TY  - JOUR
A1  - Gupta, Shishir K.
A1  - Minocha, Rashmi
A1  - Thapa, Prithivi Jung
A1  - Srivastava, Mugdha
A1  - Dandekar, Thomas
T1  - Role of the pangolin in origin of SARS-CoV-2: an evolutionary perspective
JF  - International Journal of Molecular Sciences
N2  - After the recent emergence of SARS-CoV-2 infection, unanswered questions remain related to its evolutionary history, path of transmission or divergence and role of recombination. There is emerging evidence on amino acid substitutions occurring in key residues of the receptor-binding domain of the spike glycoprotein in coronavirus isolates from bat and pangolins. In this article, we summarize our current knowledge on the origin of SARS-CoV-2. We also analyze the host ACE2-interacting residues of the receptor-binding domain of spike glycoprotein in SARS-CoV-2 isolates from bats, and compare it to pangolin SARS-CoV-2 isolates collected from Guangdong province (GD Pangolin-CoV) and Guangxi autonomous regions (GX Pangolin-CoV) of South China. Based on our comparative analysis, we support the view that the Guangdong Pangolins are the intermediate hosts that adapted the SARS-CoV-2 and represented a significant evolutionary link in the path of transmission of SARS-CoV-2 virus. We also discuss the role of intermediate hosts in the origin of Omicron.
KW  - COVID-19
KW  - SARS-CoV-2
KW  - origin
KW  - evolution
KW  - intermediate host
KW  - pangolin
KW  - mutation
KW  - recombination
KW  - adaptation
KW  - transmission
KW  - comparative sequence analysis
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285995
SN  - 1422-0067
VL  - 23
IS  - 16
ER  - 
TY  - JOUR
A1  - Hampe, Irene A. I.
A1  - Friedman, Justin
A1  - Edgerton, Mira
A1  - Morschhäuser, Joachim
T1  - An acquired mechanism of antifungal drug resistance simultaneously enables Candida albicans to escape from intrinsic host defenses
JF  - PLoS Pathogens
N2  - The opportunistic fungal pathogen Candida albicans frequently produces genetically altered variants to adapt to environmental changes and new host niches in the course of its life-long association with the human host. Gain-of-function mutations in zinc cluster transcription factors, which result in the constitutive upregulation of their target genes, are a common cause of acquired resistance to the widely used antifungal drug fluconazole, especially during long-term therapy of oropharyngeal candidiasis. In this study, we investigated if C. albicans also can develop resistance to the antimicrobial peptide histatin 5, which is secreted in the saliva of humans to protect the oral mucosa from pathogenic microbes. As histatin 5 has been shown to be transported out of C. albicans cells by the Flu1 efflux pump, we screened a library of C. albicans strains that contain artificially activated forms of all zinc cluster transcription factors of this fungus for increased FLU1 expression. We found that a hyperactive Mrr1, which confers fluconazole resistance by upregulating the multidrug efflux pump MDR1 and other genes, also causes FLU1 overexpression. Similarly to the artificially activated Mrr1, naturally occurring gain-of-function mutations in this transcription factor also caused FLU1 upregulation and increased histatin 5 resistance. Surprisingly, however, Mrr1-mediated histatin 5 resistance was mainly caused by the upregulation of MDR1 instead of FLU1, revealing a previously unrecognized function of the Mdr1 efflux pump. Fluconazole-resistant clinical C. albicans isolates with different Mrr1 gain-of-function mutations were less efficiently killed by histatin 5, and this phenotype was reverted when MRR1 was deleted. Therefore, antimycotic therapy can promote the evolution of strains that, as a consequence of drug resistance mutations, simultaneously have acquired increased resistance against an innate host defense mechanism and are thereby better adapted to certain host niches.
KW  - antimicrobial resistance
KW  - transcriptional control
KW  - Candida albicans
KW  - transcription factors
KW  - mutation
KW  - hyperexpression techniques
KW  - antifungals
KW  - point mutation
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158883
VL  - 13
IS  - 9
ER  -