Interferon-induced GTPases [guanylate-binding proteins (GBPs)] play an important role in inflammasome activation and mediate innate resistance to many intracellular pathogens, but little is known about their role in leishmaniasis. We therefore studied expression ofGbp2b/Gbp1andGbp5mRNA in skin, inguinal lymph nodes, spleen, and liver afterLeishmania majorinfection and in uninfected controls. We used two different groups of related mouse strains: BALB/c, STS, and CcS-5, CcS-16, and CcS-20 that carry different combinations of BALB/c and STS genomes, and strains O20, C57BL/10 (B10) and B10.O20, OcB-9, and OcB-43 carrying different combinations of O20 and B10 genomes. The strains were classified on the basis of size and number of infection-induced skin lesions as highly susceptible (BALB/c, CcS-16), susceptible (B10.O20), intermediate (CcS-20), and resistant (STS, O20, B10, OcB-9, OcB-43). Some uninfected strains differed in expression ofGbp2b/Gbp1andGbp5, especially ofGbp2b/Gbp1in skin. Uninfected BALB/c and STS did not differ in their expression, but in CcS-5, CcS-16, and CcS-20, which all carry BALB/c-derivedGbpgene-cluster, expression ofGbp2b/Gbp1exceeds that of both parents. These data indicatetrans-regulation ofGbps. Infection resulted in approximately 10× upregulation ofGbp2b/Gbp1andGbp5mRNAs in organs of both susceptible and resistant strains, which was most pronounced in skin. CcS-20 expressed higher level ofGbp2b/Gbp1than both parental strains in skin, whereas CcS-16 expressed higher level ofGbp2b/Gbp1than both parental strains in skin and liver. This indicates atrans-regulation present in infected mice CcS-16 and CcS-20. Immunostaining of skin of five strains revealed in resistant and intermediate strains STS, CcS-5, O20, and CcS-20 tight co-localization of Gbp2b/Gbp1 protein with mostL. majorparasites, whereas in the highly susceptible strain, BALB/c most parasites did not associate with Gbp2b/Gbp1. In conclusion, expression ofGbp2b/Gbp1andGbp5was increased even in organs of clinically asymptomatic resistant mice. It suggests a hidden inflammation, which might contribute to control of persisting parasites. This is supported by the co-localization of Gbpb2/Gbp1 protein andL. majorparasites in skin of resistant and intermediate but not highly susceptible mice.

Department of Molecular and Cellular Biology Roswell Park Cancer Institute Buffalo NY United States

Laboratory of Molecular and Cellular Immunology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czechia

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