Morphology-Independent Virulence of Candida Species during Polymicrobial Intra-abdominal Infections with Staphylococcus aureus.
Intra-abdominal polymicrobial infections cause significant morbidity and mortality. An experimental mouse model of Candida albicans-Staphylococcus aureus intra-abdominal infection (IAI) results in 100% mortality by 48 to 72 h postinoculation, while monomicrobial infections are avirulent. Mortality is associated with robust local and systemic inflammation without a requirement for C. albicans morphogenesis. However, the contribution of virulence factors coregulated during the yeast-to-hypha transition is unknown. This also raised the question of whether other Candida species that are unable to form hyphae are as virulent as C. albicans during polymicrobial IAI. Therefore, the purpose of this study was to evaluate the ability of non-albicans Candida (NAC) species with various morphologies and C. albicans transcription factor mutants (efg1/efg1 and cph1/cph1) to induce synergistic mortality and the accompanying inflammation. Results showed that S. aureus coinoculated with C. krusei or C. tropicalis was highly lethal, similar to C. albicans, while S. aureus-C. dubliniensis, S. aureus-C. parapsilosis, and S. aureus-C. glabrata coinoculations resulted in little to no mortality. Local and systemic interleukin-6 (IL-6) and prostaglandin E2 (PGE2) levels were significantly elevated during symptomatic and/or lethal coinfections, and hypothermia strongly correlated with mortality. Coinoculation with C. albicans strains deficient in the transcription factor Efg1 but not Cph1 reversed the lethal outcome. These results support previous findings and demonstrate that select Candida species, without reference to any morphological requirement, induce synergistic mortality, with IL-6 and PGE2 acting as key inflammatory factors. Mechanistically, signaling pathways controlled by Efg1 are critical for the ability of C. albicans to induce mortality from an intra-abdominal polymicrobial infection.
Department of Microbiology, Immunology, and Parasitology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Evelyn E
EE
Nash
Department of Oral and Craniofacial Biology, Dental School, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Brian M
BM
Peters
Department of Microbiology, Immunology, and Parasitology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA Department of Oral and Craniofacial Biology, Dental School, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Paul L
PL
Fidel
Department of Microbiology, Immunology, and Parasitology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA Department of Oral and Craniofacial Biology, Dental School, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA Department of Prosthodontics, Dental School, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA mnover@lsuhsc.edu.
Mairi C
MC
Noverr
D000818:Animals; D002176:Candida albicans / Q000276:immunology / Q000472:pathogenicity*; D002177:Candidiasis / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D060085:Coinfection / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D004268:DNA-Binding Proteins / Q000235:genetics; D015232:Dinoprostone / Q000276:immunology; D005260:Female; D005656:Fungal Proteins / Q000235:genetics; D007035:Hypothermia / Q000382:microbiology* / Q000401:mortality; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D013203:Staphylococcal Infections / Q000276:immunology* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics
C090837:CPH1 protein, Candida albicans; D004268:DNA-Binding Proteins; C121438:EFG1 protein, Candida albicans; D005656:Fungal Proteins; D015850:Interleukin-6; D014157:Transcription Factors; D015232:Dinoprostone