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Abstract
Immunity to severe malaria is acquired quickly, operates independently of pathogen load and represents a highly effective form of disease tolerance. The mechanism that underpins tolerance in human malaria remains unknown. We developed a re-challenge model of falciparum malaria in which healthy naive adult volunteers were infected three times over a 12-month period to track the development of disease tolerance in real-time. We found that parasitaemia triggered a hardwired emergency myeloid response that led to systemic inflammation, pyrexia and hallmark symptoms of clinical malaria across the first three infections of life. In contrast, CD4+ T cell activation was quickly modified to reduce the number and diversity of effector cells upon re-challenge. Crucially, this did not silence critical helper T cell functions but instead prevented the generation of cytotoxic effectors associated with autoinflammatory disease. Tolerised hosts were thus able to prevent collateral tissue damage and injury. Host control of T cell activation can therefore be established after a single infection and in the absence of anti-parasite immunity. And furthermore, this rapid host adaptation can protect vital organs to minimise the harm caused by systemic inflammation and sequestration. Immunity to severe malaria is acquired quickly, operates independently of pathogen load and represents a highly effective form of disease tolerance. The mechanism that underpins tolerance in human malaria remains unknown. We developed a re-challenge model of falciparum malaria in which healthy naive adult volunteers were infected three times over a 12-month period to track the development of disease tolerance in real-time. We found that parasitaemia triggered a hardwired emergency myeloid response that led to systemic inflammation, pyrexia and hallmark symptoms of clinical malaria across the first three infections of life. In contrast, CD4+ T cell activation was quickly modified to reduce the number and diversity of effector cells upon re-challenge. Crucially, this did not silence critical helper T cell functions but instead prevented the generation of cytotoxic effectors associated with autoinflammatory disease. Tolerised hosts were thus able to prevent collateral tissue damage and injury. Host control of T cell activation can therefore be established after a single infection and in the absence of anti-parasite immunity. And furthermore, this rapid host adaptation can protect vital organs to minimise the harm caused by systemic inflammation and sequestration.
Original language | English |
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Publisher | medRxiv |
Number of pages | 68 |
DOIs | |
Publication status | Published - 24 Aug 2021 |
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