Proc Indian Natn Sci Acad 85 No. 4 December 2019 pp. 1039-1050  Printed in India. DOI: 10.16943/ptinsa/2019/49724

Review Article Mycology Research in India in the Last Ten Years (2008-2018) ARUNALOKE CHAKRABARTI* Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh

(Received on 03 April 2019; Accepted on 28 October 2019)

With the rise in the incidence of fungal infections in India due to the unique environmental and socioeconomic reasons, the research activities on fungal infections and fungi causing human infections have increased manifold. The major areas of clinical research on fungal infections include (i) epidemiology fungal infections, (ii) resistance detection, surveillance and its mechanism, (iii) molecular diagnosis and pathogenesis, (iv) outbreak investigations, (v) development of management guidelines, and (vi) clinical trials. The basic scientists’ research areas include (i) understanding different molecular mechanisms on the evolution of fungi, (ii) computational models that is operating at different cellular levels of pathogenic fungi, (iii) understanding molecular details on the biosynthesis, signalling pathways involved in fungal virulence, (iv) identifying potential new antifungal drug targets, (v) basis of antifungal resistance mechanisms. The major centres in India carrying out advanced research in this field are Department of Medical Microbiology, PGIMER, Chandigarh, which also houses the National Reference Centre and WHO Collaborating Centre; Department of Pulmonary Medicine (PGIMER, Chandigarh), which focusses clinical research on respiratory mycoses; VP Chest Institute (New Delhi), JNCASR (Bengaluru), School of Life Science (JNU, New Delhi), CCMB (Hyderabad), and AIIMS (New Delhi). The two national organizations, Fungal Infection Study Forum (FISF) and Society for Indian Human and Animal Mycology (SIHAM) have conducted multicentric epidemiological studies. The fungal diseases that have been studied in India in the last decade include invasive (due to , , , ), (caused by Rhizopus arrhizus, variabilis), invasive asperillosis (A. flavus and A. fumigatus), allergic bronchopulmonary (A. flavus and A. fumigatus), fungal rhinosinusitis (A. flavus), (C. neoformans and C. gattii), , sprorotrichosis, sebrohhoeic dermatitis/dandruff ( sp.), (T. mentagrophytes, T. rubrum), mycetoma, fungal keratitis/endophthalmitis, (Cladophialophora bantiana).

Keywords: Mycology; Epidemiology; Candidiasis;

Introduction research has gained importance as a result of recent developments in the form of societies which provides India has distinct position in the research on medical a common forum for exchange of ideas between mycology, as the epidemiology of fungal infection is researchers that subsequently helps in strengthening unique. Fungal infection rate is very high in India due this branch of medical research. Two such societies to tropical region, too many patients in the hospital, namely Indian Human and Animal Mycologists and compromise in healthcare. Endemicity of certain (SIHAM), and Fungal Infection Study Forum (FISF, fungi and emergence new species of fungi causing a non-profit trust of clinicians) dedicated to clinical human infection has raised formidable challenge for research bring active researchers together. Further, researchers in India. The research in this field in India various working groups are developed under can be grossly classified in three areas, viz., International Society for Human and Animal Mycology epidemiology research – multiple multicentre studies and proposed to conduct research in specific areas sponsored by national societies, clinical research from like ‘Fungal Sinusitis’, ‘Allergic bronchopulmonary certain medical centres of excellence, and basic aspergillosis in Asthma’, ‘’ etc. mycology research related to human infection by certain non-medical Institutes. The need of mycology

*Author for Correspondence: E-mail: [email protected] 1040 Arunaloke Chakrabarti

Epidemiological Research (n = 157, P = .0001) and post-tubercular mucormycosis (n = 21, P = .006) were significantly A number of studies have been conducted on associated with north Indian cases, and north Indian epidemiology, treatment and outcome of various fungal patients have higher mortality compared to South India infections across India by various organisations. (Prakash et al., 2018).

Invasive Candidiasis Invasive Mould Infections SIHAM conducted a prospective epidemiological FISF conducted another study ‘Epidemiology and study on the ICU acquired candidemia in CU covering clinical outcomes of invasive mould infections (IMIs) 27 ICUs across India. The study highlighted a high in Indian intensive care units” - The study was burden, early onset after ICU admission, higher risk conducted over 11 ICUs across India. A total of 398 despite less severe physiology score at admission and patients with IMIs (96 proven, 302 probable) were a vast spectrum of agents causing candidemia in Indian identified over 15-month period, amounting to a ICUs with predominance of C. tropicalis prevalence of 9.5 cases/1000 ICU admissions (Chakrabarti et al., 2015). (Chakrabarti et al., 2018). The study highlighted high Mucormycosis disease burden, new susceptible patient groups, comparatively younger patients with less morbidity FISF conducted a Multi-centre (17 Centres) acquire infection early. Though flavus Observational Study on Epidemiology, Treatment, and and A. fumigatus were common mould isolated, Outcome of Mucormycosis in India –The study considerable number of mucormycosis cases were identified high incidence; rhino-orbital-cerebral also identified. mucormycosis in uncontrolled diabetics as common presentation. Rhizopus arrhizus followed by Antifungal Resistance Surveillance Apophhysomyces variabilis are common species Indian Council of Medical Research initiated isolated from those patients and Rhizopus Antimicrobial Resistance Surveillance and Research homothallicus as emerging agent of mucormycosis Network (AMRSN) since 2013. The AMRSN in India. Due to financial constraints clinicians failed currently includes six nodal centres (NCs) that are to provide antifungal treatment of choice and nearly located in four tertiary care medical institutions and 25% patients left the hospital when cost of therapy 15 regional centres (RC). For antifungal resistance explained to them (Patel et al., 2018). surveillance, PGIMER, Chandigarh is the nodal center. Another study, ‘A prospective multicentre study The NC focuses on the identified resistant organisms, on mucormycosis in India: Epidemiology, diagnosis, confirm the resistance and preserve all the resistant and treatment’ was conducted at four major tertiary isolates to build the fungal bank on the resistance fungi. care centres of India (two in north and two in south The NC also performs the research to identify the India) during 2013-2015 to compare the epidemiology, mechanism of resistance in different group of fungi. treatment strategies and outcome of mucormycosis It also helps in identifying the outbreaks caused by between the two regions. A total of 388 proven/ the fungi and provides the logistic support to other probable mucormycosis cases were reported during centres to control the outbreak and manage the the study period with overall mortality at 46.7%. patients. Candida tropicalis and A. flavus were the Uncontrolled diabetes (n = 172, 56.8%) and trauma most commonly isolated and mould respectively. (n = 31, 10.2%) were the common risk factors. Wickerhamomyces anomalous (13.1%) was Overall, R. arrhizus (n = 124, 51.9%) was the recognized as emerging yeast in paediatric patients. predominant agent identified, followed by R. Resistance in C. tropicalis against fluconazole and microsporus (n = 30, 12.6%), A. variabilis (n = 22, is a serious concern. Heterogeneous over 9.2%) and R. homothallicus (n = 6, 2.5%). While expression of efflux pumps was noticed in resistant comparing the two regions, majority (82.7%) cases C. tropicalis isolates (Paul et al., 2018a; Paul et al., were recorded from north India; uncontrolled diabetes 2015). Mycology Research in India in the Last Ten Years (2008-2018) 1041

Research in Medical Mycology Reference (Zaman et al., 2017). Also, pathogenesis of fungal Laboratories sinusitis (Kale et al., 2015), Malassezia infections (Honnavar et al., 2017) and mucormycosis were National Mycology Reference Centre at studied. Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh Clinical Trials The only WHO Collaborating Centre on Reference Utility of and prednisolone and and Research on Fungi of Medical Importance in the and prednisolone for ABPA patients world. National Culture Collection of Pathogenic Fungi complicated with asthma (Agarwal et al., 2018a, (NCCPF) is also housed at the same centre. Major 2018b). activities conducted by the center in the last 10 years are highlighted in specific categories: Outbreaks

Epidemiology Investigation and control of outbreaks such as C. auris and Candida viswanathii, Pichia anomala, It provided the leadership of multi-centre studies on Kodamaea ohmeri infections, and Saccharomyces mucormycosis, candidemia in Indian ICU settings, and cerevisiae after probiotic use etc. Used or invasive mould infections in ICU settings. The centre standardized molecular typing techniques like AFLP, also conducted epidemiological studies on allergic MLMT, MLST to investigate those outbreaks bronchopulmonary aspergillosis (Agarwal et al., 2013), (Chakrabarti et al., 2014; Roy et al., 2017; Biswal et fungal sinusitis (Chakrabarti et al., 2009), fungal al., 2017; Shankarnarayan et al., 2018). keratitis (Ghosh et al., 2016), Malassezia infections (Rudramurthy et al., 2014), mucormycosis (Prakash Management Guidelines et al., 2018), candidemia (Chakrabarti et al., 2015), Participated in European and World guideline initiatives (Rastogi et al., 2016) and for management of fungal infections due to Cladophialophora infections (Chakrabarti et al., dematiaceous fungi, and mucormycosis, aspergillosis. 2016). Also participated in management guidelines for Antifungal Resistance treating of dermatophytosis in India (Rajagopalan et al., 2018; Ullmann et al., 2018). Candida auris infection and antifungal resistance in various ICUs across India, mutation in squalene Disease Classification epioxidase gene imparting resistance to allylamines The ISHAM working group on Fungal sinusitis, in spp., Novel mutations responsible resolved the confusion that exists in the classification for the voriconazole resistance in Aspergillus flavus, of fungal sinusitis and established the new higher MIC to in Apophysomyces classification. (Chakrabarti et al., 2009a). Further, the species were identified. (Prakash et al., 2016; Paul members of ‘ABPA complicating asthma’ working et al., 2015). MALDI for identification and antifungal group of ISHAM, a new diagnosis and staging criteria drug resistance detection: Studies included expanding for ABPA was established (Agarwal et al., 2013). the data base on MALDI platform and identification of , Hyalohyphomycetes, dematiaceous fungi Basic Research and Malassezia species, detection of azole resistance using MALDI-TOF etc, (Paul et al., 2017; Paul et Characterization of biofilm formed by al., 2018b; Honnavar et al., 2018). (Singh et al., 2011), description of new species of Malassezia (Honnavar et al., 2016), stress response Molecular Diagnosis and Pathogenesis in Mucorales (Singh et al., 2016), detailed description on phenotypic characterization on Malassezia Developed molecular techniques for the diagnosis of japonica (Honnavar et al., 2015) many rare fungi from respiratory specimen causing human infection. (Ruduramurthy et al., 2018a), Mucorales from fresh tissue and formalin fixed paraffin embedded blocks. 1042 Arunaloke Chakrabarti

Department of Pulmonary Medicine, PGIMER, VP Chest Institute, New Delhi Chandigarh It is recognized as a National Reference Centre for Their primary area of research is allergic Respiratory Mycoses - the major contribution of the bronchopulmonary aspergillosis (ABPA). The group centre is in the field of cryptococcosis, endemic first described their large experience of screening mycoses of the country and allergic respiratory fungal patients with asthma for allergic bronchopulmonary diseases. The centre worked on the ecology of aspergillosis (ABPA) wherein it was demonstrated cryptococcosis and different molecular types of that the prevalence of Aspergillus hypersensitivity Cryptococcus, and prevalence of azole resistant and ABPA were substantial (27.2%) in outpatients Aspergillus fumigatus. Their laboratory has with bronchial asthma and even higher (38.6%) in generated comprehensive data on molecular types and patients with severe acute asthma. They have also antifungal susceptibility profiles of indigenous fungal calculated the burden of allergic aspergillosis at 1.4 isolates such as C. neoformans, C. gattii, Aspergillus million cases in India (Agarwal et al., 2014). They spp., Schizophyllum commune and Mucorales. The showed that asthmatic patients with Aspergillus centre also has identified multi-azole resistant clinical sensitization but without ABPA also demonstrate isolates of A. fumigatus in India and new clonal strains poorer control of asthma than those without. They of multi-drug resistant Candida auris in India. delineated certain markers of poor prognosis (Chowdhary et al., 2011; Chowdhary et al., 2014; associated with the disease such as high-attenuation Chowdhary et al., 2015; Chowdhary et al., 2017; mucoid impaction and . Aspergillus Chowdhary et al., 2018; Sharma et al., 2018). sensitization can complicate the course of other adult airway disorders such as chronic obstructive All India Institute of Medical Science, New Delhi pulmonary disease, pulmonary tuberculosis related The centre studied the epidemiology of candidemia, fibro-cavitary diseases and even after bidi azole resistant A. fumigatus, and molecular consumption. Their work proposed a new radiological identification and resistance with Trichophyton classification of ABPA and demonstrated the utility species (Dabas et al., 2017; Dabas et al., 2018) of several of the components of the currently followed diagnostic criteria including peripheral blood Research in Specific Areas eosinophils, total IgE, A. fumigatus specific IgE, A. fumigatus specific IgG and serum galactomannan. Candida auris Further, they have proposed a new diagnostic criterion Candida auris has emerged as a challenge in and published the diagnostic performance of the diagnosis, and therapy. ICU based observational study individual components of the criteria (Agarwal et al., showed the prevalence of C. auris was 5.3% (74 out 2013) and found an overlap in immune response of 1400 patients) in India (Chakrabarti et al., 2015). between allergic bronchopulmonary and chronic In case-control analysis, the infection is found to be pulmonary aspergillosis opening new avenues of common in those patients staying long time in ICU research. Regarding management, they showed the and have multiple interventions especially in public- futility of inhaled steroids in ABPA, evaluated the sector hospitals. The resistance to fluconazole has efficacy of two different glucocorticoid doses in ABPA rose to 90%, voriconazole 50%, polyenes 15-30%. (Agarwal et al., 2016) and the effectiveness of Multidrug resistance was noted in 16.2% isolates. To nebulized amphotericin B in patients with ABPA who control the spread of C. auris in Indian hospitals experience recurrent exacerbations. Recently, in two chlorhexidine washing of patients and decontamination different RCTs, they have also shown that the of environmental surfaces with stabilized hydrogen antifungal triazoles including itraconazole (Agarwal peroxide disinfectant were found to be useful. The et al., 2018b) and voriconazole are also effective as frequently used disinfectants in hospital and current monotherapy in the management of treatment-naïve hand hygiene practices were efficient against ABPA (Agarwal et al., 2018a). In another RCT, the C. auris if proper contact time and procedures were group found the lack of benefit of adjunctive vitamin followed. Evaluation of possible persistence of D therapy in ABPA. C. auris on dry fabrics showed that they can persist Mycology Research in India in the Last Ten Years (2008-2018) 1043 for up to seven days. (Rudramurthy et al., 2017; Biswal reported for the first time the increase in allylamine et al. 2017). and azole resistance and mutation in squalene epoxidase gene responsible for allylamine resistance Candida tropicalis from the T. interdigitale and T. rubrum isolated from In India, many studies have reported an increase in relapse/ recurrent cases. A T1189C mutation was C. tropicalis blood stream infections (Chakrabarti et observed in T. interdigitale and T. rubrum isolates al., 2009b; Kothari et al., 2009; Kothavade et al., that exhibited high MIC’s to allylamines (Rudramurthy 2010; Chakrabarti et al., 2015). The reason of such et al., 2018b).ÿþ Later other study from India reported high prevalence of C. tropicalis in India is still similar findings (Singh et al., 2018). unknown. Certain reports from western countries and Malassezia Infection few Asian countries have suggested that the extensive use of antifungal drugs can cause higher prevalence Studies related to pityriasis versicolor (PV), seborrheic of C. tropicalis. dermatitis/dandruff (SD/D), psoriasis (PS) and atopic dermatitis (AD) have focused mainly on Malassezia Apophysomyces variabilis species. In India, Rudramurthy et al. showed M. A maiden attempt was made to sequence and analyze restricta and M. globosa as the most prevalent the genomic structure of A. variabilis, the Mucorales species among dandruff patients. (Rudramurthy et species commonly isolated in India. The total size of al., 2014a). A new species, M. arunalokei was genome assembly of A. variabilis was 39.38 Mb with isolated from patients with either mild or moderate 12,764 protein-coding genes. The transposable SD/D and from healthy controls (Honnavar et al., elements (TEs) were low in Apophysomyces genome 2016). In pityriasis versicolor, M. globosa is the most and the retrotransposon Ty3-gypsy was the common frequently isolated species (Kaur et al., 2013). TE. Phylogenetically, Apophysomyces species were Rudramurthy et al. reported that no strong association grouped closely with Phycomyces blakesleeanus. of Malassezia species was formed with psoriatic OrthoMCL analysis revealed 3025 orthologues lesion in general; the fungi may play a role in proteins, which were common in those three exacerbation of scalp psoriasis (Rudramurthy et al., pathogenic Apophysomyces species. Expansion of 2014b). In pathogenesis of Malassezia infection, multiple gene families/duplication was observed in Honnavar et al. found that the phospholipase activity Apophysomyces genomes. Approximately 6% of significantly increased after exposure to â-endorphin Apophysomyces genes were predicted to be (in isolates from patients; M. globosa, M. restricta), associated with virulence on PHIbase analysis. The which did not occur in isolates from healthy controls virulence determinants included the protein families (Honnavar et al., 2017). of CotH proteins (invasins), proteases, iron utilization Mycetoma pathways, siderophores and signal transduction pathways. Serine proteases were the major group of A study reveals that mycetoma is endemic in western proteases found in all Apophysomyces genomes. The Rajasthan, and the maximum density of mycetoma carbohydrate active enzymes (CAZymes) constitute has been recorded at Jodhpur, northwest Rajasthan. the majority of the secretory proteins. The presence Maduromycotic mycetoma is more frequently of unique CAZymes in cell wall might be exploited in encountered at western Rajasthan than is future for antifungal drug development. (Prakash et actinomycotic mycetoma as compared to the al., 2017). southeastern parts of Rajasthan. However, the incidence of actinomycotic mycetoma has increased during the last five years, probably due to increased A changing pattern in infections due to dermatophytes irrigation by Rajasthan Canal, changing pattern of with increasing treatment failures and the emergence rainfall, urbanization of villages, and modification in of recalcitrant dermatophytosis in India has been seen. agriculture, all of which has converted desert climate Resistance was rarely reported to allylamines and to humid climate. (Bakshi et al., 2008). azoles . From PGIMER, Chandigarh 1044 Arunaloke Chakrabarti

Sporotrichosis of deaths of immunocompromised patients by fungal infections. These major discoveries led to the Studies have been done to elucidate the epidemiology foundation of quick and accurate identification of of in the sub –Himalayan region. A species from the patient samples, and identification steady rise in number of cases was seen. Seasonal of targets for developing antifungal drugs: trends showed most cases in between March- April (Verma et al., 2012). Cases are also now reported ò Identification of centromeres in a related strain from non-Himalayan belt where the index of suspicion of Candida albicans, Candida dubliniensis is low e.g.: Mysore and North Karnataka in South that revealed centromeres of these two species India. (Suchitha et al., 2008). are most rapidly diverging DNA sequence in their genomes (Padmanabhan et al., 2008). Histoplasmosis Unique centromere DNA sequences can be A rise in the cases of histoplasmosis has been noted used as a target to identify these two species after the advent of HIV infection. In the setting of (Sanyal et al., US patent 2016). disseminated disease, oral lesions are present in 30- ò Kinetochore assembly in C. albicans is unique 50% of the patients and may occur in almost every as unlike other known yeast species, an part of the oral mucosa. The most common sites are interdependent circuitry of proteins stabilizes the the tongue, palate and buccal mucosa. In some cases, centromeric chromatin and the kinetochore oral lesions appear to be the primary or only integrity in C. albicans (Roy et al., 2011; Thakur manifestation of the disease. (Bhagwat et al., 2009; and Sanyal, 2011; Thakur and Sanyal, 2012). Koley et al., 2014). ò Centromere assembly in unique DNA sequence Fungal keratitis of C. albicans on each chromosome is epigenetically regulated. These epigenetic The spectrum of fugal keratitis has been evaluated in factors include the spatial location of the many recent Indian studies. Of the 23,897 corneal centromere on the chromosome as revealed by ulcer patients who had their corneal smear examined mapping the neocentromere loci (Thakur during this period, a fungal organism was and Sanyal, 2013) and the interplay between the identified in 34.3%, a bacterial organism in 24.7% replication origin, replication-repair proteins and and no organism in 38.3%. (Vengayil et al. 2009; the kinetochore assembly. The replication forks Chidambaram et al., 2016; Ghosh AK et al., 2016; originating from the centromere-adjacent origins Prajna et al., 2017). stall at the kinetochore that activates Rad51 and Allergic Bronchopulmonary Aspergillosis Rad52, which in turn bring centromeric histone (ABPA) Complicating Asthma to recruit at the centromere in a DNA sequence independent manner (Mitra et al., 2014). This working group formed under ISHAM studied, epidemiology, genetic susceptibility factors, diagnosis, ò A rapid transition of centromere structure and and treatment. function occurred in a closely related Candida species, C. tropicalis. Unlike C. albicans and Basic Research in Mycology from Various C. dubliniensis, centromeres in C. tropicalis Centres are repeat associated and share a high degree of sequence conservation (Chatterjee et al., Jawaharlal National Center for Advanced 2016). Scientific Research (JNCASR), Bengaluru ò C. neoformans cells undergo semi-open mitosis The group under the leadership of Dr. Kaustuv Sanyal as opposed to closed mitosis in other budding working in fungal infections helped in understanding yeasts, the nuclear division takes place in the the mechanism of chromsosome segregation, daughter cell as opposed to the mother cell and kinetochore assembly, and centromere evolution in the kinetochore assembly is step-wise but not two classes of pathogenic fungi that cause majority interdependent as in C. albicans (Kozubowski Mycology Research in India in the Last Ten Years (2008-2018) 1045

et al., 2013). The RNAi-proficient transcription factor CAP2/HAP43 gene is essential Cryptococcus species maintain full length for survival under poor iron environments and functions retrotransposons at the centromeres which are as a dual regulator of iron homeostasis (Singh et al., longer than those of the RNAi-deficient species 2011; Srivastav et al., 2018). Deletion of CAP2 that lost all full-length retrotransposons at the impaired virulence in a mouse model of C. albicans centromere. This has been further evidenced virulence. It was recently identified that the by an experimental evolution experiment using transcriptional coregulator TAF12L is a subunit of the a RNAi-mutant of the RNAi-proficient species SAGA complex, a multifunctional chromatin modifying (Yadav et al., 2018). complex (Sinha et al., 2017). TAF12L is required for oxidative stress response and cell survival, iron ò A computational model has been developed to starvation response and deletion led to aberrant simulate the process of chromosome segregation filamentation and also abrogated virulence in a mouse in Candida and Cryptococcus species to infection model of C. albicans virulence. (Singh et identify the factors that are responsible for the al., 2011; Sinha et al., 2017; Srivastav et al., 2018). difference observed in the process in these two organisms. This led to identification of two Further, research led by Panwar and coworkers determinants: a) number of cytoplasmic focuses on identifying potential drug targets for the microtubules and b) the concentration of dynein development of new antifungals for treating Candida motor proteins (Sutradhar et al., 2015). infections. In this context, various roles of mitochondria in this pathogenic were deciphered and School of Life Sciences, JNU, New Delhi reported that mitochondria are indispensable for C. One of the most important aspect deals with albicans and it not only affects drug susceptibility understanding the molecular details of glycosyl- but also serves as a control point for virulence. Altering phosphatidylinositol (GPI) anchor biosynthesis in the mitochondrial functions renders this pathogen avirulent human , C. albicans. It was showed in a mouse model of candidiasis. Additionally, the role that the enzyme complex, involved in the first step of of 7-transmembrane receptor proteins (regulatory GPI anchor biosynthesis in C. albicans is mutually proteins) such as Rta2 and Rta3 in ER stress co-regulated with ergosterol biosynthesis in the resistance and biofilm formation in this pathogenic organism and is closely linked to Ras signalling/hyphal fungus, respectively were identified. Interestingly, morphogenesis. While controlling hyphal Rta3 affects biofilm development in C. albicans by morphogenesis is seen as a key step towards perturbing the asymmetric distribution of controlling virulence in this pathogen, ergosterol and phosphatidylcholine across the plasma membrane the sterol biosynthetic pathway are the most important thereby forging a link between membrane biogenesis current targets for therapeutic intervention in and biofilm formation. These 7-transmembrane controlling Candida infections. The enzyme involved receptor proteins are exclusively present in the fungal in the de-N-acetylation of GlcNAc-PI (the second kingdom and thus may have therapeutic implications. step of the pathway) was studies and showed that (Thomas et al., 2013; Thomas et al., 2015; Srivastava the C. albicans homologue shows metal-dependent et al., 2017). activity in cell-free systems unlike the E. histolytica Center for Cellular and Molecular Biology, de-N-acetylase which exhibits a unique metal- Hyderabad independent general acid-base pair catalytic mechanism. (Yadav et al., 2014; Komath et al., 2018; Research group here led by Kaur and co-workers is Jain et al., 2018). focused on delineating the virulence and antifungal drug resistance mechanisms in the pathogenic yeast Another aspects focusses on cellular Candida glabrata. Through large-scale mutant homeostasis and chromatin regulation of Candida screens, they have identified many novel antifungal albicans virulence which led to the discovery of two targets as well as factors that act synergistically with novel genes- a critical transcription factor and a key azole antifungals (Borah et al., 2011; Bhakt et al., transcriptional coregulator that control stress 2018). Recently, work with clinical isolates have responses and survival in C. albicans. The 1046 Arunaloke Chakrabarti shown that the actin network polymerization inhibition proliferation were identified (Rasheed et al., 2018). partially reverses the drug resistance in azole-resistant Currently, the research group is focussing on isolates of C. glabrata (Bhakt et al., 2018). identification of yeast and mammalian substrates for Additionally, an in-depth characterization of interaction cell surface-associated aspartyl proteases (Yapsins), of C. glabrata with macrophages was carried out that are essential for intracellular survival and virulence and it was found that C. glabrata is able to replicate of C. glabrata (Rasheed et al., 2018). The research intracellularly, prevent acidification of the over last one decade has implicated CgYapsins in many phagolysosome and suppress production of the pro- patho-biological processes including intracellular pH inflammatory cytokine IL-1b (Rai et al., 2012). Using and vacuole homeostasis, cell wall organization and the THP-1 macrophage culture model, through the activation of macrophages, and the group, currently, signature-tagged mutagenesis approach, is engaged in establishing epithelial, endothelial and phosphoinositide 3-kinase and chromatin remodelers neutrophil culture model systems to study the role of as pivotal determinants of intracellular survival and aspartyl proteases in fungal virulence (Rai et al., 2015).

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Komath SS, Singh SL, Pratyusha VA and Sah SK (2018) Generating Med Mycol 54 567-575 anchors only to lose them: The unusual story of Prakash H, Ghosh AK, Rudramurthy SM, Singh P, Xess I, Savio glycosylphosphatidyl inositol anchor biosynthesis and J, Pamidimukkala U, Jillwin J, Varma S, Das A, Panda NK, remodeling in yeast and fungi IUBMB Life 70 355-383 Singh S, Bal A and Chakrabarti A (2018) A prospective Kothari A and Sagar V (2009) Epidemiology of candida multicenter study on mucormycosis in India: bloodstream infections in a tertiary care institute in India Epidemiology, diagnosis, and treatment Med Mycol Indian J Med Microbiol 27 171-172 Prakash H, Rudramurthy SM, Gandham PS, Ghosh AK, Kumar Kothavade RJ, Kura MM, Valand AG and Panthaki MH (2010) MM, Badapanda C and Chakrabarti A (2017) Candida tropicalis: its prevalence, pathogenicity and Apophysomyces variabilis: draft genome sequence and increasing resistance to fluconazole J Med Microbiol 59 comparison of predictive virulence determinants with other 873-880 medically important Mucorales BMC Genomics 18 736 Mitra S, Gómez-Raja J, Larriba G, Dubey DD and Sanyal K Rai MN, Balusu S, Gorityala N, Dandu L and Kaur R (2012) (2014) Rad51-Rad52 mediated maintenance of centromeric Functional genomic analysis of Candida glabrata- chromatin in Candida albicans PLoS Genet 10 e1004344 macrophage interaction: role of chromatin remodeling in Padmanabhan S, Thakur J, Siddharthan R and Sanyal K (2008) virulence PLoS Pathog 8 e1002863 Rapid evolution of Cse4p-rich centromeric DNA sequences Rai MN, Sharma V, Balusu S and Kaur R (2015) An essential role in closely related pathogenic yeasts, Candida albicans for phosphatidylinositol 3-kinase in the inhibition of and Candida dubliniensis Proc Natl Acad Sci U S A 2008 phagosomal maturation, intracellular survival and virulence 105 19797-19802 in Candida glabrata Cell Microbiol 17 269-287 Patel A, Kaur H, Xess I, Michael J S, Savio J, Rudramurthy S, Rajagopalan M, Inamadar A, Mittal A, Miskeen AK, Srinivas Singh R, Shastri P, Umabala P, Sardana R, Kindo AJ, Capoor CR, Sardana K, Godse K, Patel K, Rengasamy M, M, Mohan S and Chakrabarti A (2018) Multi-centre Rudramurthy S and Dogra S (2018) Expert Consensus on Observational Study on Epidemiology, Treatment, and The Management of Dermatophytosis in India Outcome of Mucormycosis in India Open Forum Infect (ECTODERM India) BMC Dermatol 18 6 Diseases 5 S154 Rasheed M, Battu A and Kaur R (2018) Aspartyl proteases in Paul RA, Rudramurthy SM, Meis JF, Mouton JW and Chakrabarti Candida glabrata are required for suppression of the host A (2015) A Novel Y319H Substitution in CYP51C innate immune response J Biol Chem 293 6410-6433 Associated with Azole Resistance in Aspergillus flavus Rastogi V, Honnavar P, Rudramurthy SM, Pamidi U, Ghosh A Antimicrob Agents Chemother 59 6615-6619 and Chakrabarti A (2016) Molecular characterisation and Paul S, Singh P, ASS, Rudramurthy SM, Chakrabarti A and Ghosh antifungal susceptibility of clinical Trichosporon isolates AK (2018a) Rapid detection of fluconazole resistance in in India Mycoses 59 528-534 Candida tropicalis by MALDI-TOF MS Med Mycol 56 Roy B, Burrack LS, Lone MA, Berman J and Sanyal K (2011) 234-241 CaMtw1, a member of the evolutionarily conserved Mis12 Paul S, Singh P, Rudramurthy SM, Chakrabarti A and Ghosh AK kinetochore protein family, is required for efficient inner (2017) Matrix-assisted laser desorption/ionization-time kinetochore assembly in the pathogenic yeast Candida of flight mass spectrometry: protocol standardization and albicans. Mol Microbiol 80 14-32 database expansion for rapid identification of clinically Roy U, Jessani LG, Rudramurthy SM, Gopalakrishnan R, Dutta important Future Microbiol 12 1457-1466 S, Chakravarty C, Jillwin J and Chakrabarti A (2017) Seven Paul S, Singh P, Sharma S, Prasad GS, Rudramurthy SM, cases of Saccharomyces fungaemia related to use of Chakrabarti A and Ghosh AK (2018a) MALDI-TOF MS- probiotics Mycoses 60 375-380 Based Identification of Melanized Fungi is Faster and Rudramurthy SM, Chakrabarti A, Paul RA, Sood P, Kaur H, Reliable After the Expansion of In-House Database Capoor MR, Kindo AJ, Marak RS K, Arora A, Sardana R, Proteomics Clin Appl 23 e1800070 Das S, Chhina D, Patel A, Xess I, Tarai B, Singh P and Prajna VN, Prajna L and Muthiah S (2017) Fungal keratitis: The Ghosh A (2017) Candida auris candidaemia in Indian ICUs: Aravind experience Indian J Ophthalmol 65 912-919 analysis of risk factors J Antimicrob Chemother 72 1794- Prakash H, Ghosh AK, Rudramurthy SM, Paul RA, Gupta S, 1801 Negi V and Chakrabarti A (2016) The environmental source Rudramurthy SM, Honnavar P, Chakrabarti A, Dogra S, Singh P of emerging Apophysomyces variabilis infection in India and Handa S (2014b) Association of Malassezia species Mycology Research in India in the Last Ten Years (2008-2018) 1049

with psoriatic lesions Mycoses 57 483-488 Srivastav MK, Agarwal N and Natarajan K (2018) Multiple Rudramurthy SM, Honnavar P, Dogra S and Yegneswaran PP Evolutionarily Conserved Domains of Cap2 Are Required (2014a) Association of Malassezia species with dandruff for Promoter Recruitment and Iron Homeostasis Gene Indian J Med Res 139 431-437 Regulation mSphere 3 e00370-18 Rudramurthy SM, Shankarnarayan SA, Dogra S, Shaw D, Srivastava A, Sircaik S, Husain F, Thomas E, Ror S, Rastogi S, Mushtaq K, Paul RA et al. (2018b) Mutation in the Alim D, Bapat P, Andes DR, Nobile CJ and Panwar SL Squalene Epoxidase Gene of Trichophyton interdigitale and (2017) Distinct roles of the 7-transmembrane receptor Associated with Allylamine protein Rta3 in regulating the asymmetric distribution of Resistance Antimicrob Agents Chemother 62 1-9 phosphatidylcholine across the plasma membrane and Rudramurthy SM, Sharma M, Sharma M, Rawat P, Ghosh A, biofilm formation in Candida albicans Cell Microbiol 19 Venkatesan L, Aggarwal R, Singh M and Chakrabarti A 12767 (2018a) Reliable differentiation of Pneumocystis Suchitha S, Vijaya B, Sunila R, Anuradha K and Savitha R (2008) pneumonia from Pneumocystis colonisation by Sporotrichosis in Mysore: a case report to emphasize the quantification of Major Surface Glycoprotein gene using role of histopathology Indian J Pathol Microbiol 51 45-46 real-time polymerase chain reaction Mycoses 61 96-103 Sutradhar S, Yadav V, Sridhar S, Sreekumar L, Bhattacharyya D, Sanyal K, Padmanabhan S and Thakur J (2016) Poly nucleotide Ghosh SK, Paul R and Sanyal K (2015) A comprehensive sequences of Candida dubliniensis and probes for detection model to predict mitotic division in budding yeasts Mol US patents Biol Cell 26 3954-3965 Shankarnarayan SA, Rudramurthy SM, Chakrabarti A, Shaw D, Thakur J and Sanyal K (2013) Efficient neocentromere formation Paul S, Sethuraman N, Kaur H and Ghosh AK (2018) is suppressed by gene conversion to maintain centromere Molecular Typing and Antifungal Susceptibility of function at native physical chromosomal loci in Candida Candida viswanathii, India Emerg Infect Dis 24 1956- albicans Genome Res 23 638-652 1958 Thakur J and Sanyal K (2011) The essentiality of the fungus- Sharma C, Kumar R, Kumar N, Masih A, Gupta D and Chowdhary specific Dam1 complex is correlated with a one- A (2018) Investigation of Multiple Resistance Mechanisms kinetochore-one-microtubule interaction present in Voriconazole-Resistant Aspergillus flavus Clinical throughout the cell cycle, independent of the nature of a Isolates from a Chest Hospital Surveillance in Delhi, India centromere Eukaryot Cell 10 1295-1305 Antimicrob Agents Chemother 62 e01928-17 Thomas E, Roman E, Claypool S, Manzoor N, Pla J and Panwar Singh A, Masih A, Khurana A, Singh PK, Gupta M, Hagen F et SL (2013) Mitochondria influence CDR1 efflux pump al. (2018) High terbinafine resistance in Trichophyton activity, Hog1-mediated oxidative stress pathway, iron interdigitale isolates in Delhi, India harbouring mutations homeostasis, and ergosterol levels in Candida albicans in the squalene epoxidase gene Mycoses 61 477-484 Antimicrob Agents Chemother 57 5580-5599 Singh P, Paul S, Shivaprakash MR, Chakrabarti A and Ghosh AK Thomas E, Sircaik S, Roman E, Brunel JM, Johri AK, Pla J and (2016) Stress response in medically important Mucorales Panwar SL (2015) The activity of RTA2, a downstream Mycoses 59 628-635 effector of the calcineurin pathway, is required during Singh R, Shivaprakash MR and Chakrabarti A (2011) Biofilm tunicamycin-induced ER stress response in Candida formation by zygomycetes: quantification, structure and albicans FEMS Yeast Res 15 fov095 matrix composition. Microbiology 157 2611-2618 Ullmann AJ, Aguado JM, Arikan-Akdagli S, Denning DW, Groll Singh RP, Prasad HK, Sinha I, Agarwal N and Natarajan K (2011) AH, Lagrou K, Lass-Flörl C, Lewis RE, Munoz P, Verweij Cap2-HAP complex is a critical transcriptional regulator PE, Warris A, Ader F, Akova M, Arendrup MC, Barnes that has dual but contrasting roles in regulation of iron RA, Beigelman-Aubry C, Blot S, Bouza E, Brüggemann homeostasis in Candida albicans J Biol Chem 286 25154- RJM et al. (2018) Diagnosis and management of Aspergillus 25170 diseases: executive summary of the 2017 ESCMID- ECMM-ERS guideline Clin Microbiol Infect 24 e1-e38 Sinha I, Kumar S, Poonia P, Sawhney S and Natarajan K (2017) Functional specialization of two paralogous TAF12 Vengayil S, Panda A, Satpathy G, Nayak N, Ghose S, Patanaik D variants by their selective association with SAGA and and Khokhar S (2009) Polymerase chain reaction-guided TFIID transcriptional regulatory complexes J Biol Chem diagnosis of mycotic keratitis: a prospective evaluation of 292 15587 its efficacy and limitations Invest Ophthalmol Vis Sci 50 1050 Arunaloke Chakrabarti

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