Does the Leishmania major paradigm of pathogenesis and protection hold for New World cutaneous leishmaniases or the visceral disease?

Abstract

Parasitic protozoa of the genus Leishmania have provided a useful perspective for immunologists in terms of host defense mechanisms critical for the resolution of infection caused by intracellular pathogens. These organisms, which normally reside in a late endosomal, major histocompatibility complex (MHC) class II(+) compartment within host macrophages cells, require CD4(+) T-cell responses for the control of disease. The paradigm for the CD4(+) T-helper 1 (Th1)/Th2 dichotomy is largely based on the curing/non-curing responses, respectively, to Leishmania major infection. However, this genus of parasitic protozoa is evolutionarily diverse, with the cutaneous disease-causing organisms of the Old World (L. major) and New World (Leishmania mexicana/ Leishmania amazonensis) having diverged 40-80 million years ago. Further adaptations to survive within the visceral organs (for Leishmania donovani, Leishmania chagasi, and Leishmania infantum) must have been required. Consequently, significant differences in host-parasite interactions have evolved. Different virulence factors have been identified for distinct Leishmania species, and there are profound differences in the immune mechanisms that mediate susceptibility/resistance to infection and in the pathology associated with disease. These variations not only point to interesting features of the host-pathogen interaction and immunobiology of this genus of parasitic protozoa, but also have important implications for immunotherapy and vaccine development.

Splenic immune responses during canine visceral leishmaniasis

“…It is now widely accepted that protective immunity against Leishmania parasites is mediated by type-1 immune responses [26]. This study established that a type-1 immune response is present in the spleen of L. infantum-infected dogs.…”

“…It is now widely accepted that protective immunity against Leishmania parasites is mediated by type-1 immune responses [26]. However, infection of L. major-susceptible inbred mouse strains with the visceralizing parasite, L. donovani, manifested a mixed pattern of Th1 and Th2 cytokines resulting in resistance [27].…”

Inhibition of caspase-8 activity promotes protective Th1- and Th2-mediated immunity toLeishmania majorinfection

“…The outcome of immunity versus disease progression in Leishmaniasis is multifactorial and depends on Leishmania species and development of innate and adaptive immune responses [1][2][3]. Early recruitment and death of neutrophils, which interact and are phagocytosed by infected macrophages and DCs [4], may affect resistance versus susceptibility upon infection with Leishmania major [5][6][7][8][9][10].…”

Interleukin-10 from T Cells, but Not Macrophages and Granulocytes, Is Required for Chronic Disease in Leishmania mexicana Infection

“…The classical Th1/Th2 immunologic paradigm does not adequately explain the immune response to Leishmania species that cause chronic New World cutaneous leishmaniasis (L. mexicana complex parasites, such as L. mexicana, L. amazonensis, and L. pifanoi) (4). This is not too surprising, as L. mexicana is separated from L. major by 40 million to 80 million years of evolution (4).…”

“…This is not too surprising, as L. mexicana is separated from L. major by 40 million to 80 million years of evolution (4). For example, although interleukin-12 (IL-12) is the master regulator of Th1 responses, IL-12-deficient mice show no phenotype and display chronic disease similar to that of wild-type (WT) B6 mice when infected with L. mexicana (5).…”