Immune Receptor Repertoire Analyses Reveal Dynamics of Adaptive Immunity in Acute Invasive Fungal Sinusitis

Acute invasive fungal sinusitis (AIFS) is a highly fatal infection affecting immunocompromised patients. While defects in innate immunity have been studied as the primary focus in AIFS, adaptive immunity has yet to be explored in this condition.

Sinonasal biopsies from consenting surgical patients were collected from 13 AIFS patients, 8 immunocompromised patients without fungal infection, and 4 healthy controls. B- and T-cell receptor (BCR/TCR) sequences were reconstructed from bulk transcriptome sequencing. Clonal homeostasis, repertoire diversity, and V gene usage were compared for both BCRs and TCRs. Somatic hypermutation (SHM) rates, isotype distribution, and biophysical properties of BCRs were further analyzed. Lastly, bulk transcriptomic deconvolution was performed to examine the abundance of adaptive immune cells in AIFS.

Both B and T cells in AIFS exhibited increased clonal expansion, coupled with decreased receptor diversity compared with control groups. V gene usage in BCRs and TCRs demonstrated immunosuppression-associated and AIFS-specific patterns. SHM was decreased in AIFS compared with both healthy and immunocompromised controls, particularly in IgG and IgA BCRs. The light and heavy chains of BCRs in AIFS were biophysically distinct from those of controls. Bulk deconvolution reveals depletion of naïve and memory B cells, as well as CD4 and CD8 T cells in AIFS compared with immunosuppressed controls.

Our results suggest that adaptive immunity is dysregulated in AIFS. Further studies should focus on single-cell profiling to further dissect the cellular dynamics underlying this dysregulation. Recombinant cytokine therapies to boost adaptive responses represent promising medical therapies to complement surgical debridement and antifungal medications.