IFN-λ3 is induced by Leishmania donovani and can inhibit parasite growth in cell line models but not in the mouse model, while it shows a significant association with leishmaniasis in humans.

The intracellular protozoan parasite Leishmania donovani causes debilitating human diseases that involve visceral and dermal manifestations. Type 3 interferons (IFNs), also referred to as lambda IFNs (IFNL, IFN-L, or IFN-λ), are known to play protective roles against intracellular pathogens at the epithelial surfaces. Herein, we show that L. donovani induces IFN-λ3 in human as well as mouse cell line-derived macrophages. Interestingly, IFN-λ3 treatment significantly decreased parasite load in infected cells, mainly by increasing reactive oxygen species production. Microscopic examination showed that IFN-λ3 inhibited uptake but not replication, while the phagocytic ability of the cells was not affected. This was confirmed by experiments that showed that IFN-λ3 could decrease parasite load only when added to the medium at earlier time points, either during or soon after parasite uptake, but had no effect on parasite load when added at 24 h post-infection, suggesting that an early event during parasite uptake was targeted. Furthermore, the parasites could overcome the inhibitory effect of IFN-λ3, which was added at earlier time points, within 2-3 days post-infection. BALB/c mice treated with IFN-λ3 before infection led to a significant increase in expression of IL-4 and ARG1 post-infection in the spleen and liver, respectively, and to different pathological changes, especially in the liver, but not to changes in parasite load. Treatment with IFN-λ3 during infection did not decrease the parasite load in the spleen either. However, IFN-λ3 was significantly increased in the sera of visceral leishmaniasis patients, and the IFNL genetic variant rs12979860 was significantly associated with susceptibility to leishmaniasis.

Gender-dependent multiple cross-phenotype association of interferon lambda genetic variants with peripheral blood profiles in healthy individuals.

BACKGROUND: Type III interferons (IFN), also called as lambda IFNs (IFN-λs), are antiviral and immunomodulatory cytokines that are evolutionarily important in humans. Given their central roles in innate immunity, they could be influencing other aspects of human biology. This study aimed to examine the association of genetic variants that control the expression and/or activity of IFN-λ3 and IFN-λ4 with multiple phenotypes in blood profiles of healthy individuals. METHODS: In a cohort of about 550 self-declared healthy individuals, after applying several exclusion criteria to determine their health status, we measured 30 blood parameters, including cellular, biochemical, and metabolic profiles. We genotyped them at rs12979860 and rs28416813 using competitive allele-specific PCR assays and tested their association with the blood profiles under dominant and recessive models for the minor allele. IFN-λ4 variants rs368234815 and rs117648444 were also genotyped or inferred. RESULTS: We saw no association in the combined cohort under either of the models for any of the phenotypes. When we stratified the cohort based on gender, we saw a significant association only in males with monocyte (p = 1 × 10-3 ) and SGOT (p = 7 × 10-3 ) levels under the dominant model and with uric acid levels (p = 0.01) under the recessive model. When we tested the IFN-λ4 activity modifying variant within groupings based on absence or presence of one or two copies of IFN-λ4 and on different activity levels of IFN-λ4, we found significant (p < 0.05) association with several phenotypes like monocyte, triglyceride, VLDL, ALP, and uric acid levels, only in males. All the above significant associations did not show any confounding when we tested for the same with up to ten different demographic and lifestyle variables. CONCLUSIONS: These results show that lambda interferons can have pleiotropic effects. However, gender seems to be an effect modifier, with males being more sensitive than females to the effect.