Role of cmv-IL-10 in an HCMV & Aspergillus fumigatus co-infection model

Introduction: Human cytomegalovirus (HCMV) causes severe infections in immunocompromised patients and can also predispose them to fungal co-infections. For instance, we previously found that HCMV co-infection attenuated proinflammatory response of human monocyte-derived dendritic cells (moDCs) to the opportunistic mold Aspergillus fumigatus. Of note, HCMV employs several immune evasion strategies, including its interleukin-10 homolog (cmv-IL-10), to counteract host immunosurveillance and establish life-long latency.

Goals: We studied the role of HCMV in the interplay between A. fumigatus and human moDCs, focusing on the role of cmv-IL-10 in immune cell-mediated cross-kingdom interactions.

Materials & Methods: We exposed moDCs to wildtype HCMV TB40E or UL111A (HCMV lacking cmv-IL-10) and/or A. fumigatus, either individually (single infection) or in combination (co-infection). In addition, moDCs were stimulated with recombinant cmv-IL-10, with and without subsequent A. fumigatus challenge. We used a multifaced approach (RNA-seq, flow cytometry, ELISA) to study moDC activation and various effector responses.

Results: In contrast to single A. fumigatus infection, co-infection with A. fumigatus and TB40E but not UL111A resulted in reduced expression of various genes associated with DC activation (e.g., IRF5 and TLR4). Moreover, exposure of moDCs to cmv-IL-10 led to diminished expression of genes involved in the initiation of anti-Aspergillus defense and tissue repair (e.g., CXCL8 and VEGFA). Additionally, simultaneous confrontation with rcmv-IL-10 dampened several DC effector responses to A. fumigatus, including IL-1β and CXCL10 release.

Conclusion: We provide inaugural evidence that cmv-IL-10 contributes to attenuated antifungal host response during HCMV-associated aspergillosis.