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.
Highlights
Phagocytes and phagocytosis were first described by Elie Metchnikoff in 1883
Fusion of phagosomes with azurophilic granules containing myeloperoxidase (MPO) has been described during infection of human neutrophils in vitro with L. major and L. donovani [49], little is known about the phagolysosome biology of neutrophils during Leishmania infection and an important question that remains to be elucidated is if the differences in phagolysosome maturation influences promastigote-amastigote differentiation in different phagocytic cells and how this might impact the development of disease
Other important questions related to dendritic cells (DCs) and still to be elucidated are: 1) if cDC1s represent an important source of IL-12 during early stages of the disease, before the recruitment of monocytes to the site of infection; 2) if continuous local activation of cDC1s, after the priming of Th1 immunity by mon-DCs in draining lymph nodes (dLNs) is required for ongoing protection; and 3) why the dermal resident cDC1s, which are already at the site of infection are not required for Th1 priming
Summary
Phagocytes and phagocytosis were first described by Elie Metchnikoff in 1883. At that time phagocytosis was primarily described in frogs and associated with homeostasis, nutrition and tissue reabsorption. Metchnikoff described how this process could act as a protective mechanism against pathogens [1]. Since the late 1970s Leishmania parasites have been described as phagosomal pathogens that reside and proliferate within phagocytic cells [5,6,7,8]. We understand that even a single Leishmania parasite transmitted by a sand fly bite is sufficient to establish infection [9, 10], corroborating data discussed throughout this review that innate mechanisms of immunity are not sufficient to provide protection and that the development of an adaptive immune response, mediated largely by Th1 CD4 cells, is required to activate phagocytic cells [11]. Molecules expressed by pathogens, or the host, to surface receptors expressed on phagocytic cells and is a contact-dependent process. The engulfment of either promastigotes or amastigotes is associated with an arrangement of the cytoskeleton and a transient polymerization of F-actin around the parasites [26, 27]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
