Abstract
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 of Gbp2b/Gbp1 and Gbp5 mRNA in skin, inguinal lymph nodes, spleen, and liver after Leishmania major infection 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 of Gbp2b/Gbp1 and Gbp5, especially of Gbp2b/Gbp1 in 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-derived Gbp gene-cluster, expression of Gbp2b/Gbp1 exceeds that of both parents. These data indicate trans-regulation of Gbps. Infection resulted in approximately 10× upregulation of Gbp2b/Gbp1 and Gbp5 mRNAs in organs of both susceptible and resistant strains, which was most pronounced in skin. CcS-20 expressed higher level of Gbp2b/Gbp1 than both parental strains in skin, whereas CcS-16 expressed higher level of Gbp2b/Gbp1 than both parental strains in skin and liver. This indicates a trans-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 most L. major parasites, whereas in the highly susceptible strain, BALB/c most parasites did not associate with Gbp2b/Gbp1. In conclusion, expression of Gbp2b/Gbp1 and Gbp5 was 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 and L. major parasites in skin of resistant and intermediate but not highly susceptible mice.
Highlights
Guanylate-binding proteins (GBPs) are components of cellautonomous immunity playing a key role in response to intracellular infections [reviewed in Ref. [1,2,3]]
We found that the levels of Gbp2b/Gbp1 and Gbp5 mRNAs are influenced by L. major infection and by genome of the host
Infection induced increase of Gbp2b/Gbp1 in inguinal lymph nodes of all strains except BALB/c and CcS-20, the highest expression was observed in CcS-5 (Figure 5A), which differed from all tested strains except STS (Figure S1B in Supplementary Material; Table 2B), but only increase of expression of B10.O20 and OcB-43 was significant after correction for multiple testing; we did not observe significant increase of Gbp5 mRNA in lymph nodes (Figure 5B)
Summary
Guanylate-binding proteins (GBPs) are components of cellautonomous immunity playing a key role in response to intracellular infections [reviewed in Ref. [1,2,3]]. Guanylate-binding proteins (GBPs) are components of cellautonomous immunity playing a key role in response to intracellular infections [reviewed in Ref. [1,2,3]] Besides their role in defense against pathogens, they influence cellular proliferation, adhesion, and migration [reviewed in Ref. There are currently seven GBPs known in humans (encoded by genes located on the chromosome 1) [reviewed in Ref. Gbp2b/Gbp, Gbp, Gbp, Gbp, and Gbp map to chromosome 3, whereas Gbp, Gbp, Gbp, Gbp, Gbp, and Gbp are localized on chromosome 5 [9] These proteins are highly conserved and belong to dynamin superfamily— multidomain mechano-chemical GTPases, which are implicated in nucleotide-dependent membrane remodeling events [10, 11]
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