Figure 3.

Proposed model to explain how the sacrifice of some parasites is thought to disable the innate immune response mediated by myeloid cells, allowing efficient host colonization by a second wave of invaders. In the absence of membrane stress, low basal levels of intracellular cAMP are produced following the combined actions of TbPDEB1/2 and low dimerization tendency of AC catalytic domains (red triangle). In the presence of stress, upon phagocytosis of the parasites by the acidic phagosome environment or following mTNF-mediated trypanolysis, CHDs dimerize, triggering a massive synthesis of cAMP that is translocated through an unknown mechanism into the myeloid cells cytosol or by phagocytosis/direct membrane fusion of extracellular vesicles (EVs) produced during phagocytic stress, blocking the synthesis of mTNF through activation of the host PKA. In this altruistic strategy, the sacrifice of the first pathogen invaders enables a second wave of trypanosomes to proliferate in the absence of local TNF-α, essential for the establishment of infection.