Myeloid-specific ablation of Cblb is necessary to bolster defense against pulmonary fungal infection

• Published in: The Journal of immunology (1950) 2023-05, Vol.210 (1_Supplement), p.81-81.21
• Main Authors: Sharma, Jaishree, Nanjappa, Somashekarappa Gowda
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.210.Supp.81.21

Fungal pneumonia is a severe clinical problem, especially in patients with compromised immunity. The long-term therapeutic and prophylactic use of antifungal drugs in high-risk patients has promoted the emergence of multidrug-resistant fungi. Myeloid cells, mainly alveolar macrophages, are critical for orchestrating the immune responses, limiting pathogen growth, and resolving pathology during lung fungal infection. Thus, it is essential to understand mechanisms and uncover the host-fungus interface regulating early immune responses in the lung. Here, we studied the myeloid cell-specific role of the host element, CBLB, an E3 ubiquitin ligase, for antifungal immunity in the lungs. Using a mouse model of pulmonary blastomycosis, we found that targeted ablation of Cblb in myeloid cells (LysM cre/creCblb fl/fl), but not in all the cells, was essential to mediate protective immunity. Myeloid-specific Cblb deletion enhanced survival, reduced fungal burden, and reduced inflammation following lethal lung fungal infection. Mechanistically, myeloid-specific ablation of Cblb led to enhanced numbers of alveolar macrophages and increased activation and ROS production by neutrophils. Interestingly, we found an augmented type 17 innate lymphocytes in LysM cre/creCblb fl/flmice than in controls, suggesting their potential crosstalk with Cblb-deficient myeloid cells. Our study suggests that myeloid-specific ablation of Cblb is necessary to enhance immunity against pulmonary fungal infections and proposes this as a potential therapeutic avenue. Supported by grants from American Lung Association (IA-697123, to SGN), NIH (R01 AI53522, to SGN), and UIUC (Faculty Start-up Funds, to SGN)