**1. Introduction**

Leishmaniasis considers one of the neglected tropical diseases with a wide global distribution (**Figure 1**) [2]. WHO mentioned that leishmaniasis is from the important tropical diseases and represents a serious health problem. It includes a broad

**Figure 1.** *Worldwide distribution of cutaneous leishmaniasis [1].*

spectrum of clinical symptoms which may led to the fatal [3]. Leishmaniasis is endemic in 98 countries with over 350 million people at risk. There are more than 12 million infections with leishmaniasis and nearly 2 million new infections occurring annually; 0.7 to 1.2 million cases of cutaneous leishmaniasis and 200,000–400,000 cases of visceral leishmaniasis [4, 5]. Overall, two million new cases of cutaneous leishmaniasis are discovered annually in Afghanistan, Iran, Saudi Arabia, Syria, Iraq, Algeria, Brazil and Peru [6].

There are approximately 20 species confirmed for *Leishmania* are pathogenic to humans [7], that may cause different clinical symptoms (Cutaneous Leishmaniasis (CL), Muco-cutaneous Leishmaniasis (MCL) and Visceral Leishmaniasis (VL)) [8]. However, *Leishmania* parasites infect phagocytic cells. Virulence factors cause an inhibition or modification of host cell signaling pathways (interleukin and chemokine) which effect on other immune cells [9].

### **1.1 Prevalence of CL and geographical distribution**

Although CL is considered as a global health problem, it remains as a neglected disease [10]. Leishmaniasis infections spread in geographically different regions. However, more infections occur in sub- or/and tropics of Africa, the Middle East, Southern and Central America and South Europe and Asia [11]. It is prevailing at a broad global level and there is an increase worldwide in recorded cases number, also is most neglectful diseases. There is a geographical expansion and a global increase in infection of visceral and cutaneous leishmaniasis, which is still associated with vector population expansion [12]. Environment conditions may overlap many biological processes that effect directly on geographically sandfly distribution, reproductive rates and abundance [13]. Further, *Leishmania* showed as an opportunistic pathogen with HIV-infected adults and even children [14]. Depending to recent reports, leishmaniasis considers an endemic disease in 98 countries and about 1.3 million new cases annually [15]. However, CL is an endemic disease in several countries in the Middle East and North Africa. Foci of *L. major* (zoonotic cutaneous leishmaniasis) are mainly in Sudan, Egypt, Libya, Tunisia, Jordan and Palestine while in Syria, Saudi Arabia, Iraq and Iran are endemic for both *L. tropica* (ACL) and *L. major* (ZCL) [16]. Nearly, there are 500,000 cases of ZCL occur annually, while ACL appear in 400,000 cases. Ninety percent of cutaneous leishmaniasis occur in Afghanistan, Ethiopia, Algeria, Syria, Saudi Arabia, Sudan, Iran, Iraq, Brazil and Peru [17]. In Sri Lanka, leishmaniasis has recorded 8487 cases from 2009 to 2016 [18]. In Pakistan, nearly 21,000–35,000 cases of CL are reported annually [19]. Moroccan Health Ministry mentioned that were 16,852 cases of ACL and 24,804 cases of ZCL in 2004–2013 [13]. Abdellatif *et al*. [20] observed 140 cases with cutaneous leishmaniasis in one provinces of Libya. Khosravi *et al*. [21] recorded 869 (4.7%) cases of CL after were examined 18,308 in Kerman province, Iran. In Syria, 22.882 cases via the period 2004–2008 [14], while 53,000 cases in 2012, only in the first half of 2013, were reported 41,000 cases [22]. In Iraq, Alsamarai and Alobaidi [23] are indicated to 107 cases with CL in Alhaweja General Hospital, Kirkuk. Al-Mayali [24] mentioned that infection rate in urban regions population high from rural regions, where most cases was in Diwania center. Al-Obaidi *et al*. [25] have conducted a survey based on Iraqi CDC database (2008–2015), 17,001 cases recorded in all parts Iraq. Flaih *et al.,* [26] recorded 247 cases of CL in Thi-Qar.

#### **1.2 Pathogenesis**

Leishmaniasis is caused by flagellated *Leishmania* parasites, obligate intracellular protozoa and infect humans and other mammals [27]. The infection is transmitted

#### *Geographical Distribution of Cutaneous Leishmaniasis and Pathogenesis DOI: http://dx.doi.org/10.5772/intechopen.101841*

by infected females sandfly bite and the disease highly spreads in poor populations of tropical and subtropical countries [28]. The putative vectors of the disease are species belonging to the genus *Phlebotomus* and *Lutzomyia* [3].

Cutaneous leishmaniasis lesion continues in size and depth, about 4–6 weeks after the sandfly bite, to forms an ulcer that considers primary characteristic of late CL [29]. The clinical appearance of CL is determined by a genetic variation, complex, host immune status and response mechanism, site of the sandfly bite, size and duration of lesion and secondary infections. A combination of these factors is more likely to overlap [19]. Lesions of CL mostly appears on exposed body parts or that are mainly open to the environment as arm, legs, face and neck, but it a little occurs on body parts which are usually covered such as the back and abdomen [30, 31]. In addition, multiple lesions may be as result to the sandflies feeding behaviors which tend to occur multiple bites, prevalence of high numbers of infected insects or rubbing of the lesion to transmit for other areas [6].

CL is often leave a disfiguring scar, especially on visible body sites, causing also social, psychological, and economic problems [30]. Metacyclic promastigotes deposited into the mammalian host skin are engulfed, target host cells are macrophages. Promastigotes differentiate into amastigotes within it. Generally, amastigote replication leads to rupture of the macrophage. The free amastigotes invade other macrophages [7, 32]. Metacyclic promastigotes are highly motile, able to migrate via a collagen matrix, therefore phagocytosis of *Leishmania* may occur at far locations from the bite site [33]. When metacyclic promastigotes enter the host body, within minutes, the metacyclic promastigotes are engulfed by phagocytic cells, including: macrophages and neutrophils. Neutrophil has very short life span, so macrophages are the main host cells. Metacyclic differentiate into non-motile, small amastigote forms which reproduce by binary fission even rupturing the macrophages to infect other macrophages [32, 34]. However, neutrophils and dendritic cells are act as Trojan horses, which let the parasites to enter macrophages, *Leishmania* spp. does not activate parasite killing mechanisms (silent entry) [35]. *Leishmania* parasite can delay neutrophil apoptosis, which allows to the parasite replicates within these cells [36]. Although macrophages are host cells. Neutrophils, dendritic cells, and fibroblasts may be implicated in various stages of the infection [37]. Other cell types, as mast cells, natural killer cells (NK) and Langerhans cells are also involved in leishmaniasis establishment [38]. Both parasitic forms (amastigotes and promastigotes) have different ways, alter the structure of the parasitophorous vacuole and the environment of macrophage, to prevent series of cellular signaling events which lead to the parasite killing within the phagolysosome vacuole that provides an environment for parasite [35].

*Leishmania* must evade from the innate and adaptive immune responses. It is engulfed by macrophage but resist proteolysis and degradation in the phagolysosome [39, 40]. Macrophages engulf *Leishmania* directly via interactions with multiple cellular receptors as fibronectin receptor, mannose receptor, Toll-like receptors and CR1 and CR3 complement receptors, also engulf apoptotic neutrophils that contain Leishmanial parasites [7, 41]. Inside host cells, *Leishmania* parasites to be able to establish and survive. They resist and circumvent anti-parasitic immune response pathways. In some cases, *Leishmania* spp*.* smartly invest immune responses or induce cellular signaling pathways to facilitate entry and establishment of parasite [7]. An infection of any type of *Leishmania* depends on complex, virulence factors and host immunologic response [42].

The first sign of the infection appears as a small erythema around the site of the sandfly bite, amastigotes start to multiply inside dermal macrophages and after a variable incubation period. The erythema gradually converts to an inflammatory papule, usually few millimeters in diameter. It increases in a size and progresses to a nodule that often ulcerates to cause a non-painful ulcer, which appears discoloration of surrounding skin. The lesion may be multiple and/or small lesions surrounding the larger lesion. The development is slow range weeks to moths. The healing occurs after an adaptive cellular immune response that possible to fight the infection [43]. Ulcers become painful if accompanied secondary bacterial or fungal infection [44].

#### **1.3 Essential virulence factors**

A virulence is one of the important concepts which researches being on them. Also identification and determination of the virulence factors is a target for researchers in order to provide the road map of a vaccine design, identify of interactions with host defense mechanisms and a role of virulence factors in disease pathogenicity [45]. There are virulence factors have been identified of various *Leishmania* spp. that are possible at pathogenesis in the host. Some factors help in an engulfment and attachment of the parasite within host cells while other factors act as intracellular survival. Pathogen stops signaling pathways inside the host cell that activate immune response, thereby development of the disease [7].

The outcome of leishmaniasis infections depend both host status and pathogen virulence factors. *Leishmania* produces various virulence factors to facilitate transmission of parasite and infect mammalian host [46]. All of *Leishmania* surface coats with a glycocalyx that has a diversity in the composition. Notable, all of the surface-bound molecules share a common structural feature. They all contain a highly conserved glycosylphosphatidylinositol (GPI)-anchor. This type of GPIlipid anchor is structurally different from those found in mammalian cells. The glycocalyx in the *Leishmania* promastigote is dominated by GPI-anchored phosphoglycosylated glycans. However, during the life cycle of the parasite, occur changes in composition of the *Leishmania* surface glycocalyx [47]. Metacyclic promastigote has a thick glycocalyx. The glycocalyx is made of glycoproteins and other glycosylated species anchored into the surface membrane via a glycosylphosphatidylinositol (GPI) linkage [39]. For survival inside macrophages containing microbicidal factors, *Leishmania* spp*.* modulate or/and inhibit cell signaling pathways cascades involved in their synthesis [9].

A number of important molecules that had identified as factors in parasite virulence as lipophosphoglycan (LPG), the surface protease (gp63), cysteine proteinases (CPs), proteophosphoglycan (PPG), glicoinositol-phospholipids (GIPLs) and the 11 kDa kinetoplastid membrane protein (KMP-11) [43, 48]. Glycoproteins, LPGs, PPGs, and GIPLs are GPI-anchored molecules in dense surface glycocalyx, Leishmanial parasites also secrete various glycoconjugates especially PPGs. Secreted and surface glycoconjugates for promastigote has importance in an infection, survival, or virulence but are not necessary in order to *Leishmania* viability inside culture [49].

## **2. Lipophosphoglycan (LPG)**

LPG is most abundant glycolipid that densely coats surface of *Leishmania* promastigotes. It is composed of a glycan core which is joined a long polymer consist from repeating units of phosphoglycan (PGs) which is terminated with oligosaccharide capping structure. LPG connects to promastigote membrane by a phosphatidylinositol lipid (PI) anchor. The number of repeating units and the cap may differ between *Leishmania* spp. Also, the amount and structure of LPG varies during parasite life cycle [50, 51]. In all *Leishmania* species, LPG expresses high amounts on surface of procyclic and metacyclic promastigotes, in contrast with

amastigotes [52]. LPG on metacyclic promastigote surface is much longer from procyclic and almost completely absent in amastigotes [39]. Indeed, this molecule has an important role not only in invertebrate and vertebrate host, but too during early steps for establishment of the infection [50]. *L. major* mutants which lack lpg1 and lpg2 genes are sensitive to host complement system. This leads to unable survival in both intermediate or definitive host [53]. LPG1 is one of the key enzymes in the LPG biosynthesis, that involved in the synthesis of the LPG glycan core [54]. As well as, *Leishmania* lack lpg1 gene expresses imperfect LPG, not contains PG domain [55]. *L. major* and *Labrus donovani* need LPG1 for infection establishment inside macrophages, phagocytosis eliminates LPG1- null mutants, then restoration of LPG expression given capacity to replication of parasite within macrophage [52, 54].

LPG acts as a ligand to attach promastigotes to midgut epithelium of sandfly and also protects promastigotes from destruction by proteolytic enzymes that are destined for blood meal digestion [56]. In mammalian host, leishmanial LPG plays an essential role to avoid the parasite lysis by the host complement system, either by prevent of complement molecules attachment or inactivate the assembly of complement complex on promastigote surface [47]. It has ability to modulation and creating an appropriateness environment in order to parasite survival but the mechanisms of underlying modulation remain completely unknown and not goodly understood [57]. LPGs delay lysosomes formation and allow *Leishmania* to covert to intracellular amastigote forms [58]. It has been shown to protection of the lysis by complement system, adhesion and entry in macrophages, inhibition of protein kinase C (PKC), inhibition of phagosomal maturation, modulation of nitric oxide (NO) production [59].

LPG interferes with the pro-inflammatory responses for host cell through binding with Toll-like receptor (TLR) 2 and 4 on macrophages and NK cells [57]. LPG-TLR interactions induce ERK phosphorylation, while suppressing of p38 MAP kinase phosphorylation (ERK and p38 MAP kinase are from components of MAP kinases), modulate production of reactive oxygen species (ROS) and nitric oxide and inhibit secretion of pro-inflammatory cytokine [47]. For example, if p38 MAP kinase activate will produced IL-12 and IL-10, that inhibit activation of ERK [57]. LPG binds with complement receptor (CR3) and anchored molecules on macrophage surface to facilitate parasite engulfment [7, 60]. Furthermore, Leishmanial LPG can to impair the nuclear translocation of NF-κB in monocytes which lead to decrease in IL-12 production, and this effects early immune response of the host [43].
