Figure 7.

Controlling T cell activation protects host tissues. (A) A surrogate dataset from Reuling et al. (2018) was used to extract information on the frequency and severity of abnormal ALT during a first-in-life infection (up to 6 days after treatment). All volunteers were infected with P. falciparum (3D7 or NF54) as part of a CHMI trial that used equivalent end-points to our own study and in every case abnormal ALT was scored using the same adaptation of the WHO adverse event grading system (see Materials and methods). Data from 95 volunteers in Reuling et al. (those enrolled in the EHMI-3, LSA-3, EHMI-8B, EHMI-9, ZonMw2, TIP5, and CHMI-trans1 studies) and the three first infection volunteers in VAC063C were pooled for analysis. (B) Frequency and severity of liver injury; Barnard’s test was used to statistically determine whether an abnormal ALT reading was more prevalent during a first-in-life infection compared with the second or third infection (a P value below 0.05 was considered significant). (C) Pearson correlation matrix showing the fold-change of differentially abundant plasma analytes, lymphocytes, and hemoglobin during VAC063C. Fold-change was calculated either at diagnosis or T6 (relative to baseline) according to when this was largest for each feature. Also included are maximum parasite density, maximum core temperature (up to 48 h after treatment), and class-switched antibody titer (28 days after challenge). Finally, circulating ALT is shown at T6 together with the frequency of activated (CD38^hi) effector (effector memory) CD4⁺ T cells, regulatory T cells, and cytotoxic T cells (defined as granzyme B^pos). All data were log₂ transformed and the order of features was determined by unsupervised hierarchical clustering. (D) PBMC were isolated during VAC063C from volunteers undergoing their first infection of life, restimulated in vitro with PMA/ionomycin, and cocultured with HepG2 cells for 24 h. Cytotoxicity was measured by the release of LDH. Experiments were performed using baseline and T6 samples, and data are shown as baseline subtracted values (i.e., absorbance at T6 minus absorbance at baseline). Curves were fit using a cubic polynomial function (the shaded areas represent 95% confidence intervals). Note that LDH release was shown experimentally to be specific to HepG2 cells and all assays were run in duplicate. In A and B, n = 98 for the first infection and n = 8 for rechallenge (2 second infection and 6 third infection). In C, n = 10 (3 first infection, 2 second infection, and 5 third infection) and in D, n = 3 (first infection only).