Fig. 4. Functional interplay between human STING genotype and bacterial NADase activity regulates disease outcome in NSTI patients.

a Overview of the STING alleles and combinations analyzed for the 73 NSTI patients, amino acid substitutions G230A and R232H, representing the minor alleles, are indicated in red. b Allele frequency analysis of the two SNPs rs78233829 and rs1131769 corresponding to amino acid G or A at position 230, and R or H at position 232, respectively. The patient cohort was compared to ~13,000 Swedish individuals in the Genome Aggregation Database (GnomAD), representing the allele frequencies within the general Swedish population (Fisher’s exact test: rs87233829: p = 0.6; rs1131769: p = 0.13). c Pie chart summary of the STING genotypes of the 73 NSTI patients. Color coding relates to the amino acid substitutions indicated in a. d Frequencies of major and minor allele carriers (as defined in c), respectively, that required amputation of the infected limb. Specific STING genotypes of amputated minor allele carriers are indicated to the right. This analysis is based on 61 NSTI patients with infection localized to extremities, including 27 homozygous major allele carriers and 34 minor allele carriers (generalized linear model: genotype: χ² = 4.48, df = 1, p = 0.034). e Frequencies of major and minor allele carriers (as defined in c), respectively, that developed septic shock (genotype: p > 0.22). f Relative NADase activity in overnight cultures of the 53 S. pyogenes NSTI patient isolates grouped based on whether or not the patients developed septic shock. g, h Same analysis as in f above, but S. pyogenes isolates where further divided based on whether the patients were homozygote major allele carriers (g) or minor allele carriers (h). Results (f–h) are based on three independent experiments. Two-sided unpaired t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.