Diverse outcomes of controlled human malaria infection originate from host-intrinsic immune variation and not var gene switching
Milne K., Ivens A., Reid AJ., Lotkowska ME., O’Toole Á., Sankaranarayanan G., Sandoval DM., Nahrendorf W., Regnault C., Edwards NJ., Silk SE., Payne RO., Minassian AM., Venkatraman N., Sanders M., Hill AVS., Barrett MP., Berriman M., Draper SJ., Rowe JA., Spence PJ.
AbstractFalciparum malaria is clinically heterogeneous and the relative contribution of parasite and host in shaping disease severity remains unclear. We explored the interaction between inflammation and parasite variant surface antigen (VSA) expression, asking whether this relationship underpins the variation observed in controlled human malaria infection (CHMI). We uncovered marked heterogeneity in the response of naive hosts to blood challenge; some volunteers remained quiescent, others triggered interferon-stimulated inflammation and some showed transcriptional evidence of myeloid cell suppression. Significantly, only inflammatory volunteers experienced hallmark symptoms of malaria. When we tracked temporal changes in parasite VSA expression to ask whether variants associated with severe disease preferentially expand in naive hosts (as predicted by current theory) we found that var gene profiles were unchanged after 10-days of infection. The diverse outcomes of CHMI therefore depend upon human immune variation and there is no evidence for switching or selection of var genes in naive hosts.