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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 ? (PI3K?), 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, PI3K?, plays a critical role in pathogenesis of chronic cutaneous leishmaniasis caused by L. mexicana. Using the isoform-selective PI3K? inhibitor, AS-605240 and PI3K? gene-deficient mice, we show that selective blockade or deficiency of PI3K? 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 PI3K? 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.

SUBMITTER: Cummings HE

PROVIDER: S-EPMC3268302 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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

Cummings Hannah E HE Barbi Joseph J Reville Patrick P Oghumu Steve S Zorko Nicholas N Sarkar Anasuya A Keiser Tracy L TL Lu Bao B Rückle Thomas T Varikuti Sanjay S Lezama-Davila Claudio C Wewers Mark D MD Whitacre Caroline C Radzioch Danuta D Rommel Christian C Seveau Stéphanie S Satoskar Abhay R AR

Proceedings of the National Academy of Sciences of the United States of America 20120109 4

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 c ...[more]

PMID: 22232690

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Project description:BACKGROUND:Sepsis-associated encephalopathy (SAE) is an early and frequent event of infection-induced systemic inflammatory response syndrome. Phosphoinositide 3-kinase ? (PI3K?) is linked to neuroinflammation and inflammation-related microglial activity. In homeotherms, variations in ambient temperature (Ta) outside the thermoneutral zone lead to thermoregulatory responses, mainly driven by a gradually increasing sympathetic activity, and may affect disease severity. We hypothesized that thermoregulatory response to hypothermia (reduced Ta) aggravates SAE in PI3K?-dependent manner. METHODS:Experiments were performed in wild-type, PI3K? knockout, and PI3K? kinase-dead mice, which were kept at neutral (30 ± 0.5?°C) or moderately lowered (26 ± 0.5?°C) Ta. Mice were exposed to lipopolysaccharide (LPS, 10??g/g, from Escherichia coli serotype 055:B5, single intraperitoneal injection)-evoked systemic inflammatory response (SIR) and monitored 24?h for thermoregulatory response and blood-brain barrier integrity. Primary microglial cells and brain tissue derived from treated mice were analyzed for inflammatory responses and related cell functions. Comparisons between groups were made with one-way or two-way analysis of variance, as appropriate. Post hoc comparisons were made with the Holm-Sidak test or t tests with Bonferroni's correction for adjustments of multiple comparisons. Data not following normal distribution was tested with Kruskal-Wallis test followed by Dunn's multiple comparisons test. RESULTS:We show that a moderate reduction of ambient temperature triggers enhanced hypothermia of mice undergoing LPS-induced systemic inflammation by aggravated SAE. PI3K? deficiency enhances blood-brain barrier injury and upregulation of matrix metalloproteinases (MMPs) as well as an impaired microglial phagocytic activity. CONCLUSIONS:Thermoregulatory adaptation in response to ambient temperatures below the thermoneutral range exacerbates LPS-induced blood-brain barrier injury and neuroinflammation. PI3K? serves a protective role in suppressing release of MMPs, maintaining microglial motility and reinforcing phagocytosis leading to improved brain tissue integrity. Thus, preclinical research targeting severe brain inflammation responses is seriously biased when basic physiological prerequisites of mammal species such as preferred ambient temperature are ignored.

Dataset Information

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

Publications

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

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