Critical role for phosphoinositide 3-kinase gamma in parasite invasion and disease progression of cutaneous leishmaniasis.
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.
Department of Microbiology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
Hannah E
HE
Cummings
Joseph
J
Barbi
Patrick
P
Reville
Steve
S
Oghumu
Nicholas
N
Zorko
Anasuya
A
Sarkar
Tracy L
TL
Keiser
Bao
B
Lu
Thomas
T
Rückle
Sanjay
S
Varikuti
Claudio
C
Lezama-Davila
Mark D
MD
Wewers
Caroline
C
Whitacre
Danuta
D
Radzioch
Christian
C
Rommel
Stéphanie
S
Seveau
Abhay R
AR
Satoskar
D000818:Animals; D000967:Antimony Sodium Gluconate / Q000627:therapeutic use; D060467:Disease Resistance / Q000187:drug effects*; D005434:Flow Cytometry; D006790:Host-Parasite Interactions / Q000187:drug effects; D006801:Humans; D007894:Leishmania mexicana; D016773:Leishmaniasis, Cutaneous / Q000469:parasitology* / Q000503:physiopathology; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009504:Neutrophils; D010586:Phagocytes / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use
D000967:Antimony Sodium Gluconate; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D045162:Thiazolidinediones; C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; C523442:PIK3R3 protein, human