinical manifestations of infection with *L*. (*Leishmania*) and *L*. (*Viannia*) species vary from spontaneous self-healing localized lesions (cutaneous leishmaniasis; CL) to life-threatening systemic multi-organ disease (visceral leishmaniasis; VL, also known as kala-azar). Nearly all *Leishmania* parasites can cause CL of varying severity ranging from sub-clinical (also referred to as asymptomatic;

#### **Figure 1.**

*The development of Leishmania parasites and their interaction with cells of the immune system. (A) During blood feeding, promastigotes are injected into the skin. (B) Neutrophils are the first phagocytic cells to arrive at the site of inoculation and play several roles. They arrive rapidly and release interleukin-1*β *(IL-1*β*), which is triggered by sandfly gut microbiota and promotes phagocytosis. (C) Neutrophils release neutrophil extracellular traps (NETs) and kill promastigotes through NETosis. (D) Neutrophils phagocytose promastigotes and (E) infected neutrophils interact with dendritic cells (DCs) inducing IL-10 which favors parasite survival. (F) DCs also phagocytose promastigotes and (G) interact with natural killer cells, resulting in the production of IFN*γ*. (H) Leishmania can escape apoptotic neutrophils. (I) Neutrophils degranulate and release mediators, such as macrophage inflammatory protein (MIP-1*β*), which recruits monocytes and macrophages. (J) Macrophages phagocytose promastigotes and neutrophils can then activate infected macrophages to induce intracellular parasite killing by releasing reactive oxygen species (ROS). (K) Apoptotic infected-neutrophils are engulfed by macrophages providing a silent entry for the parasite by downregulating ROS and nitric oxide (NO). (L) Within the macrophage, the promastigotes undergo significant biochemical and metabolic changes by transforming into their intracellular amastigote form to proliferate and infect more cells and/or (M) persist indefinitely. The life cycle is continued when (N) a female phlebotomine sandfly ingests a blood meal containing Leishmania infected phagocytes. (O) Within the vector, the amastigotes develop into the promastigote stage, (P) replicate and undergo further development (not shown here) (Q ) concluding in a migration to the stomodeal valve to enable transmission to a mammalian host. Created with BioRender.com*

reviewed in [4]) and self-resolving lesions to persistent chronic infections that result in severe tissue destruction and disfigurement (**Table 1**) [1].

The interaction between the parasite and the host immune response is complex and varied leading to a range of possible different disease outcomes. While the species of *Leishmania* parasite plays a large role in determining disease manifestations, host immunity and genetics largely influence the severity of infection. The classic T helper 1/T helper 2 (TH1/TH2) model has been applied for many years to explain the disease severity and outcome, with CD4+ TH1 cells mediating resistance to *Leishmania* and CD4+ TH2 cells promoting host susceptibility [12]. However, this assumption is based primarily on an experimental *Leishmania* (*L*.) *major* model of infection in congenic mouse strains, which are not entirely relevant to human infections. The model fails to explain the different immune responses and clinical presentations observed in the range of CL phenotypes caused by the various *Leishmania* species. Similar to the immunological spectrum observed in humans, the combination of mouse strain (reviewed in [13]), mode of challenge [14], infectious dose [15] and infecting parasite species or strain (reviewed in [16]), influences clinical presentation. With a focus on innate and adaptive immunity and subsequent immunopathology, here we describe


*Protective and Pathogenic Immune Responses to Cutaneous Leishmaniasis DOI: http://dx.doi.org/10.5772/intechopen.101160*

*\*Abbreviations: NW, New World; OW, Old World; LCL, localized cutaneous leishmaniasis; MCL, mucocutaneous leishmaniasis; DCL, diffuse cutaneous leishmaniasis; DsCL, disseminated cutaneous leishmaniasis.*

#### **Table 1.**

*Clinical manifestations of cutaneous leishmaniasis caused by medically important Old World and New World Leishmania parasites.\**

the key immune responses induced by cutaneous *Leishmania* infection. We further discuss the coordination between innate and adaptive immune responses in parasite control and how persistent parasites play an important role in protective immunity.
