Secondary Streptococcus pneumoniae infection increases morbidity and mortality during murine cryptococcosis

• Published in: Immunology 2024-01, Vol.171 (1), p.92-103
• Main Authors: Miranda, Bárbara A., Freitas, Gustavo J. C., Leocádio, Victor A. T., Costa, Marliete C., Emídio, Elúzia C. P., Ribeiro, Noelly Q., Carmo, Paulo H. F., Gouveia‐Eufrásio, Ludmila, Hubner, Josy, Tavares, Luciana P., Arifa, Raquel D. N., Brito, Camila B., Silva, Monique F., Teixeira, Mauro M., Paixão, Tatiane A., Peres, Nalu T. A., Fagundes, Caio T., Santos, Daniel A.
• Format: Article
• Language: English
• Subjects: Bacteria; Central nervous system; coinfection; Cryptococcosis; Cryptococcus gattii; cytokine storm; Fungi; Gene expression; Inflammation; Inflammatory response; Lethality; Lungs; Macrophages; Microenvironments; Microorganisms; Morbidity; Mortality; Necrosis; Phenotypes; Pneumonia; Streptococcus infections; Streptococcus pneumoniae; Translocation
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.13701

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. Secondary Streptococcus pneumoniae (Sp) infection increases morbidity and mortality during murine cryptococcosis. The Infection with Cryptococcus gattii induces tissue damage providing a favourable lung microenvironment for initial adhesion and colonization of Sp during coinfection. Consequently, this contributes to Sp invasiveness, resulting in increased bacterial burden in the lungs and dissemination to the brain. In this context, an exacerbated and ineffective inflammatory response occurs, characterized by a cytokine storm, increased recruitment of neutrophils and polarization of M2 macrophages, which is decisive for the increase in morbidity and mortality due to coinfection.