Investigating disease tolerance using a human re-challenge model of Falciparum Malaria
Item statusRestricted Access
Embargo end date31/07/2022
Muñoz Sandoval, Diana Carolina
Malaria infection by P. falciparum is clinically heterogeneous, causing asymptomatic, mild and, in some cases, severe life-threatening disease. Despite continuous efforts, the mechanisms that drive severe disease still remain unclear. According to epidemiological data, higher presence of severe malaria can be observed during the first few infections of life with a shift towards mild and asymptomatic episodes as exposure increases. These observations suggest that protection to severe malaria would usually be acquired after the first few infections without a concurrent reduction in parasite density. Hence, this indicates that protection to severe malaria in exposed individuals comes from an early learning to tolerate the disease in order not to develop a severe outcome, an acquired form of disease tolerance. We hypothesise that malaria reprograms the immune system after the first few infections to reduce inflammation, thus minimising pathology achieving disease tolerance. Over the last decades, controlled human malaria infections have been used as important tools for the development of vaccines but also represent an ideal setting in which to study the human immune response. Therefore, to test our hypothesis, we developed a human re-challenge model where volunteers were infected up to three times over 12-months. In this way, we explored whether the immune response changes through the first three malaria infections of life in a controlled clinical setting. Our results show that volunteers did not acquire anti-parasite immunity with parasite densities remaining the same in their first, second and third infection. These results complement observations in the field where no control of parasite burden is reported during the first infections of life. Analysis of clinical data coupled with systems immunology tools involving plasma proteins and whole blood transcriptomes showed comparable results pointing towards a systemic pro-inflammatory response driven by IFN amongst all infections in this re-challenge model. Nonetheless, dramatic changes were found in the T cell compartment with a massive activation in T cell populations during first infections while a complete shutdown of this activation was observed in re-challenges. This increase in T cell activation in first infections was parallel to a substantial increase in ALT levels which is a biomarker of tissue damage. Importantly, no increase in ALT levels were observed during re-challenge infections. These results point towards a possible mechanism of host protection taking place during re-challenge infections based on tolerising T cell responses. These results validate our re-challenge model, further supporting the concept that disease tolerance develops after the first few malaria infections.