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Infection and Immunity, January 2004, p. 598-601, Vol. 72, No. 1
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.1.598-601.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Relationship between Candida albicans Virulence during Experimental Hematogenously Disseminated Infection and Endothelial Cell Damage In Vitro

Angela A. Sanchez,1 Douglas A. Johnston,1 Carter Myers,1 John E. Edwards Jr.,1,2 Aaron P. Mitchell,3 and Scott G. Filler1,2*

St. Johns Cardiovascular Research Center, Division of Infectious Diseases, Department of Medicine, Harbor-UCLA Research and Education Institute, Torrance, California 90502,1 The David Geffen School of Medicine at UCLA, Los Angeles, California 90024,2 Department of Microbiology and Integrated Program in Cellular, Molecular, and Biophysical Studies, Columbia University, New York, New York 100323

Received 4 September 2003/ Returned for modification 15 September 2003/ Accepted 22 September 2003


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ABSTRACT
 
Candida albicans must penetrate the endothelial cell lining of the vasculature to invade the deep tissues during a hematogenously disseminated infection. We compared 27 C. albicans mutants with their wild-type parent for their capacity to damage endothelial cells in vitro and cause a lethal infection in mice following tail vein inoculation. Of 10 mutants with significantly impaired capacity to damage endothelial cells, all had attenuated virulence. Therefore, the endothelial cell damage assay can be used as a screen to identify some virulence factors relevant to hematogenously disseminated candidiasis.


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TEXT
 
During the initiation of hematogenously disseminated candidiasis, blood-borne organisms must adhere to and penetrate the endothelial cell lining of the blood vessels to invade the deep tissues. One mechanism by which Candida albicans can penetrate the vascular endothelium is by damaging and eventually killing the endothelial cells. Damaged endothelial cells detach from the basement membrane, leaving gaps through which the organism can invade. Also, the exposed basement membrane can be avidly bound by additional organisms (18).

C. albicans damages human vascular endothelial cells in vivo and in vitro (5, 10, 17, 25). Maximal endothelial cell damage (ECD) occurs in vitro when C. albicans adheres to and invades the endothelial cells and then secretes lytic enzymes (2, 10, 11, 13, 16). Moreover, some C. albicans mutants with filamentation defects cause significantly less ECD than the wild-type parent strain (24). These filamentation mutants also have attenuated virulence in various experimental models of infection (reviewed in reference 23). We hypothesized that the in vitro assay for C. albicans-induced ECD (ECD assay) can serve as a model for certain aspects of host-pathogen interactions in vivo, such as the ability of the organism to adhere to, invade, and injure host cells. This hypothesis predicts that some mutants with virulence defects will be defective in the ECD assay. The goal of the present study was to investigate this prediction.

C. albicans strains. The genotypes and sources of the C. albicans strains used here are listed in Tables 1 and 2. Each strain was grown overnight in yeast nitrogen base broth (Difco, Detroit, Mich.) supplemented with 2% glucose (wt/vol) at 20°C on a rotating drum. The blastospores were harvested by centrifugation, washed with phosphate-buffered saline, enumerated with a hemacytometer, and suspended in RPMI 1640 medium (Irvine Scientific, Santa Ana, Calif.).


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  		TABLE 1. Relationship between the ability of C. albicans mutants to damage endothelial cells in vitro and virulence


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  		TABLE 2. ECD caused by complemented strains of C. albicans

ECD assay. We used our standard 51Cr release ECD assay to determine the abilities of mutants of C. albicans to damage endothelial cells in vitro (24). The ECD assay was performed in 96-well tissue culture plates (Corning Inc., Acton, Mass.) with endothelial cells isolated from human umbilical cord veins, as described previously (24). The inoculum was 4 x 104 organisms per well, and the organisms were incubated with the endothelial cells for 3 h in 5% CO2 at 37°C. At the end of the incubation period, the wells were examined with an inverted microscope, and the morphology of each strain was recorded. Each strain was tested in triplicate on two separate occasions. The wild-type parent strain, SC5314, was included as a positive control in all assays, and the results were expressed as a percentage of the ECD caused by this strain.

Virulence testing. To provide a uniform assessment of the virulence of all mutants, we grew and processed them as described for the ECD assay, except that the growth medium was YPD broth (1% yeast extract, 2% peptone, and 2% glucose [wt/vol]) and the organisms were suspended in phosphate-buffered saline. We infected 10 to 12 male BALB/c mice (20 g; National Cancer Institute, Bethesda, Md.) with 5 x 105 blastospores of each strain via the tail vein. All inocula were confirmed by colony counting. The mice were monitored at least three times daily, and moribund mice were euthanized. The survival of mice infected with the different mutants was compared with that of mice infected with the wild-type parent, SC5314. All mouse experiments were carried out according to the NIH guidelines for the ethical treatment of animals.

Statistics. Differences in ECD caused by the different strains were compared by using analysis of variance, and differences in survival of the mice were analyzed with the log-rank test. The Bonferroni correction for multiple comparisons was applied to all statistical analyses. P values of <=0.05 were considered significant.

ECD- mutants had attenuated virulence. Of the 27 C. albicans mutants tested in the ECD assay, 10 caused significantly less damage to endothelial cells than the wild-type control strain (Table 1). We have designated mutants that cause reduced damage to endothelial cells ECD-. To verify that the ECD- phenotype was the result of disruption of the genes of interest, we measured the ECD caused by the complemented strain of each ECD- mutant. The ECD caused by all of the complemented strains was similar to that induced by the wild-type control strain (Table 2).

Next, we investigated the virulence of each of the mutants in the murine model of disseminated candidiasis. Seventeen of the 27 mutants had significantly attenuated virulence compared to the wild-type control strain (Table 1). The virulence of the complemented strains of 15 of these 17 mutants was tested either in this study (ura3/ura3) or previously by other investigators (3, 7, 9, 19, 22, 28, 30, 33, 34, 35) (all but the cat1/cat1/cat1 and czf1/czf1 strains) and was found to be restored.

Of note, all 10 strains that were ECD- were also significantly less virulent. The genes that were disrupted in the ECD- mutants specify transcription factors, signal transduction pathway members, and enzymes, the majority of which have been postulated or shown to have a role in virulence. Many of the ECD- strains had defects in signal transduction pathways that govern hyphal formation (Cla4p, Efg1p, Cph1p, and Tec1p) (20-22). It has been found that the cla4/cla4 and efg1/efg1 strains are ECD- at least in part, because they have reduced capacity to invade endothelial cells (24). Mds3p, Phr1p, and Rim101p all regulate filamentation in response to pH (8, 9, 27) and are required for maximal ECD. Interestingly, when the mds3/mds3 strain was incubated with endothelial cells, it formed hyphae that were only about 30% shorter than those of the wild-type strain. Therefore, Mds3p likely governs the ability of C. albicans to damage endothelial cells independently of filamentation. Conversely, the czf1/czf1 and pmt6/pmt6 strains, which formed only short hyphae on the endothelial cells, were ECD+. Therefore, C. albicans factors other than the ability to form long hyphae are necessary for the organism to damage endothelial cells.

Two of the ECD- strains did not have mutations in signal transduction pathways. The pmt1/pmt1 strain, which is defective in O-mannosylation of multiple proteins, has been reported to adhere poorly to host cells because of reduced mannosylation of adhesins such as Als1p (33). Thus, this strain is probably ECD- because it adheres poorly. CAI4 (ura3/ura3), a simple uridine auxotroph, was also ECD-. Uridine, in the form of UDP, is required to transfer sugars to carbohydrate polymers and glycoproteins, such as those that make up the cell wall. As a result, Ura- strains have decreased adherence to host cells (1), and we observed that the Ura- strain was unable to form true hyphae on endothelial cells in the absence of uridine. Therefore, the Ura- strain was almost certainly ECD- because of its defects in adherence and hyphal formation, rather than growth rate.

It has been reported that the locus at which URA3 is integrated can influence the virulence of C. albicans (L. L. Sharkey, W.-L. Lia, and W. A. Fonzi, Abstr. 6th ASM Conf. Candida Candidiasis, abstr. S-11, 2002) (31, 32). We measured the amount of ECD caused by two different hwp1/hwp1 mutants: CAL3, in which URA3 was integrated at the HWP1 locus, and CAL3-URA, in which URA3 was integrated at its native locus. The extent of ECD caused by both strains was not significantly different from that caused by the wild-type strain (Table 1). However, CAL3 had significantly attenuated virulence in the mouse model, whereas CAL3-URA did not. Therefore, the results of the ECD assay appear to be relatively independent of the locus at which URA3 is integrated in C. albicans.

Although 17 of the 27 mutants had reduced virulence, 7 of them were ECD+. Thus, the ECD assay has a significant false-negative rate. Such a result is not unexpected, because factors other than the ability to damage endothelial cells are clearly important for the normal virulence of C. albicans. Some of these mutants may be defective in virulence either before or after their interactions with endothelial cells. For example, the cat1/cat1/cat1 strain has been shown to be more susceptible to leukocyte killing than the wild-type parent strain (36). Also, some genes, such as TPK2, have homologs (TPK1) in the genome that may compensate partially for the null mutant defect. Finally, it is possible that some of the strains that were ECD+ when tested under the current conditions (3-h incubation with the endothelial cells in RPMI 1640 medium) might have been ECD- when exposed to the endothelial cells for different incubation times or in different media.

In summary, the C. albicans ECD assay identifies some classes of virulence factors. It also provides the opportunity for detailed analysis of certain host-pathogen interactions under controlled experimental conditions. We are currently using this assay to screen random insertion mutants of C. albicans to identify new virulence factors and virulence regulatory pathways.


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ACKNOWLEDGMENTS
 
We are grateful for the numerous investigators who provided the strains of C. albicans used in these experiments, and we thank the nurses at Harbor-UCLA Medical Center for collecting umbilical cords and Quynh T. Phan for help with tissue culture. The Olympus phase-contrast microscope used for these studies was generously donated by Toyota U.S.A.

Financial support included Public Health Service grants R01 AI19990, P01 AI37194, R29 AI040636, R01 DE13974, R01 AI50931 and MO1 RR00425 from the National Institutes of Health. S. G. Filler was supported by the Burroughs Wellcome Fund New Investigator Award in Molecular Pathogenic Mycology.


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FOOTNOTES
 
* Corresponding author. Mailing address: Division of Infectious Diseases, Harbor-UCLA Research and Education Institute, 1124 W. Carson St., Torrance, CA 90502. Phone: (310) 222-6426. Fax: (310) 782-2016. E-mail: sfiller{at}ucla.edu. Back

Editor: T. R. Kozel


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Infection and Immunity, January 2004, p. 598-601, Vol. 72, No. 1
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.1.598-601.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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