Leishmania amazonensis from distinct clinical forms/hosts has polymorphisms in Lipophosphoglycans, displays variations in immunomodulatory properties and, susceptibility to antileishmanial drugs

Abstract

Lipophosphoglycan (LPG), the major Leishmania glycoconjugate, induces pro‐inflammatory/immunosuppressive innate immune responses. Here, we evaluated functional/biochemical LPG properties from six Leishmania amazonensis strains from different hosts/clinical forms. LPGs from three strains (GV02, BA276, and LV79) had higher pro‐inflammatory profiles for most of the mediators, including tumor necrosis factor alpha and interleukin 6. For this reason, glycoconjugates from all strains were biochemically characterized and had polymorphisms in their repeat units. They consisted of three types: type I, repeat units devoid of side chains; type II, containing galactosylated side chains; and type III, containing glucosylated side chains. No relationship was observed between LPG type and the pro‐inflammatory properties. Finally, to evaluate the susceptibility against antileishmanial agents, two strains with high (GV02, BA276) and one with low (BA336) pro‐inflammatory activity were selected for chemotherapeutic tests in THP‐1 cells. All analyzed strains were susceptible to amphotericin B (AmB) but displayed various responses against miltefosine (MIL) and glucantime (GLU). The GV02 strain (canine visceral leishmaniasis) had the highest IC50 for MIL (3.34 μM), whereas diffuse leishmaniasis strains (BA276 and BA336) had a higher IC50 for GLU (6.87–12.19 mM). The highest IC50 against MIL shown by the GV02 strain has an impact on clinical management. Miltefosine is the only drug approved for dog treatment in Brazil. Further studies into drug susceptibility of L. amazonensis strains are warranted, especially in areas where dog infection by this species overlaps with those caused by Leishmania infantum.

Phenotypical Differences between Leishmania (Leishmania) amazonensis PH8 and LV79 Strains May Impact Survival in Mammal Host and in Phlebotomine Sand Flies

“…LPG polymorphisms in L. ( L. ) amazonensis have already been reported in several strains from different clinical manifestations/hosts. In this species, LPGs were categorized according to the absence/presence of side chains in three types (I–III) [ 39 ]. Herein, FACE analysis revealed the absence of side chains in PH8 LPG (type I), different to what has previously been observed [ 28 , 39 ].…”

“…In this species, LPGs were categorized according to the absence/presence of side chains in three types (I–III) [ 39 ]. Herein, FACE analysis revealed the absence of side chains in PH8 LPG (type I), different to what has previously been observed [ 28 , 39 ]. On the other hand, the repeat units of the LV79 strain showed one to two side chains, consisting of a type III LPG.…”

IL-17A/IFN-γ producing γδ T cell functional dichotomy impacts cutaneous leishmaniasis in mice

“…Lipophosphoglycans (LPGs), the main glycoconjugates identified on the surface membranes of Leishmania parasites, are consistently expressed in promastigote forms. In the case of L. amazonensis , depending on the strain, LPGs display polymorphisms in their structures and can differentially immunomodulate NO and cytokine production by murine macrophages 61,62 Additionally, LPG serves as a virulence factor, playing a direct role in the attachment and establishment of parasites within the midgut of sand flies 63,64 . Furthermore, Leishmania’s LPG can induce exhaustion molecules such as PD-1 in lymphocytes and their ligands PD-L2 in macrophages, potentially contributing to infection 65,66 .…”

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

“…Based on these results, the most emphatic impression left is that the PLG molecule seems to act in a bidirectional manner from an immunobiological point of view, depending on the subgenus, Leishmania [L. amazonensis] or Viannia [L. braziliensis], involved in the process, although, more recently, it has been shown that LPG of L. (L.) amazonensis isolates from different origins, that is, from an ADCL case (State of Bahia, Brazil), from a domestic dog with visceral leishmaniasis (State of Minas Gerais, Brazil) and from a wild rodent (Proechmys sp.) in the Brazilian Amazon, showed a significant pro-inflammatory response with expression of TNF-α and IL-6 cytokines [111].…”