Bacteria and fungi can form a range of physical associations that depend on various modes of molecular communication for their development and functioning. These bacterial-fungal interactions often result in changes to the pathogenicity or the nutritional influence of one or both partners toward plants or animals (including humans). They can also result in unique contributions to biogeochemical cycles and biotechnological processes. Thus, the interactions between bacteria and fungi are of central importance to numerous biological questions in agriculture, forestry, environmental science, food production, and medicine. Here we present a structured review of bacterial-fungal interactions, illustrated by examples sourced from many diverse scientific fields. We consider the general and specific properties of these interactions, providing a global perspective across this emerging multidisciplinary research area. We show that in many cases, parallels can be drawn between different scenarios in which bacterial-fungal interactions are important. Finally, we discuss how new avenues of investigation may enhance our ability to combat, manipulate, or exploit bacterial-fungal complexes for the economic and practical benefit of humanity as well as reshape our current understanding of bacterial and fungal ecology.

Bacterial-Fungal Interactions: Hyphens between Agricultural, Clinical, Environmental, and Food Microbiologists

Fungi cause serious infections in the immunocompromised and debilitated, and the incidence of invasive mycoses has increased significantly over the last 3 decades. Slow diagnosis and the relatively few classes of antifungal drugs result in high attributable mortality for systemic fungal infections. Azole antifungals are commonly used for fungal infections, but azole resistance can be a problem for some patient groups. High-level, clinically significant azole resistance usually involves overexpression of plasma membrane efflux pumps belonging to the ATP-binding cassette (ABC) or the major facilitator superfamily class of transporters. The heterologous expression of efflux pumps in model systems, such Saccharomyces cerevisiae, has enabled the functional analysis of efflux pumps from a variety of fungi. Phylogenetic analysis of the ABC pleiotropic drug resistance family has provided a new view of the evolution of this important class of efflux pumps. There are several ways in which the clinical significance of efflux-mediated antifungal drug resistance can be mitigated. Alternative antifungal drugs, such as the echinocandins, that are not efflux pump substrates provide one option. Potential therapeutic approaches that could overcome azole resistance include targeting efflux pump transcriptional regulators and fungal stress response pathways, blockade of energy supply, and direct inhibition of efflux pumps.

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Efflux-Mediated Antifungal Drug Resistance

The human body plays host to interactions between a diverse range of microorganisms, including bacteria and fungi. In this Review, Mylonakis and colleagues describe the characteristics of medically important bacterial–fungal interactions and highlight how imbalances in these interactions can contribute to human disease. Whether it is in the setting of disease or in a healthy state, the human body contains a diverse range of microorganisms, including bacteria and fungi. The interactions between these taxonomically diverse microorganisms are highly dynamic and dependent on a multitude of microorganism and host factors. Human disease can develop from an imbalance between commensal bacteria and fungi or from invasion of particular host niches by opportunistic bacterial and fungal pathogens. This Review describes the clinical and molecular characteristics of bacterial–fungal interactions that are relevant to human disease.

Medically important bacterial–fungal interactions

The ability of Acinetobacter baumannii to adhere to and persist on surfaces as biofilms could be central to its pathogenicity. The production of pili and a biofilm-associated protein and the expression of antibiotic resistance are needed for robust biofilm formation on abiotic and biotic surfaces. This multistep process also depends on the expression of transcriptional regulatory functions, some of which could sense nutrients available to cells. This report extends previous observations by showing that although outer membrane protein A (OmpA) of A. baumannii 19606 plays a partial role in the development of robust biofilms on plastic, it is essential for bacterial attachment to Candida albicans filaments and A549 human alveolar epithelial cells. In contrast to abiotic surfaces, the interaction with biotic surfaces is independent of the CsuA/BABCDE-mediated pili. The interaction of A. baumannii 19606 with fungal and epithelial cells also results in their apoptotic death, a response that depends on the direct contact of bacteria with these two types of eukaryotic cells. Furthermore, the bacterial adhesion phenotype correlates with the ability of bacteria to invade A549 epithelial cells. Interestingly, the killing activity of cell-free culture supernatants proved to be protease and temperature sensitive, suggesting that its cytotoxic activity is due to secreted proteins, some of which are different from OmpA.

The Acinetobacter baumannii 19606 OmpA Protein Plays a Role in Biofilm Formation on Abiotic Surfaces and in the Interaction of This Pathogen with Eukaryotic Cells

Bacteria and fungi are found together in a myriad of environments and particularly in a biofilm, where adherent species interact through diverse signaling mechanisms. Yet, despite billions of years of coexistence, the area of research exploring fungal-bacterial interactions, particularly within the context of polymicrobial infections, is still in its infancy. However, reports describing a multitude of wide-ranging interactions between the fungal pathogen Candida albicans and various bacterial pathogens are on the rise. An example of a mutually beneficial interaction is coaggregation, a phenomenon that takes place in oral biofilms where the adhesion of C. albicans to oral bacteria is considered crucial for its colonization of the oral cavity. In contrast, the interaction between C. albicans and Pseudomonas aeruginosa is described as being competitive and antagonistic in nature. Another intriguing interaction is that occurring between Staphylococcus aureus and C. albicans, which although not yet fully characterized, appears to be initially synergistic. These complex interactions between such diverse and important pathogens would have significant clinical implications if they occurred in an immunocompromised host. Therefore, understanding the mechanisms of adhesion and signaling involved in fungal-bacterial interactions may lead to the development of novel therapeutic strategies for impeding microbial colonization and development of polymicrobial disease.

Cross-kingdom interactions: Candida albicans and bacteria.

Interactions between bacteria and Candida in the burn wound

was conducted over a period of 15 months. This study revealed that 75% of the HIV/AIDS patients had OPC. MIC testing revealed that 5% of the Candida isolates were fluconazole resistant. A correlation between CD4-T-cell counts and development of OPC in HIV/AIDS patients was also observed. Molecular typing of C. albicans isolates showed that all were genetically unrelated. Oropharyngeal candidiasis (OPC) was at the top of the list of opportunistic infections in Indian human immunodeficiency virus (HIV)/AIDS patients before the era of highly active antiretroviral therapy (1, 20, 27, 33). Although the incidences of opportunistic infection have been reduced around the globe by highly active antiretroviral therapy, the situation remains the same in most developing countries, including India, where patients can hardly afford this treatment. World Health Organization predictions have put India as one of the biggest repositories of HIV/AIDS patients in the coming decades (38, 39). In order to get an insight into the present scenario of OPC in an Indian hospital, in the present prospective study, an attempt was made to characterize the Candida species isolated from OPC over a period of 15 months in HIV/AIDS patients, mainly to know (i) the spectrum of isolates and (ii) its in vitro pattern of susceptibility to fluconazole (FLC), a common antifungal used for prophylaxis and treatment of OPC. In addition, the genetic relatedness of the isolates was also investigated to get some idea about the primary source of infection. All of the isolates included in this study were collected from 125 randomly selected HIV/AIDS patients. Whereas 100 patients showed clinical signs of OPC, 25 patients reported discomfort or pain during chewing. All of them were attending the clinic as outpatients of the All India Institute of Medical Sciences, New Delhi, India, from December 1999 to March 2001. These patients were attending the clinic for the first time and had no history of prior treatment with antifungal and antiretroviral drugs. Samples were collected with two sterile cotton swabs. One swab was used to detect the presence of any yeast by Gram staining, and the other was used to test growth on Sabouraud dextrose agar slants containing 2 g of gentamicin per ml and 0.5% cycloheximide. In the case of positive growth, yeast identification was done by conventional methods. The method used was the germ tube production test, which was done by inoculation of a single colony into 0.5 ml of horse serum, followed by incubation at 37°C for 2 h. Morphology testing for the presence of chlamydospores, pseudohyphae, true mycelium, and blastospore arrangement was done on corn meal agar. An enzymatic triphenyl tetrazolium chloride reduction test was performed in which each Candida species grows with a distinct texture and color. For further characterization, each isolate was subjected to carbohydrate assimilation and fermentation tests (2, 3). To differentiate Candida albicans from C. dubliniensis, all C. albicans isolates (confirmed by conventional methods) were subjected to growth at 45°C and a Tween 80 opacity test (13, 31). Out of 100 samples, 75 were found to be positive for Candida species infection by direct microscopy and culture. This value (75% positive) is lower than that reported (90%) in western populations (5, 10, 23, 35), and one can speculate that the Candida carriage rate in the Indian population is probably lower. Species identification revealed that C. albicans (86%) was the most predominant species; as reported earlier (20), a small percentage of other species has also been identified, i.e., C. parapsilosis (8%) and C. glabrata and C. krusei (3%). The most interesting fact is that C. tropicalis and C. dubliniensis were not isolated. This is a surprising observation in view of reports from developed countries, where non-C. albicans candidiasis is a major problem in HIV/AIDS patients (9, 11, 12, 18, 19). Antifungal drug prophylaxis is rarely practiced in India, and this may be the reason for this observation. Currently, the most widely used drug for treating candidiasis is FLC (16, 17, 24, 28, 36). In vitro FLC susceptibility testing of all of the isolates was done by microdilution susceptibility assay (22). More than 93% of the Candida isolates were found to be susceptible, with MICs of 8 g/ml; 2% were found to be dose-dependently susceptible, with MICs of 16 to 32 g/ml; and only 5% (two isolates of C. albicans and one each of C. glabrata and C. krusei) were found to be resistant, with MICs of 64 g/ml. The resistant strains (5%) were from patients who never took FLC. These resistant isolates can be described as primarily or intrinsically resistant strains. It is

https://jcm.asm.org/content/jcm/42/3/1260.full.pdf

Susceptibility Pattern and Molecular Type of Species-Specific Candida in Oropharyngeal Lesions of Indian Human Immunodeficiency Virus-Positive Patients

This study, spread over a span of 2 years describes Candida infections in burn patients of an Indian hospital. A total of 220 burn patients were monitored and Candida could be isolated from 138 patients. A total of 228 different Candida species were obtained from various body locations of these patients. Species identification revealed that Candida albicans was the most predominant (45%) followed by Candida tropicalis (33%), Candida glabrata (13.5%), C. parapsilosis (4%), C. krusei (2.75%) and C. kefyr (1.75%). DNA fingerprinting of all C. albicans isolates was done by using CARE-2 probe. Fingerprinting analyses of all the C. albicans strains revealed that strains collected from different patients were different. It is noteworthy that patients with disseminated candidiasis had a similar, but unique strain isolated from all body locations, suggesting a possibility that commensal isolates might be turning pathogenic. Taken together, this is probably the first ever detailed survey of Candida infections in burn patients in India and is expected to lead to better clinical management of this group of patients.

Absarul Haque

Papers

Interactions between bacteria and Candida in the burn wound

Susceptibility Pattern and Molecular Type of Species-Specific Candida in Oropharyngeal Lesions of Indian Human Immunodeficiency Virus-Positive Patients

Epidemiology and molecular typing of Candida isolates from burn patients.

Allelic variants of ABC drug transporter Cdr1p in clinical isolates of Candida albicans.