Interferon-mediated innate immune responses against malaria parasite liver stages.
Mosquito-transmitted malaria parasites infect hepatocytes and asymptomatically replicate as liver stages. Using RNA sequencing, we show that a rodent malaria liver-stage infection stimulates a robust innate immune response including type I interferon (IFN) and IFNγ pathways. Liver-stage infection is suppressed by these infection-engendered innate responses. This suppression was abrogated in mice deficient in IFNγ, the type I IFN α/β receptor (IFNAR), and interferon regulatory factor 3. Natural killer and CD49b(+)CD3(+) natural killer T (NKT) cells increased in the liver after a primary infection, and CD1d-restricted NKT cells, which secrete IFNγ, were critical in reducing liver-stage burden of a secondary infection. Lack of IFNAR signaling abrogated the increase in NKT cell numbers in the liver, showing a link between type I IFN signaling, cell recruitment, and subsequent parasite elimination. Our findings demonstrate innate immune sensing of malaria parasite liver-stage infection and that the ensuing innate responses can eliminate the parasite.
Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
Jessica L
JL
Miller
Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
Brandon K
BK
Sack
Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
Michael
M
Baldwin
Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
Ashley M
AM
Vaughan
Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA; Department of Global Health, University of Washington, Seattle, WA 98195, USA. Electronic address: stefan.kappe@seattlebiomed.org.
Stefan H I
SHI
Kappe
D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate; D039421:Integrin alpha2 / Q000235:genetics / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000469:parasitology*; D008288:Malaria / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010961:Plasmodium / Q000276:immunology / Q000472:pathogenicity; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D034101:Sporozoites / Q000276:immunology*
D055610:Antigens, CD1d; C584692:CD1d antigen, mouse; D039421:Integrin alpha2; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C494233:Irf3 protein, mouse; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma