Background: Interferon (IFN)- λ4, a type III IFN, production is controlled by a dinucleotide frameshift variant (rs368234815-dG/TT) within the first exon of the IFNL4 gene. Carriers of the IFNL4-dG allele but not the IFNL4-TT allele are able to produce the IFN-λ4 protein. Patients with hepatitis C virus that do not produce the IFN-λ4 protein have higher rates of viral clearance suggesting a potential inhibitory role of IFN-λ4 in liver-tropic infections.Methods: In this study, we investigated whether children infected with Plasmodium falciparum, which has a well-characterized liver stage infection, would be more susceptible to clinical malaria relative to their IFNL4- rs368234815 allele. We analyzed a cohort of 122 children from a malaria holoendemic region of Kenya. Episodes of clinical malaria and upper respiratory tract infections (URTIs) were determined using information collected from birth to two years of age. The dinucleotide frameshift variant IFNL4-rs368234815-dG/TT was genotyped using a TaqMan assay.Results: In this cohort, we found that 33% had the dG/dG genotype, 45 % had the dG/TT genotype, and 22% had TT/TT genotype. We evaluated the number and time to first episode of clinical malaria and URTIs with respect to the IFNL4-rs368234815 allele. We found that children that carried the IFNL4-rs368234815-dG allele had an increased number of clinical malaria episodes. In addition, there was a significant association between earlier age of first malaria infection with carriers of the IFNL4-dG allele (p-value: 0.021).Conclusion: Our results suggest that the ability to produce IFN-λ4 negatively affects host immune protection against P. falciparum malaria in Kenyan children.Classification: Immunology, Microbiology, Genetics

Early Plasmodium falciparum and P. vivax infection requires parasite replication within host hepatocytes, referred to as liver stage (LS). However, limited understanding of infection dynamics in human LS exists due to species-specificity challenges. Reported here is a reproducible, easy-to-manipulate, and moderate-cost in vivo model to study human Plasmodium LS in mice; the ectopic huLiver model. Ectopic huLiver tumors were generated through subcutaneous injection of the HC-04 cell line and shown to be infectible by both freshly dissected sporozoites and through the bite of infected mosquitoes. Evidence for complete LS development was supported by the transition to blood-stage infection in mice engrafted with human erythrocytes. Additionally, this model was successfully evaluated for its utility in testing antimalarial therapeutics, as supported by primaquine acting as a causal prophylactic against P. falciparum. Presented here is a new platform for the study of human Plasmodium infection with the potential to aid in drug discovery.

Background We identified whether maternal HIV infection during pregnancy affects transplacental transfer of Kaposi’s sarcoma-associated herpesvirus (KSHV) specific antibodies and subsequent infant infection. Methods We followed pregnant Kenyan women through delivery and their infants until age two years. Children were classified as HIV-exposed uninfected (HEU) or HIV-unexposed uninfected (HUU) based on maternal HIV status. Maternal venous and cord blood at delivery and child venous blood every six months were tested for antibodies to 20 KSHV antigens by multiplex bead-based immunoassay. Multiple comparisons were adjusted using false discovery rate (FDR). Results Maternal HIV infection was significantly associated with decreased transplacental transfer of antibodies against all KSHV antigens and lower cord blood levels for eight antigens at FDR p<0.10. Neither birth to six-month antibody level changes nor six-month levels differed in HEU and HUU, except for ORF50. 74% of children KSHV seroconverted by age 24 months but HEU and HUU did not differ in time to seroconversion nor two-year seropositivity after adjustment for child malaria infection. Conclusions Maternal HIV infection reduced a child’s initial KSHV antibody levels but did not affect age of infection. Regardless of HIV exposure in utero, KSHV seroconversion in Kenyan children occurred early; associated factors must be identified.

No abstract