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Infection and Immunity, January 2008, p. 97-102, Vol. 76, No. 1
0019-9567/08/$08.00+0     doi:10.1128/IAI.00982-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Use of a Genetically Engineered Strain To Evaluate the Pathogenic Potential of Yeast Cell and Filamentous Forms during Candida albicans Systemic Infection in Immunodeficient Mice{triangledown}

Stephen P. Saville,1 Anna L. Lazzell,1 Ashok K. Chaturvedi,1 Carlos Monteagudo,2 and Jose L. Lopez-Ribot1*

Department of Biology, The University of Texas at San Antonio, San Antonio, Texas,1 Departmento de Patología, Universidad de Valencia, Facultad de Medicina y Odontología, Valencia, Spain2

Received 18 July 2007/ Returned for modification 17 August 2007/ Accepted 17 October 2007


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
The pathogenesis of Candida albicans systemic infection is complex and results from the balance between its intrinsic virulence attributes and the host immune responses. Morphogenetic transitions between yeast cell and filamentous forms are considered one of the main virulence attributes in C. albicans. We have examined the pathogenesis of a genetically engineered C. albicans strain in which morphogenetic conversions can be externally manipulated in immunodeficient mice; these included B-cell deficient, nude (T cell deficient), SCID (lacking both functional T and B cells), and DBA/2N (C5 deficient with impaired neutrophil activity) mice. We also tested mice severely immunosuppressed by cyclophosphamide-cortisone acetate treatment. Mice with specific immune defects were able to survive an infection by yeast cells but not filamentous forms. However, yeast cells displayed a pathogenic effect leading to lethality in the severely immunosuppressed mice.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
Candida albicans remains the main causative agent of invasive fungal infection in an expanding population of immunocompromised patients with associated high morbidity and mortality rates (4, 5, 26, 28). C. albicans pathogenesis is a complex phenomenon that results from a delicate balance between its intrinsic virulence attributes and host immune responses (7-10). This gives rise to the highly complex and dynamic nature of the host-fungus interaction that ultimately determines the outcome of an infection. The host responses during systemic candidiasis range from nonspecific innate mechanisms to sophisticated adaptive responses (14, 17, 18, 23). While morphogenetic conversions, the ability to reversibly switch between yeast cell and filamentous forms, constitute one of the most important virulence attributes of this organism (6, 12, 15, 19), it is also clear that all studies of putative C. albicans virulence factors, including dimorphism, must be analyzed in the context of the immune status of the host, since clinical experience teaches us that even the so-called virulent forms of the fungus are unlikely to cause infection in an immunocompetent host.

We have previously reported on the construction of a genetically engineered C. albicans strain (SSY50-B) in which NRG1 (a negative regulator of filamentation) was placed under the control of a tetracycline-regulatable promoter (21) and in which morphogenetic conversions can be controlled by the presence or absence of doxycycline (DOX). Using immunocompetent mice in a widely used murine model of hematogenously disseminated candidiasis, we have previously shown that, with this strain, mortality is achieved only when NRG1 expression is downregulated and morphogenetic conversions are allowed to occur (i.e., when the antibiotic is present in the drinking water) (21). To further examine the interplay between fungal dimorphism and host immune responses during C. albicans systemic infections, we have now used this strain to examine the pathogenic potential of yeast cell and filamentous forms in various inbred strains of mice with specific immune defects as well as in mice severely immunosuppressed by drug treatment and compared the outcomes with those in immunocompetent mice.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS AND DISCUSSION
 REFERENCES
 
C. albicans strain and culture conditions. The C. albicans tet-NRG1 strain (SSY50-B) was routinely maintained and grown on yeast extract-peptone-dextrose (YPD) medium. This strain was constructed by introducing bacterially derived tetO promoter sequences upstream of the C. albicans NRG1 open reading frame in vitro and integrating this promoter-altering fragment into the NRG1 locus as previously described (21). In this strain, morphogenetic conversions can be modulated both in vitro and in vivo by the presence or absence of DOX. In the absence of the antibiotic, high levels of NRG1 expression block the yeast-to-hypha transition, whereas the presence of DOX inhibits expression of the tet-NRG1 allele and allows filamentation to occur normally in response to the appropriate environmental stimuli (21).

Animal experiments. Cultures of strain SSY50-B for injection were grown overnight at 25°C in YPD medium without DOX. Yeast cells were harvested by centrifugation and washed three times in sterile pyrogen-free saline. After cells were counted using a hemocytometer, dilutions were made to allow the appropriate number of yeast cells to be injected in a final volume of 200 µl into the lateral tail veins of 6- to 8-week-old female mice (five to eight mice per group). Confirmation of the number and viability of cells present in the infecting inocula was performed by plate count. Different mouse strains were used, including both BALB/c and C57BL/6 (both immunocompetent), and different immunodeficient strains including B-cell-deficient mice bearing a homozygous deletion of the igh locus (C.129B6-IgH-Jhdtm1Dhu), nude (T-cell-deficient mice; CANn.Cg-Foxn1nu/Crl), and SCID (lacking functional T and B cells; Prkdcscid) mice—all three in a BALB/c background—were used as well as DBA/2N mice, which are C5 deficient (a component of the complement pathway) and are considered to have impaired neutrophil activity (1, 2, 11, 27). We also tested the impact of the yeast cell and filamentous forms in BALB/c mice severely immunosuppressed through cyclophosphamide-cortisone acetate treatment (CPM-treated mice). Briefly, injections of cyclophosphamide (200 mg/kg of body weight, intraperitoneally) and cortisone acetate (250 mg/kg, subcutaneously) were administered on days 4 and 1 prior to infection. For each different mouse strain, two groups were injected: one group of mice did not receive DOX in their drinking water whereas the other group of mice received 2 mg/ml DOX in their water, starting 3 days prior to infection. Mice were monitored for survival for 21 days postinfection. Days on which mice died were recorded; moribund animals were euthanized and recorded as dying the following day. BALB/c, nude, SCID, C57BL/6, and DBA/2N mice were obtained from the National Cancer Institute (Bethesda, MD). B-cell-deficient mice were obtained from Taconic Farms (Germantown, NY).

For all animals, upon death or sacrifice, kidneys were removed for the determination of fungal burden and histology. Briefly, kidneys for histological analysis were fixed in 10% buffered formalin and embedded in paraffin, and thin tissue slices were removed and stained with Grocott-Gomori methenamine-silver to visualize fungal elements present in tissues and with hematoxylin and eosin to evaluate necrosis and inflammation. Cell counts were determined by weighing and homogenizing the kidneys and then plating samples onto solid YPD medium to determine the number of viable CFU. All animal experiments were performed in accordance with institutional regulations. After the mice were received, they were allowed a 1-week acclimatization period before experiments were started.

Statistical analyses. Survival data and differences between groups were analyzed using the Kaplan-Meier log rank test. Organ fungal burdens were monitored by determining the total number of CFU per gram of tissue in kidney. Thereafter, logarithmic values for the different groups were obtained, and results were expressed as geometric means and standard deviations. A Mann-Whitney test was used to determine statistical significance for differences in CFU data. Analyses were performed using GraphPad Prism, version 4.00, for Windows (San Diego, CA).


   RESULTS AND DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
REFERENCES
 
Survival curves for groups of mice with disseminated C. albicans infection in the presence and absence of DOX. As mentioned before, in previous studies using this engineered strain, we have demonstrated that in BALB/c immunocompetent mice mortality is achieved only in the presence of DOX, i.e., when filamentation is allowed to occur. In order to confirm the strict association between filamentation and lethality in immunocompetent mice, we first performed a set of infection experiments using the C57BL/6 mouse strain as an additional/independent control. Mirroring our previous results obtained with the BALB/c strain, the C57BL/6 mice succumbed to infection only when DOX was added to their drinking water (Fig. 1A), although the dose of infecting inoculum needed to be higher in the case of the C57BL/6 mice (about twice the dose) in order to achieve comparable survival curves. Similar to results in their immunocompetent wild-type counterparts, mortality in the B-cell deficient, nude, and SCID (all three mouse strains in a BALB/c background) mice and in the DBA/2N mice was achieved only when filamentation was allowed to occur (in the presence of DOX; NRG1 downregulated) (Fig. 1B to E). Under these conditions, infections in B-cell deficient, nude, and SCID mice progressed similarly to infections in immunocompetent mice, whereas DBA/2N mice died much more rapidly than BALB/c mice (P = 0.0005). This agrees with previous reports in the literature that nude and SCID mice are equally as susceptible to disseminated candidiasis as wild-type mice and that DBA/2N mice, which are deficient in complement component 5 and impaired in their ability to recruit neutrophils to foci of fungal growth, are extremely susceptible to systemic candidiasis (1, 3, 13). In the absence of DOX (NRG1 on; cells remain in the yeast cell form), however, all the B-cell-deficient, nude, SCID, and DBA/2N mice survived the length of infection. This was particularly remarkable and somewhat surprising in the case of the DBA/2N mice, since the dose used for these experiments is approximately 2 to 3 logs above the typical 50% lethal dose for this mouse strain. In stark contrast, infection of the CPM-treated (severely immunosuppressed) mice resulted in rapid mortality both in the presence (filamentous growth) and absence (growth as yeast cells) of DOX although it should be noted that the animals treated with DOX still died slightly earlier after infection than those that did not receive the antibiotic (P = 0.0009) (Fig. 1F). In addition to its effects on B and T cells, the CPM treatment depresses innate immunity mechanisms, including neutrophils, macrophages, and NK cells (22, 24, 25). Despite its lack of selectivity, this method of immunosuppression is relevant to human disease, since many patients at risk for candidiasis receive similar drugs. Interestingly, a comparison of the survival data of the immunocompetent BALB/c mice in the presence of DOX with data obtained from the CPM-treated mice in the absence of the antibiotic indicates that the severely immunodepressed mice succumbed to a "yeast" infection faster than their immunocompetent counterparts to a "filamentous" infection (P = 0.0339). These results suggest that, in the pathogenesis of candidiasis as determined by host-fungus interplay, the immune status of the host may take precedence over the virulence mechanisms displayed by the fungus in determining the outcome of an infection.


Figure 1
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  		FIG. 1. Survival curves for different groups of mice infected with the C. albicans tet-NRG1 strain SSY50-B in both the presence and absence of DOX compared to immunocompetent BALB/c mice. (A) Survival of immunocompetent C57BL/6 (filled squares) and BALB/c (open circles) mice in the presence of DOX and in the absence of antibiotic (filled circles for both strains as no deaths were recorded and curves overlap). Infecting inoculum was 4 x 106 cells/mouse for C57BL/6 mice and 1.9 x 106 cells/mouse for BALB/c mice. (B) Survival of B-cell deficient (filled squares) and BALB/c (open circles) mice in the presence of DOX and in the absence of antibiotic (filled circles for both strains). Infecting inoculum was 1.9 x 106 cells/mouse for both strains. (C) Survival of nude (filled squares) and BALB/c (open circles) mice in the presence of DOX and in the absence of antibiotic (filled circles for both strains). Infecting inoculum was 1.6 x 106 cells/mouse for both strains. (D) Survival of SCID (filled squares) and BALB/c (open circles) mice in the presence of DOX and in the absence of antibiotic (filled circles for both strains). Infecting inoculum was 1.6 x 106 cells/mouse for both strains. (E) Survival of DBA/2N (filled squares) and BALB/c (open circles) mice in the presence of DOX and in the absence of antibiotic (filled circles for both strains). Infecting inoculum was 1.7 x 106 cells/mouse for both strains. (F) Survival of CPM-treated mice in the presence (filled squares) and absence (open squares) of DOX compared to immunocompetent (untreated) BALB/c mice in the presence (open circles) and absence (filled circles) of antibiotic. Infecting inoculum was 1.7 x 106 cells/mouse for both CPM-treated and untreated groups.

 
It should be noted that the experimental design for all of the above experiments was selected to maximize any chances of observing lethality associated with a yeast cell-only infection (in the absence of DOX). Thus, the high dose of inoculum used resulted in acute disseminated candidiasis leading to rapid mortality in all of the corresponding groups of mice treated with the antibiotic, regardless of the immune defect. It is still possible that a larger separation of survival curves among the different DOX-treated mouse experimental groups could have been observed using a lower dose of infecting inoculum more closely mimicking a chronic type of infection.

Fungal burden, fungal morphology, and histopathological findings in kidney tissues of animal hosts with disseminated candidiasis. Since the kidney represents the main target organ in this model of hematogenously disseminated candidiasis, we determined the CFU counts in the kidneys recovered from the different groups of mice at time of death (Table 1). For most mouse strains and treatment groups, tissue burdens were essentially identical to those observed using immunocompetent BALB/c mice, with the exception of DBA/2N mice, which displayed slightly lower organ loads (P = 0.0109), probably a reflection of their increased susceptibility to candidiasis and also of the fact that all deaths in this group occurred very early within the first 24 h postinfection. Also, the CPM-treated mice infected in the absence of DOX exhibited higher fungal loads than both BALB/c (P = 0.0303) and CPM-treated mice in the presence of antibiotic (P = 0.0087), although the increased plating efficiency of yeast cell forms versus their filamentous counterparts may have contributed to these minor differences. We also observed that significant fungal bioburdens were maintained throughout the course of the infection in all of the mouse strains even in the absence of DOX, as detected in animals sacrificed at the end of the experimental period (21 days) (data not shown).


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  		TABLE 1. Organ fungal burdens at time of death in different groups of mice challenged with C. albicans SSY50-Ba

 
Histological observations were used to confirm that the anticipated morphology of the fungal cells (yeast cells in the absence of DOX and mostly filaments in the presence of the antibiotic) was present within the infected tissues. The results presented in Fig. 2 demonstrate that this was the case with the tissues recovered from immunodeficient mice that succumbed to the infection in the presence of DOX, revealing a predominantly hyphal morphology with lesions similar to those normally observed during infections with wild-type C. albicans strains. However, fungal elements almost exclusively with a yeast cell morphology were detected in CPM-treated severely immunosuppressed mice in the absence of DOX, which still resulted in a lethal outcome without the need for filamentation.


Figure 2
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  		FIG. 2. Morphology of fungal cells present in kidneys retrieved from immunodeficient mice at the time of death after infection with C. albicans strain SSY50-B in the presence or absence of DOX as revealed by Grocott-Gomori methenamine-silver staining. Filamentous forms and mostly hyphal lesions were observed in kidneys from animals treated with DOX, including nude (death on day 3 postinfection) (A), SCID (death on day 3 postinfection) (B), and CPM-treated (death on day 1 postinfection) (C) mice whereas only yeast microabscesses were observed in the kidneys of a CPM-treated mouse that died 2 days after infection with the same strain in the absence of DOX (D). Magnification is x200 for panels A and B and x400 for panels C and D.

 
The results from both the survival and tissue burden experiments raised an interesting question regarding the differences observed between CPM-treated and DBA/2N mice in regard to host response to infection, particularly in the absence of DOX, since under these conditions the severely immunosuppressed CPM-treated animals succumbed to infection characterized by the yeast cell morphology but DBA/2N, with defects in neutrophil function only, survived the length of infection. Answering this question could shed some light on potential protective mechanisms during candidiasis, also depending on cell morphology. To address this issue, we performed histopathological analyses of kidneys recovered from infected animals at time of death or sacrifice (Fig. 3). Other groups using murine models of hematogenously disseminated candidiasis have previously reported that in wild-type (immunocompetent) mice a mostly neutrophil infiltrate is evident early on at the infection site, which is very similar to what we observed in our BALB/c mice infected with the C. albicans tet-NRG1 strain in the presence of DOX (Fig. 3A). Conversely, BALB/c mice survived the infection in the absence of DOX, and histopathological examination at time of sacrifice revealed only moderate tissue damage and mild inflammatory infiltration with a predominance of macrophages and lymphocytes (Fig. 3B). As expected, in severely immunosuppressed CPM-treated mice, no inflammatory infiltration was present, irrespective of the presence or absence of DOX (Fig. 3C and D). Thus, it would seem that the inflammatory response to infection in the kidney is completely ablated in CPM-treated mice, although a caveat here is that these animals died very soon after infection. The same was true for the DOX-treated DBA/2N mice that also died very shortly (within hours) after infection (Fig. 3E). In stark contrast, histopathological examination of kidneys recovered from DBA/2N mice that survived the infection in the absence of DOX revealed an inflammatory infiltrate composed mainly of macrophages and lymphocytes (Fig. 3F). These results suggest that a yeast cell-only infection can be contained in the absence of functional neutrophils, probably involving compensatory mechanisms and the participation of other components of the innate immune system (i.e., macrophages).


Figure 3
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  		FIG. 3. Histopathological analysis of kidneys retrieved from mice at the time of death or sacrifice after infection with C. albicans strain SSY50-B in the presence or absence of DOX as revealed by hematoxylin and eosin staining. Panel A shows necrotic cortical lesions found in the kidney of a BALB/c mouse treated with DOX that succumbed to infection, with an important inflammatory component of numerous neutrophils and few macrophages (an abundant number of mycelial cells were present in the lesions). (B) Medullary and cortical lesions with a moderate inflammatory infiltration composed of macrophages and lymphocytes (and a small number of yeast cells) in kidneys recovered from a BALB/c mouse that survived the infection in the absence of DOX. No inflammatory infiltration was present in kidneys recovered from CPM-treated mice who succumbed to the infection in either the presence (C) or absence (D) of DOX. In the animals exposed to DOX (C), kidney lesions were small and mostly cortical, and mycelial cells were found in low to moderate numbers. In the absence of DOX (D) larger necrotic lesions with abundant yeast cells were found. (E) Small, mostly cortical lesions with a moderate number of mycelial cells (virtually devoid of inflammatory cells) in the kidney of a DBA/2N mouse with DOX added to the drinking water. The animal died within the first 24 h of infection. (F) Cortical and medullary lesions (a few yeast cells are visible in these lesions) present in the kidney of a DBA/2N mouse sacrificed at the end of the observational period in the absence of DOX. Macrophages and lymphocytes were numerous whereas eosinophils and neutrophils were very scarce. Magnification is x400 for panels A, B, and F and x40 for panels C, D, and E.

 
The results presented here confirm the different pathogenic potentials of the yeast cell and filamentous forms of C. albicans and reinforce the importance of morphogenetic conversions in virulence in relation to the immune status of the host. As with their immunocompetent counterparts, mice with specific immune defects in T-cell, B-cell, and, perhaps more surprisingly, neutrophil function were able to contain an infection by yeast cells but succumbed to the infection when NRG1 expression was downregulated and filamentation was allowed to occur. Since the model used here can be considered a model of acute primary candidiasis, this likely reflects the primacy of innate immune mechanisms over acquired immunity in the initial control of a yeast cell infection in this particular animal model. Thus, antibodies and T cells seem not to be critical for the host defense against an acute-phase disseminated yeast cell infection, although it is conceivable that some mechanisms of adaptive immunity will start playing a role as the infection persists and the organs become progressively invaded by the fungus, even in the absence of filamentation (note that previous experiments in our laboratory have demonstrated that even in the absence of DOX, the yeast cells reach and infect target organs, and a significant fungal burden is maintained for several weeks) (20, 21). Current experiments in our laboratory are aimed at a more detailed characterization of host immune responses to C. albicans infection using this model. It is also possible, particularly in the case of mice with defects in neutrophil function, that other compensatory mechanisms may be responsible for protection from a yeast cell form of infection. However, although it is widely accepted that yeast cells of C. albicans do not express the entire repertoire of virulence factors, our results clearly demonstrate that yeast cells can still exert their full pathogenic potential and lead to lethality in severely immunosuppressed mice without the need for filamentation. This observation carries important clinical implications, particularly in this era when aggressive immunosuppressive therapies are becoming increasingly common and are putting more patients at risk of fungal infections, even with species that were not typically considered pathogenic before. A perfect example is the increased incidence in systemic infections caused by Candida glabrata, a nonfilamenting yeast, over the last decade (16).

Overall, the results presented here reaffirm that the C. albicans tet-NRG1 strain represents a powerful tool to investigate different aspects of C. albicans pathogenesis. They also highlight the importance of properly integrating and taking into account the interplay between host immunity and mechanisms of fungal virulence, an area which has been largely overlooked in the study of C. albicans pathogenesis, as we try to better understand the clinical scenario in patients suffering from these insidious infections.


   ACKNOWLEDGMENTS
 
The work presented here was funded in part by grants RO1AI064562 and RO1AI063256 from the National Institute of Allergy and Infectious Diseases to J.L.L.-R. and S.P.S., respectively.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.


   FOOTNOTES
 
* Corresponding author. Mailing address: Department of Biology, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249. Phone: (210) 458-7022. Fax: (210) 458-7023. E-mail: jose.lopezribot{at}utsa.edu Back

{triangledown} Published ahead of print on 29 October 2007. Back

Editor: A. Casadevall


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
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Infection and Immunity, January 2008, p. 97-102, Vol. 76, No. 1
0019-9567/08/$08.00+0     doi:10.1128/IAI.00982-07
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