title: The yeast to hyphal transition following hematogenous candidiasis induces shock and organ injury independent of circulating tumor necrosis factor-alpha.
abstract: OBJECTIVE
  Dimorphic Candida albicans spp. increasingly cause lethal septic shock and disseminated infection in the critically ill. Following candidemia, production of specific fungal exotoxins coincident with the yeast to hyphal phenotypic transition is believed to be important in the pathogenesis of Candida septic shock. However, overexpression of the pleiotropic cytokine tumor necrosis factor (TNF)-alpha by the host following hyphal germination is also thought to be a mechanism of Candida-related cardiopulmonary dysfunction, as well as of bacteremic shock. In this study, we hypothesized that increases in circulating TNF-alpha coinciding with the yeast to hyphal transition modulate the onset and progression of shock with multiple organ injury early after hematogenous candidiasis.
  
  
  METHODS
  Prospective, controlled laboratory animal study.
  
  
  METHODS
  University hospital animal research facility.
  
  
  METHODS
  Pathogen-free, male Sprague-Dawley rats (n = 26).
  
  
  METHODS
  Conscious, antibiotic-treated animals with chronic indwelling carotid arterial and jugular venous catheters were intravenously infected with 10(9) viable blastoconidia of the C. albicans clinical pathogen, CA-MEN (n = 10), over 30 mins and ending at t = 0 hr, compared with an equivalent inoculum of its viable agerminative mutant, CA-MM2002 n = 11), or an intravenous infusion of 0.9% sodium chloride (n = 5).
  
  
  RESULTS
  Mean arterial pressure (MAP), pulse rate, respiratory frequency, rectal temperature, acid-base status, quantitative blood cultures, circulating alanine aminotransferase (ALT), and bioactive TNF-alpha were serially measured in all three groups over 24 hrs or until death. Organ cultures, wet/dry weight ratios, and histopathologic changes in the lungs, heart, liver, and kidneys were determined in Candida-infected and 0.9% sodium chloride (normal saline)-infused subgroups at 6 and 24 hrs. Animals hematogenously infected with the C. albicans clinical isolate developed lethal nonendotoxemic shock in < or = 6 hrs (MAP 49 +/- 7 mm Hg [SEM]; p < .05 vs. t = 0 hr), and at death (7.0 +/- 0.3 hrs) were acidotic, hypocapnic, and hypothermic (rectal temperature 33.2 +/- 0.7 degrees C). Despite similar peak concentrations of circulating fungal colony-forming units (cfu) and kinetics of vascular clearance in both Candida-infected groups, survival and MAP in rats challenged with the agerminative C. albicans mutant were unchanged for > 8 hrs, as were pH, Pco2, and rectal temperature. No germination of the agerminative fungal strain occurred in vivo over 6 hrs. Serum TNF was nearly undetectable at t = 0 hr in all three groups. Although shock developed soon after fungemia with the C. albicans clinical isolate, TNF-alpha concentrations did not increase above normal saline values in either candidemic group at t = 1.5, 4.5, or 6 hrs (17 +/- 7 vs. 14 +/- 1 U/mL in the parent C. albicans organism vs. its agerminative mutant at t = 6 hrs). Greater numbers of agerminative C. albicans than its dimorphic parent strain were recovered from the lungs (5.41 +/- 1.0 vs. 2.02 +/- 0.38 x 10(7) cfu/g, respectively; p < .05) and kidneys (p < .01). By 24 hrs, modest germination of the mutant Candida strain was observed in the tissues. However, lung wet/dry ratios, intrapulmonary hyphal proliferation, and alveolar hemorrhage were all greater after infection with the parent fungal isolate. Likewise, myocardial necrosis and hepatic glycogen depletion with vacuolization were more severe after infection with the C. albicans clinical isolate vs. candidemia with its agerminative mutant, although serum ALT values did not differ between these groups.
  
  
  CONCLUSIONS
  Lethal C. albicans sepsis with lung injury and multiple organ damage are temporally associated with the in vivo yeast to hyphal transition in this model. However, this candidemic septic shock syndrome is modulated by circulating fungal virulence factors or host mediators other than TNF-alpha, a cytokine considered essen
authors.affiliation: Department of Internal Medicine, Saint Louis University Health Sciences Center, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Matuschak
authors.forename: A J
authors.initials: AJ
authors.lastname: Lechner
mesh_terms: D000818:Animals; D001769:Blood / Q000382:microbiology; D002176:Candida albicans / Q000254:growth & development* / Q000378:metabolism / Q000472:pathogenicity*; D002177:Candidiasis / Q000097:blood / Q000150:complications* / Q000382:microbiology*; D002318:Cardiovascular Diseases / Q000209:etiology; D004195:Disease Models, Animal; D016469:Fungemia / Q000097:blood / Q000150:complications* / Q000382:microbiology*; D008099:Liver / Q000382:microbiology; D008168:Lung / Q000382:microbiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000097:blood / Q000382:microbiology* / Q000401:mortality; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*
chemical_list: D014409:Tumor Necrosis Factor-alpha