Critical role for phosphoinositide 3-kinase gamma in parasite invasion and disease progression of cutaneous leishmaniasis

Abstract

Obligate intracellular pathogens such as Leishmania specifically target host phagocytes for survival and replication. Phosphoinositide 3-kinase γ (PI3Kγ), a member of the class I PI3Ks that is highly expressed by leukocytes, controls cell migration by initiating actin polymerization and cytoskeletal reorganization, which are processes also critical for phagocytosis. In this study, we demonstrate that class IB PI3K, PI3Kγ, plays a critical role in pathogenesis of chronic cutaneous leishmaniasis caused by L. mexicana. Using the isoform-selective PI3Kγ inhibitor, AS-605240 and PI3Kγ gene-deficient mice, we show that selective blockade or deficiency of PI3Kγ significantly enhances resistance against L. mexicana that is associated with a significant suppression of parasite entry into phagocytes and reduction in recruitment of host phagocytes as well as regulatory T cells to the site of infection. Furthermore, we demonstrate that AS-605240 is as effective as the standard antileishmanial drug sodium stibogluconate in treatment of cutaneous leishmaniasis caused by L. mexicana. These findings reveal a unique role for PI3Kγ in Leishmania invasion and establishment of chronic infection, and demonstrate that therapeutic targeting of host pathways involved in establishment of infection may be a viable strategy for treating infections caused by obligate intracellular pathogens such as Leishmania.

Topical treatment with nanoliposomal Amphotericin B reduces early lesion growth but fails to induce cure in an experimental model of cutaneous leishmaniasis caused by Leishmania mexicana

“…L. mexicana (MNYC/BZ/62/m379) parasites were obtained and maintained as described previously (Cummings et al, 2012). L. mexicana amastigotes were aspirated from a previously infected stock mouse and cultured in vitro in M199 medium supplemented with 10% FBS, 1% Penicillin/streptomycin at 25 °C to generate metacyclic promastigotes.…”

The Abl and Arg Kinases Mediate Distinct Modes of Phagocytosis and Are Required for Maximal Leishmania Infection

“…Lesion size differences in cutaneous leishmaniasis result from both disparities in parasite invasion and the subsequent burden and from differences in the hosts' inflammatory/immune responses (54). For example, inhibition of phosphoinositide 3-kinase ␥, signaling through which has been linked to Abl family kinases (1), affects both the uptake of L. mexicana and the host's inflammatory response to infection, which results in less severe disease in the mouse model (9). We did not observe significant differences in cytokine secretion between stimulated splenic cells isolated from imatinib and DMSO-treated mice, with the exception of IFN-␥, which decreased in imatinib-treated splenic cells at higher antigen stimulation.…”

Mechanisms of cellular invasion by intracellular parasites

“…Targeting MAPK signaling pathway using the specific MKP-1 inhibitor, triptolide, could be an effective therapeutic option for controlling L. major infection [79]. Similarly, AS-605240, a PI3Kγ inhibitor, is another promising therapeutic candidate as it confers resistance against L. mexicana infection and showed similar protection as sodium stibogluconate[82]. Furthermore, cysteine proteases, important for intracellular survival of Leishmania amastigotes, are targeted by cystatin, a natural cysteine protease inhibitor, for curing experimental VL and could be developed as potential therapeutic candidate[83, 84].…”