Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first discovered in December 2019, has led to an ongoing, unprecedented global pandemic due to coronavirus disease 2019 (COVID-19). This novel single-stranded RNA virus infects airway epithelial and other cell types expressing surface angiotensin-converting enzyme 2, with clinical manifestations ranging from asymptomatic infection to acute respiratory distress syndrome and severe organ dysfunction [1, 2]. Symptom onset is typically between 4 to 12 days of incubation. Older age and co-morbidities such as cancer, diabetes, and cardiovascular disease increase the risk for more severe disease, and a hyper-inflammatory response to the virus plays a key role in the multi-organ damage that is seen in severe cases [3]. Case reports of patients with inborn errors of immunity (IEI) suggest that the presence of B cells may contribute to immunopathology compared to a milder course in patients lacking B cells [4, 5]. A larger international retrospective cohort reported the clinical course of 94 patients with IEI,

The malaria parasite Plasmodium invades a host erythrocyte, multiplies within a parasitophorous vacuole (PV) and then ruptures the PV and erythrocyte membranes in a process known as egress. Both egress and invasion are controlled by effector proteins discharged from specialized secretory organelles. The aspartic protease plasmepsin X (PM X) regulates activity for many of these effectors, but it is unclear how PM X accesses its diverse substrates that reside in different organelles. PM X also autoprocesses to generate different isoforms. The function of this processing is not understood. We have mapped the self-cleavage sites and have constructed parasites with cleavage site mutations. Surprisingly, a quadruple mutant that remains full-length retains in vitro activity, is trafficked normally, and supports normal egress, invasion and parasite growth. The N-terminal half of the prodomain stays bound to the catalytic domain even after processing and is required for proper intracellular trafficking of PM X. We find that this enzyme cleaves microneme and exoneme substrates before discharge, while the rhoptry substrates that are dependent on PM X activity are cleaved after exoneme discharge into the PV. The data give insight into the temporal, spatial and biochemical control of this unusual but important aspartic protease.