Disease severity in human malaria varies from asymptomatic to life-threatening and the mechanisms underpinning pathology are poorly understood. The risk of severe malaria peaks in the first few infections in life. Protection from severe disease is then acquired quickly, operates independently of pathogen load and represents a highly effective form of disease tolerance. What underpins tolerance in human malaria remains unknown.
To better understand the host response to infection, we used human infection models for P. vivax and P. falciparum, two parasites which vary notably in terms of virulence. Combining plasma protein profiling, whole blood RNAseq and mass cytometry, we found remarkable conservation of systemic inflammation caused by both parasite species. In contrast, levels of T cell activation were significantly higher following infection with P. falciparum compared to P. vivax. Given the key role of T cells in malaria pathogenesis, these findings may help explain the lower incidence of severe disease associated with P. vivax.
To study how disease tolerance evolves as a result of exposure, we reinfected two cohorts of volunteers multiple times with either P. vivax or P. falciparum. Parasite growth, systemic inflammation and clinical presentation appeared unaltered in P. falciparum reinfections. Despite this, T cell responses where significantly reduced in breadth and magnitude. Reinfection with P. vivax also led to reductions in T cell activation and was accompanied by reductions of fever and haematological changes associated with infection. Reinfections with both parasites were associated with reductions of biomarkers of tissue damage, suggesting the acquisition of disease tolerance.
Our data show host control of T cell activation can be established after a single infection, even in the absence of anti-parasite immunity. This rapid host adaptation can protect vital organs to minimise the harm caused by systemic inflammation and parasite sequestration: in vivo evidence of disease tolerance in humans.