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Talaromyces marneffei Mp1p Is a Virulence Factor that Binds and Sequesters a Key Proinflammatory Lipid to Dampen Host
Kong-Hung Sze1, Wai-Hei Lam2, Hongmin Zhang3
1State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China; Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong SAR, China.
Abstract:
Talaromyces (Penicillium) marneffei is one of the leading causes of systemic mycosis in immunosuppressed or AIDS patients in Southeast Asia. How this intracellular pathogen evades the host immune defense remains unclear. We provide evidence that T. marneffei depletes levels of a key proinflammatory lipid mediator arachidonic acid (AA) to evade the host innate immune defense. Mechanistically, an abundant secretory mannoprotein Mp1p, shown previously to be a virulence factor, does so by binding AA with high affinity via a long hydrophobic central cavity found in the LBD2 domain. This sequesters a critical proinflammatory signaling lipid, and we see evidence that AA, AA's downstream metabolites, and the cytokines interleukin-6 and tumor necrosis factor α are downregulated in T. marneffei-infected J774 macrophages. Given that Mp1p-LBD2 homologs are identified in other fungal pathogens, we expect that this novel class of fatty-acid-binding proteins sequestering key proinflammatory lipid mediators represents a general virulence mechanism of pathogenic fungi.
Insights
Talaromyces marneffei evades immune defense by depleting the proinflammatory lipid arachidonic acid (AA). A mannoprotein, Mp1p, binds AA, reducing its levels and host inflammatory responses, a potential general virulence mechanism in fungal pathogens.
Area of Science:
- Mycology
- Immunology
- Biochemistry
Background:
- Talaromyces marneffei causes systemic mycosis in immunocompromised individuals, particularly in Southeast Asia.
- The mechanisms by which this intracellular pathogen evades host immune defenses are not fully understood.
Purpose of the Study:
- To investigate how Talaromyces marneffei evades host innate immune defense.
- To identify the molecular mechanisms involved in immune evasion.
Main Methods:
- Investigated the role of arachidonic acid (AA) in T. marneffei infection.
- Characterized the interaction between the mannoprotein Mp1p and AA using its LBD2 domain.
- Quantified levels of AA, its metabolites, and cytokines (IL-6, TNF-α) in infected macrophages.
Main Results:
- T. marneffei depletes the proinflammatory lipid mediator arachidonic acid (AA) to evade host innate immunity.
- The secreted mannoprotein Mp1p binds AA with high affinity via its LBD2 domain, sequestering this signaling lipid.
- AA, its downstream metabolites, and pro-inflammatory cytokines IL-6 and TNF-α were downregulated in T. marneffei-infected macrophages.
Conclusions:
- Mp1p-mediated sequestration of AA is a novel virulence mechanism for T. marneffei immune evasion.
- Homologs of Mp1p-LBD2 in other fungal pathogens suggest this mechanism may be a general strategy for fungal virulence.
- Targeting this fatty-acid-binding protein interaction could offer new therapeutic strategies against fungal infections.
