CD146 deficiency promotes inflammatory type 2 responses in pulmonary cryptococcosis

Area of Science:

• Immunology
• Mycology
• Pathogen-host interactions

Background:

• Cryptococcus neoformans is a significant opportunistic fungal pathogen causing pulmonary infections.
• Previous research identified CD146 as a mediator of C. neoformans adhesion to airway epithelium.
• The role of CD146 in the inflammatory response during pulmonary cryptococcosis remained unexplored.

Purpose of the Study:

• To investigate the function of CD146 in the inflammatory response to pulmonary cryptococcosis.
• To determine the impact of CD146 reduction on the severity of C. neoformans infection.

Main Methods:

• Analysis of CD146 expression in lung tissues from human patients and infected mice.
• Utilizing CD146 knockout (KO) mice and bone marrow chimeric mice for infection studies.
• Assessing fungal burden, survival rates, cytokine profiles, macrophage activation, and chemokine production.

Main Results:

• CD146 expression was decreased in pulmonary tissues during C. neoformans infection.
• CD146 deficiency aggravated infection, leading to increased fungal loads and reduced survival.
• CD146 KO mice exhibited elevated type 2 inflammatory cytokines (IL-4, IL-5, TNF-α) and alternatively activated macrophages.
• CD146 deficiency in immune cells, not non-immune cells, increased pulmonary fungal burden.
• CD146-deficient macrophages produced more KC and TNF-α, with reduced fungicidal activity and ROS production.

Conclusions:

• C. neoformans infection downregulates pulmonary CD146, contributing to type 2 inflammatory responses.
• CD146 plays a critical protective role in controlling C. neoformans infection, particularly via immune cells.
• Loss of CD146 exacerbates pulmonary cryptococcosis by impairing macrophage function and promoting inflammation.