Functional complexity of the Leishmania granuloma and the potential of in silico modeling

Abstract

In human and canine visceral leishmaniasis and in various experimental models of this disease, host resistance is strongly linked to efficient granuloma development. However, it is unknown exactly how the granuloma microenvironment executes an effective antileishmanial response. Recent studies, including using advanced imaging techniques, have improved our understanding of granuloma biology at the cellular level, highlighting heterogeneity in granuloma development and function, and hinting at complex cellular, temporal, and spatial dynamics. In this mini-review, we discuss the factors involved in the formation and function of Leishmania donovani-induced hepatic granulomas, as well as their importance in protecting against inflammation-associated tissue damage and the generation of immunity to rechallenge. Finally, we discuss the role that computational, agent-based models may play in answering outstanding questions within the field.

Gamma Interferon-Regulated Chemokines in Leishmania donovani Infection in the Liver

“…Our results for chemokine-deficient mice also serve to reemphasize that in L. donovani infection in the liver, (i) recruited mononuclear cells and granulomas are not necessary to control intracellular infection or respond to Sb chemotherapy and (ii) granuloma assembly, control of infection, and Sb's efficacy are not invariably linked expressions of the same or a similar T cell-dependent, cytokine-mediated, macrophageactivating mechanism (3,5,8,12,30,36,37). In the presence of little or no discernible tissue inflammation, for example, early parasite replication was better controlled in one setting (in CXCL10 Ϫ/Ϫ mice) and Sb's killing action was entirely preserved in others (in CXCL10 Ϫ/Ϫ , CCL2 Ϫ/Ϫ , CCL5 Ϫ/Ϫ , and CXCR3 Ϫ/Ϫ mice).…”

“…Liver granulomas in this model in B6 and BALB/c WT mice are complex and dynamic (5,8,30), allowing initially parasitized Kupffer cells, recruited mononuclear cells, inflammatory cytokines, and the intracellular mechanisms of the activated macrophage to interdigitate and eventually eradicate L. donovani (3,14,35). Administered chemotherapy also interacts with the same factors in the parasitized tissue focus, and for pentavalent antimony (Sb), expression of its intracellular killing action in the liver is also usually associated with tissue inflammation.…”

“…One such IFN-␥-dependent effect, granulomatous inflammation, typically accompanies a successful antileishmanial defense in the liver (3,7,8,30).…”

“…CD4 ϩ and CD8 ϩ T cells, NK and NKT cells, and blood monocytes are primary influxing cells (1-3, 5, 8, 26, 27); neutrophils are also initially recruited to the liver (1,5,7,8,28) but are indifferent or not active toward amastigotes (8,29), limited in granulomas (8), and seldom discernible microscopically by or after week 2 (2,3,27). Although the dynamic mononuclear cell response is recognized to be asynchronous (8,30), in the livers of WT mice it is usually (i) evident at week 2, with early-developing granulomas being ϳ50% of parasitized foci, (ii) fully expressed by week 4, with ϳ90% of infected foci being surrounded by developing or mature (sometimes parasite-free) granulomas, and (iii) comprised at week 8 of mostly parasite-free, mature, and/or involuting granulomas (3,30). IFN-␥ Ϫ/Ϫ mice showed none of these effects, with virtually no cells being recruited to progressively more heavily parasitized foci until weeks 8 to 12 (3,4,13).…”

Antileishmanial activity and evaluation of the mechanism of action of strychnobiflavone flavonoid isolated from Strychnos pseudoquina against Leishmania infantum

“…The liver appears to serve as an indicator of the multiplication of parasites in the acute phase of the infection (Oliveira et al, 2012), and granuloma formation has been associated with a selflimiting hepatic infection, whereas these same granuloma fail to take form in the spleen, where parasites more commonly persist (Murray, 2001). Together, these observations suggest a causal association between granuloma formation and host resistance to visceralizing species of Leishmania spp., such as L. infantum (Moore et al, 2013). The ex vivo biodistribution studies and scintigraphic images performed here showed a high radioactivity uptake of 99m Tc-strychnobiflavone by the animals' liver and spleen.…”