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Published on: July 9, 2014
Card9 Broadly Regulates Host Immunity against Experimental Pulmonary Cryptococcus neoformans 52D Infection
Isabelle Angers1, Wided Akik1,2, Annie Beauchamp1
1Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre, McGill University, Montreal, QC H4A 3J1, Canada.
Abstract:
The ubiquitous soil-associated fungus Cryptococcus neoformans causes pneumonia that may progress to fatal meningitis. Recognition of fungal cell walls by C-type lectin receptors (CLRs) has been shown to trigger the host immune response. Caspase recruitment domain-containing protein 9 (Card9) is an intracellular adaptor that is downstream of several CLRs. Experimental studies have implicated Card9 in host resistance against C. neoformans; however, the mechanisms that are associated with susceptibility to progressive infection are not well defined. To further characterize the role of Card9 in cryptococcal infection, Card9em1Sq mutant mice that lack exon 2 of the Card9 gene on the Balb/c genetic background were created using CRISPR-Cas9 genome editing technology and intratracheally infected with C. neoformans 52D. Card9em1Sq mice had significantly higher lung and brain fungal burdens and shorter survival after C. neoformans 52D infection. Susceptibility of Card9em1Sq mice was associated with lower pulmonary cytokine and chemokine production, as well as reduced numbers of CD4+ lymphocytes, neutrophils, monocytes, and dendritic cells in the lungs. Histological analysis and intracellular cytokine staining of CD4+ T cells demonstrated a Th2 pattern of immunity in Card9em1Sq mice. These findings demonstrate that Card9 broadly regulates the host inflammatory and immune response to experimental pulmonary infection with a moderately virulent strain of C. neoformans.
Insights
Caspase recruitment domain-containing protein 9 (Card9) is crucial for controlling Cryptococcus neoformans infection. Mice lacking Card9 showed increased fungal burden and susceptibility, highlighting Card9's role in immune defense against fungal pneumonia.
Area of Science:
- Immunology
- Mycology
- Genetics
Background:
- Cryptococcus neoformans causes life-threatening pneumonia and meningitis.
- C-type lectin receptors (CLRs) recognize fungal cell walls, initiating immune responses.
- Caspase recruitment domain-containing protein 9 (Card9) is a key adaptor protein downstream of CLRs.
Purpose of the Study:
- To investigate the role of Card9 in host resistance against Cryptococcus neoformans.
- To elucidate the mechanisms underlying susceptibility to progressive cryptococcal infection.
Main Methods:
- CRISPR-Cas9 genome editing was used to create Card9-deficient mice (Card9em1Sq).
- Mice were intratracheally infected with Cryptococcus neoformans 52D.
- Fungal burdens, survival rates, pulmonary immune cell populations, cytokine/chemokine levels, and T cell responses were analyzed.
Main Results:
- Card9em1Sq mice exhibited significantly higher fungal burdens in the lungs and brain.
- These mice showed reduced survival rates following C. neoformans infection.
- Lower pulmonary cytokine and chemokine production, and decreased CD4+ lymphocytes, neutrophils, monocytes, and dendritic cells were observed.
- Histological analysis and intracellular cytokine staining revealed a Th2-biased immune response in Card9em1Sq mice.
Conclusions:
- Card9 plays a broad regulatory role in the host's inflammatory and immune response to experimental pulmonary Cryptococcus neoformans infection.
- Deficiency in Card9 leads to increased susceptibility and a Th2-skewed immune response.
- These findings underscore the importance of Card9 in host defense against fungal pathogens.
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