The Paradox of a Phagosomal Lifestyle: How Innate Host Cell-Leishmania amazonensis Interactions Lead to a Progressive Chronic Disease

Abstract

Intracellular phagosomal pathogens represent a formidable challenge for innate immune cells, as, paradoxically, these phagocytic cells can act as both host cells that support pathogen replication and, when properly activated, are the critical cells that mediate pathogen elimination. Infection by parasites of the Leishmania genus provides an excellent model organism to investigate this complex host-pathogen interaction. In this review we focus on the dynamics of Leishmania amazonensis infection and the host innate immune response, including the impact of the adaptive immune response on phagocytic host cell recruitment and activation. L. amazonensis infection represents an important public health problem in South America where, distinct from other Leishmania parasites, it has been associated with all three clinical forms of leishmaniasis in humans: cutaneous, muco-cutaneous and visceral. Experimental observations demonstrate that most experimental mouse strains are susceptible to L. amazonensis infection, including the C57BL/6 mouse, which is resistant to other species such as Leishmania major, Leishmania braziliensis and Leishmania infantum. In general, the CD4+ T helper (Th)1/Th2 paradigm does not sufficiently explain the progressive chronic disease established by L. amazonensis, as strong cell-mediated Th1 immunity, or a lack of Th2 immunity, does not provide protection as would be predicted. Recent findings in which the balance between Th1/Th2 immunity was found to influence permissive host cell availability via recruitment of inflammatory monocytes has also added to the complexity of the Th1/Th2 paradigm. In this review we discuss the roles played by innate cells starting from parasite recognition through to priming of the adaptive immune response. We highlight the relative importance of neutrophils, monocytes, dendritic cells and resident macrophages for the establishment and progressive nature of disease following L. amazonensis infection.

From Biology to Disease: Importance of Species-Specific Leishmania Antigens from the Subgenera Viannia (L. braziliensis) and Leishmania (L. amazonensis) in the Pathogenesis of American Cutaneous Leishmaniasis

“…However, in order for the amastigote form of the parasite to resist the lethal action of a highly hostile environment inside the macrophage's phagolysosome [highly acidic, oxidative, containing antimicrobial peptides, proteases and restrict nutrient access], the parasite makes use of a series of molecules on the surface of its plasma membrane, called glycoconjugates, in order to neutralize the lethal action of these hostile elements into the macrophage's phagolysosome [104,105]. This is a critical phase for the parasite that will result in its survival or death, so that, if overcome by the parasite, the infection will be definitively established in the vertebrate host [106,107]. However, in addition to the protective effect that these glycoconjugate molecules exert on the survival of the parasite, it is also known that their action can play an important role in the virulence of the parasite, reason why these glycoconjugate molecules are recognized here as species-specific Leishmania-antigens of both subgenera Leishmania and Viannia, with pivotal role in the pathogenesis of the disease caused by these Leishmania parasites, represented here by L. (V.) braziliensis and L. (L.) amazonensis.…”

Unrevealing the Mystery of Latent Leishmaniasis: What Cells Can Host Leishmania?

“…Professional phagocytes of the mammalian immune system (e.g., neutrophils, macrophages, monocytes, dendritic cells, eosinophils, and mast cells) play an essential role in homeostasis and inflammation, enabling pathogen clearance and host tissue healing [ 17 , 18 ]. They are equipped with phagocytic receptors (Toll-like receptors, complement receptors, Fc-gamma receptors, scavenger receptors, etc.)…”

Biochemical Properties of Parasite Virulence Factor: Lesson Learned from Leishmania

“…This safe location actually facilitates them to circumvent the work of the humoral immune feedback because in this situation, the pathogen is keep safe inside an intact cell that belongs to their host's and actually not in blood vessels where open blood flow is likely to increase its contact with the immune cells. Furthermore, it may avert the immune cells from destroying the host's own tissue through the mechanism of non-danger surface signals which unfortunately for the host dettered the process of apoptosis [49] The primary cell types that the parasite Leishmania actually attack and then infiltrates are subset of phagocytotic cells, e.g., neutrophils and macrophages, and this is what determines the fate of the chronicity of this infection [50].…”

“…Unfortunately, this smart parasite corrupt its defence properties for their own welfare [27,28,52]. They use the mechanism of immune evasion by using phagocytosing cell named the polymorphonuclear neutrophil granulocytes (PMNs) carefully as their hidden vehicle, where they proliferate silently and undetected from the immune system and then enter the long-lived macrophages, unnoticed by the immune armamentarium to create a "dormant" infection [47,50].…”

“…A key factor in elongating infection is by way of the reticence of the adaptive immune cells [48][49][50]. This took place primarily during the intracellular inhabition phases, when amastigotes search for newly prone uninfected macrophages and then infecting them [44,51,52].…”