Secondary Streptococcus pneumoniae infection increases morbidity and mortality during murine cryptococcosis
Bárbara A Miranda1, Gustavo J C Freitas1, Victor A T Leocádio1
1Departamento de Microbiologia/Laboratório de Micologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Abstract:
Microorganisms that cause pneumonia and translocate to the central nervous system (CNS) are responsible for high mortality worldwide. The fungus Cryptococcus gattii (Cg) and the bacteria Streptococcus pneumoniae (Sp) target the same infection organs. This study aimed to investigate the consequences of secondary Sp infection during murine cryptococcosis. Mice infected with Sp after Cg showed significantly increased lethality and a drop in scores of motor behaviour, neuropsychiatric status and autonomous function. Previous Cg infection favoured Sp multiplication in the lungs, causing intense inflammation and necrosis, with further increased bacterial translocation to the spleen, liver and brain. This phenotype was associated with increased platelet-activating factor receptor (Pafr) gene expression, reduced M1 macrophage recruitment, and high levels of proinflammatory mediators. Strategies to overcome early mortality (i.e., infection of Pafr-/- mice, treatment with IL-1 inhibitor or corticoid) were insufficient to revert this phenotype. These results suggest that Cg infection makes the lung microenvironment favourable for Sp colonization and dissemination. Altogether, it leads to an exacerbated and ineffective inflammatory response, decisive for the increased morbidity and mortality during coinfection. In conclusion, our results highlight the importance of more studies addressing coinfections and their consequences in the host, aiming to establish more effective therapeutical strategies.
Insights
Secondary Streptococcus pneumoniae infection dramatically increases mortality in mice previously infected with Cryptococcus gattii. This coinfection exacerbates lung damage and bacterial spread to the brain, highlighting the critical need for new therapeutic strategies.
Area of Science:
- Immunology
- Microbiology
- Neuroscience
Background:
- Pneumonia-causing microorganisms, including Cryptococcus gattii (Cg) and Streptococcus pneumoniae (Sp), can spread to the central nervous system (CNS), leading to high mortality.
- Both Cg and Sp target similar organs, suggesting potential interactions during coinfection.
Purpose of the Study:
- To investigate the consequences of a secondary Sp infection in a murine model of established Cg cryptococcosis.
- To understand the impact of Cg pre-infection on Sp pathogenesis and host response.
Main Methods:
- Mice were infected with Cg, followed by secondary Sp infection.
- Assessed mortality, behavioral changes (motor, neuropsychiatric, autonomous functions), bacterial load in organs, lung pathology, and gene expression (Pafr).
- Investigated interventions including Pafr knockout mice, IL-1 inhibition, and corticosteroid treatment.
Main Results:
- Secondary Sp infection significantly increased mortality and caused severe behavioral deficits.
- Prior Cg infection promoted Sp multiplication in lungs, leading to inflammation, necrosis, and enhanced bacterial translocation to the spleen, liver, and brain.
- The observed phenotype was linked to increased Pafr expression, reduced M1 macrophages, and elevated pro-inflammatory mediators.
- Interventions targeting Pafr, IL-1, or inflammation did not fully reverse the detrimental effects.
Conclusions:
- Cg infection creates a lung microenvironment conducive to Sp colonization and dissemination.
- Coinfection results in an exacerbated yet ineffective inflammatory response, driving increased morbidity and mortality.
- Further research into coinfections is crucial for developing effective therapeutic strategies.
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