Malaria blood stage infection suppresses liver stage infection via host-induced interferons but not hepcidin

Hardik Patel, Nana K. Minkah, Sudhir Kumar, Gigliola Zanghi, Antonino Schepis, Debashree Goswami, Janna Armstrong, Biley A. Abatiyow, Will Betz, Laura Reynolds, Nelly Camargo, Amina A. Sheikh and Stefan H. I. Kappe ()
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Hardik Patel: Seattle Children’s Research Institute
Nana K. Minkah: Seattle Children’s Research Institute
Sudhir Kumar: Seattle Children’s Research Institute
Gigliola Zanghi: Seattle Children’s Research Institute
Antonino Schepis: Seattle Children’s Research Institute
Debashree Goswami: Seattle Children’s Research Institute
Janna Armstrong: Seattle Children’s Research Institute
Biley A. Abatiyow: Seattle Children’s Research Institute
Will Betz: Seattle Children’s Research Institute
Laura Reynolds: Seattle Children’s Research Institute
Nelly Camargo: Seattle Children’s Research Institute
Amina A. Sheikh: Seattle Children’s Research Institute
Stefan H. I. Kappe: Seattle Children’s Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Malaria-causing Plasmodium parasites first replicate as liver stages (LS), which then seed symptomatic blood stage (BS) infection. Emerging evidence suggests that these stages impact each other via perturbation of host responses, and this influences the outcome of natural infection. We sought to understand whether the parasite stage interplay would affect live-attenuated whole parasite vaccination, since the efficacy of whole parasite vaccines strongly correlates with their extend of development in the liver. We thus investigated the impact of BS infection on LS development of genetically attenuated and wildtype parasites in female rodent malaria models and observed that for both, LS infection suffered severe suppression during concurrent BS infection. Strikingly and in contrast to previously published studies, we find that the BS-induced iron-regulating hormone hepcidin is not mediating suppression of LS development. Instead, we demonstrate that BS-induced host interferons are the main mediators of LS developmental suppression. The type of interferon involved depended on the BS-causing parasite species. Our study provides important mechanistic insights into the BS-mediated suppression of LS development. This has direct implications for understanding the outcomes of live-attenuated Plasmodium parasite vaccination in malaria-endemic areas and might impact the epidemiology of natural malaria infection.

Date: 2024
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DOI: 10.1038/s41467-024-46270-3

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