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Article ; Online: Aspergillus fumigatus secretes a protease(s) that displays in silico binding affinity towards the SARS-CoV-2 spike protein and mediates SARS-CoV-2 pseudovirion entry into HEK-293T cells.

Mjokane, Nozethu / Akintemi, Eric O / Sabiu, Saheed / Gcilitshana, Onele M N / Albertyn, Jacobus / Pohl, Carolina H / Sebolai, Olihile M

Virology journal

2024 Volume 21, Issue 1, Page(s) 58

Abstract: Background: The novel coronavirus disease of 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Data from the COVID-19 clinical control case studies showed that this disease could also ... ...

Abstract	Background: The novel coronavirus disease of 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Data from the COVID-19 clinical control case studies showed that this disease could also manifest in patients with underlying microbial infections such as aspergillosis. The current study aimed to determine if the Aspergillus (A.) fumigatus culture media (i.e., supernatant) possessed protease activity that was sufficient to activate the SARS-CoV-2 spike protein. Methods: The supernatant was first analysed for protease activity. Thereafter, it was assessed to determine if it possessed proteolytic activity to cleave a fluorogenic mimetic peptide of the SARS-CoV-2 spike protein that contained the S1/S2 site and a full-length spike protein contained in a SARS-CoV-2 pseudovirion. To complement this, a computer-based tool, HADDOCK, was used to predict if A. fumigatus alkaline protease 1 could bind to the SARS-CoV-2 spike protein. Results: We show that the supernatant possessed proteolytic activity, and analyses of the molecular docking parameters revealed that A. fumigatus alkaline protease 1 could bind to the spike protein. To confirm the in silico data, it was imperative to provide experimental evidence for enzymatic activity. Here, it was noted that the A. fumigatus supernatant cleaved the mimetic peptide as well as transduced the HEK-293T cells with SARS-CoV-2 pseudovirions. Conclusion: These results suggest that A. fumigatus secretes a protease(s) that activates the SARS-CoV-2 spike protein. Importantly, should these two infectious agents co-occur, there is the potential for A. fumigatus to activate the SARS-CoV-2 spike protein, thus aggravating COVID-19 development.
MeSH term(s)	Humans ; Peptide Hydrolases ; Spike Glycoprotein, Coronavirus ; Aspergillus fumigatus ; SARS-CoV-2 ; HEK293 Cells ; Molecular Docking Simulation ; COVID-19 ; Peptides
Chemical Substances	Peptide Hydrolases (EC 3.4.-) ; spike protein, SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; Peptides
Language	English
Publishing date	2024-03-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2160640-7
ISSN	1743-422X ; 1743-422X
ISSN (online)	1743-422X
ISSN	1743-422X
DOI	10.1186/s12985-024-02331-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Cryptococcal proteases exhibit the potential to activate the latent SARS-CoV-2 spike protein

Nozethu Mjokane / Saheed Sabiu / Olufemi S. Folorunso / Onele M.N. Gcilitshana / Jacobus Albertyn / Carolina H. Pohl / Olihile M. Sebolai

Journal of Infection and Public Health, Vol 17, Iss 2, Pp 263-

2024 Volume 270

Abstract: Background: The COVID-19 pandemic has affected more than 650 million people and resulted in over 6.8 million deaths. Notably, the disease could co-manifest with microbial infections, like cryptococcosis, which also presents as a primary lung infection. ... ...

Abstract	Background: The COVID-19 pandemic has affected more than 650 million people and resulted in over 6.8 million deaths. Notably, the disease could co-manifest with microbial infections, like cryptococcosis, which also presents as a primary lung infection. Objective: In this contribution, we sought to determine if cryptococcal supernatant (which contains secreted furin-like proteases) could activate the SARS-CoV-2 spike protein. Methods: Molecular docking of the crystal structures of the SARS-CoV-2 spike protein (target) and selected cryptococcal proteases (ligands) was executed using the high ambiguity driven protein-protein docking (HADDOCK) server, with the furin protease serving as a reference ligand. The furin protease is found in human cells and typically activates the SARS-CoV-2 spike protein.Importantly, in order to provide experimental evidence for enzymatic activity, we also assessed the biochemical efficiency of cryptococcal proteases to initiate viral entry into HEK-293 T cells by SARS-CoV-2 spike pseudotyped Lentivirus. Results: We show that the selected cryptococcal proteases could interact with the spike protein, and some had a better or comparable binding affinity for the spike protein than furin protease following an in silico comparative analysis of the molecular docking parameters. Furthermore, it was noted that the biochemical efficiency of the cryptococcal supernatant to transduce HEK-293 T cells with SARS-CoV-2 pseudovirions was comparable (p > 0.05) to that of recombinant furin. Conclusions: Taken together, these data show that cryptococcal proteases could activate the SARS-CoV-2 spike protein. In practice, it may be critical to determine if patients have an underlying cryptococcal infection, as this microbe could secrete proteases that may further activate the SARS-CoV-2 viral particles, thus undermining COVID-19 intervention measures.
Keywords	Cryptococcal protease ; Furin protease ; HEK-293 T cells ; Protein-protein docking ; SARS-CoV-2 spike protein ; Infectious and parasitic diseases ; RC109-216 ; Public aspects of medicine ; RA1-1270
Subject code	612
Language	English
Publishing date	2024-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: The Possible Role of Microbial Proteases in Facilitating SARS-CoV-2 Brain Invasion.

Mjokane, Nozethu / Folorunso, Olufemi S / Ogundeji, Adepemi O / Sebolai, Olihile M

Biology

2021 Volume 10, Issue 10

Abstract: SARS-CoV-2 has been shown to display proclivity towards organs bearing angiotensin-converting enzyme (ACE2) expression cells. Of interest herein is the ability of the virus to exhibit neurotropism. However, there is limited information on how this virus ... ...

Abstract	SARS-CoV-2 has been shown to display proclivity towards organs bearing angiotensin-converting enzyme (ACE2) expression cells. Of interest herein is the ability of the virus to exhibit neurotropism. However, there is limited information on how this virus invades the brain. With this contribution, we explore how, in the context of a microbial co-infection using a cryptococcal co-infection as a model, SARS-CoV-2 could reach the brain. We theorise that the secretion of proteases by disseminated fungal cells might also activate the S2 domain of the viral spike glycoprotein for membrane fusion with brain endothelial cells leading to endocytosis. Understanding this potential invasion mechanism could lead to better SARS-CoV-2 intervention measures, which may also be applicable in instances of co-infection, especially with protease-secreting pathogens.
Language	English
Publishing date	2021-09-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology10100966
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Article ; Online: Cryptococcal proteases exhibit the potential to activate the latent SARS-CoV-2 spike protein.

Mjokane, Nozethu / Sabiu, Saheed / Folorunso, Olufemi S / Gcilitshana, Onele M N / Albertyn, Jacobus / Pohl, Carolina H / Sebolai, Olihile M

Journal of infection and public health

2023 Volume 17, Issue 2, Page(s) 263–270

Abstract	Background: The COVID-19 pandemic has affected more than 650 million people and resulted in over 6.8 million deaths. Notably, the disease could co-manifest with microbial infections, like cryptococcosis, which also presents as a primary lung infection. Objective: In this contribution, we sought to determine if cryptococcal supernatant (which contains secreted furin-like proteases) could activate the SARS-CoV-2 spike protein. Methods: Molecular docking of the crystal structures of the SARS-CoV-2 spike protein (target) and selected cryptococcal proteases (ligands) was executed using the high ambiguity driven protein-protein docking (HADDOCK) server, with the furin protease serving as a reference ligand. The furin protease is found in human cells and typically activates the SARS-CoV-2 spike protein. Importantly, in order to provide experimental evidence for enzymatic activity, we also assessed the biochemical efficiency of cryptococcal proteases to initiate viral entry into HEK-293 T cells by SARS-CoV-2 spike pseudotyped Lentivirus. Results: We show that the selected cryptococcal proteases could interact with the spike protein, and some had a better or comparable binding affinity for the spike protein than furin protease following an in silico comparative analysis of the molecular docking parameters. Furthermore, it was noted that the biochemical efficiency of the cryptococcal supernatant to transduce HEK-293 T cells with SARS-CoV-2 pseudovirions was comparable (p > 0.05) to that of recombinant furin. Conclusions: Taken together, these data show that cryptococcal proteases could activate the SARS-CoV-2 spike protein. In practice, it may be critical to determine if patients have an underlying cryptococcal infection, as this microbe could secrete proteases that may further activate the SARS-CoV-2 viral particles, thus undermining COVID-19 intervention measures.
MeSH term(s)	Humans ; Furin/chemistry ; Furin/metabolism ; COVID-19 ; Spike Glycoprotein, Coronavirus/chemistry ; SARS-CoV-2 ; Peptide Hydrolases/metabolism ; Molecular Docking Simulation ; Pandemics ; HEK293 Cells
Chemical Substances	Furin (EC 3.4.21.75) ; spike protein, SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2023-12-14
Publishing country	England
Document type	Journal Article
ZDB-ID	2467587-8
ISSN	1876-035X ; 1876-0341
ISSN (online)	1876-035X
ISSN	1876-0341
DOI	10.1016/j.jiph.2023.12.008
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Article: The Possible Role of Microbial Proteases in Facilitating SARS-CoV-2 Brain Invasion

Mjokane, Nozethu / Folorunso, Olufemi S. / Ogundeji, Adepemi O. / Sebolai, Olihile M.

Biology. 2021 Sept. 27, v. 10, no. 10

2021

Abstract	SARS-CoV-2 has been shown to display proclivity towards organs bearing angiotensin-converting enzyme (ACE2) expression cells. Of interest herein is the ability of the virus to exhibit neurotropism. However, there is limited information on how this virus invades the brain. With this contribution, we explore how, in the context of a microbial co-infection using a cryptococcal co-infection as a model, SARS-CoV-2 could reach the brain. We theorise that the secretion of proteases by disseminated fungal cells might also activate the S2 domain of the viral spike glycoprotein for membrane fusion with brain endothelial cells leading to endocytosis. Understanding this potential invasion mechanism could lead to better SARS-CoV-2 intervention measures, which may also be applicable in instances of co-infection, especially with protease-secreting pathogens.
Keywords	Severe acute respiratory syndrome coronavirus 2 ; brain ; endocytosis ; fungi ; glycoproteins ; membrane fusion ; mixed infection ; models ; peptidyl-dipeptidase A ; proteinases ; secretion ; viruses
Language	English
Dates of publication	2021-0927
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology10100966
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Cryptococcal Protease(s) and the Activation of SARS-CoV-2 Spike (S) Protein.

Mjokane, Nozethu / Maliehe, Maphori / Folorunso, Olufemi S / Ogundeji, Adepemi O / Gcilitshana, Onele M N / Albertyn, Jacobus / Pohl, Carolina H / Sebolai, Olihile M

Cells

2022 Volume 11, Issue 3

Abstract: In this contribution, we report on the possibility that cryptococcal protease(s) could activate the SARS-CoV-2 spike (S) protein. The S protein is documented to have a unique four-amino-acid sequence (underlined, SPRRAR↓S) at the interface between the S1 ...

Abstract	In this contribution, we report on the possibility that cryptococcal protease(s) could activate the SARS-CoV-2 spike (S) protein. The S protein is documented to have a unique four-amino-acid sequence (underlined, SPRRAR↓S) at the interface between the S1 and S2 sites, that serves as a cleavage site for the human protease, furin. We compared the biochemical efficiency of cryptococcal protease(s) and furin to mediate the proteolytic cleavage of the S1/S2 site in a fluorogenic peptide. We show that cryptococcal protease(s) processes this site in a manner comparable to the efficiency of furin (
MeSH term(s)	Amino Acid Sequence ; Aspartic Acid Proteases/genetics ; Aspartic Acid Proteases/metabolism ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Binding Sites ; COVID-19/epidemiology ; COVID-19/prevention & control ; COVID-19/virology ; Cryptococcus neoformans/enzymology ; Cryptococcus neoformans/genetics ; Fluorescent Dyes/chemistry ; Furin/genetics ; Furin/metabolism ; Humans ; Pandemics ; Peptides/chemistry ; Peptides/metabolism ; Proteolysis ; SARS-CoV-2/metabolism ; SARS-CoV-2/physiology ; Spike Glycoprotein, Coronavirus/metabolism
Chemical Substances	Bacterial Proteins ; Fluorescent Dyes ; Peptides ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Aspartic Acid Proteases (EC 3.4.-) ; Furin (EC 3.4.21.75)
Language	English
Publishing date	2022-01-27
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11030437
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Article: The Repurposing of Acetylsalicylic Acid as a Photosensitiser to Inactivate the Growth of Cryptococcal Cells.

Ogundeji, Adepemi O / Mjokane, Nozethu / Folorunso, Olufemi S / Pohl, Carolina H / Nyaga, Martin M / Sebolai, Olihile M

Pharmaceuticals (Basel, Switzerland)

2021 Volume 14, Issue 5

Abstract: Photodynamic treatment (PDT) is often successful when used against aerobic microbes, given their natural susceptibility to oxidative damage. To this end, the current study aimed to explore the photodynamic action of acetylsalicylic acid (ASA; aspirin, ... ...

Abstract	Photodynamic treatment (PDT) is often successful when used against aerobic microbes, given their natural susceptibility to oxidative damage. To this end, the current study aimed to explore the photodynamic action of acetylsalicylic acid (ASA; aspirin, which is commonly used to treat non-infectious ailments), when administered to respiring cryptococcal cells. The treatment of cryptococcal cells, i.e., exposure to 0.5 or 1 mM of ASA in the presence of ultraviolet light (UVL) for 10 min, resulted in a significant (
Language	English
Publishing date	2021-04-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph14050404
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Article: The first survey of cryptococcal cells in bird droppings across Bloemfontein, South Africa.

Kankam, Gloria / Christians, Byron / Maliehe, Maphori / Mjokane, Nozethu / Ogundeji, Adepemi O / Folorunso, Olufemi S / Pohl, Carolina H / Sebolai, Olihile M

Veterinary world

2021 Volume 14, Issue 10, Page(s) 2739–2744

Abstract: Background and aim: Cryptococcal yeast cells are spread across different ecosystems through bird movement and are deposited in bird guano. These cells may be inhaled by humans and lead to cryptococcal pneumonia. In individuals with reduced immune T-cell ...

Abstract	Background and aim: Cryptococcal yeast cells are spread across different ecosystems through bird movement and are deposited in bird guano. These cells may be inhaled by humans and lead to cryptococcal pneumonia. In individuals with reduced immune T-cell populations, cells may disseminate to the brain and cause the often-deadly cryptococcal meningitis. In this study, we surveyed cryptococcal cells in bird droppings across the city of Bloemfontein, South Africa. Materials and methods: We aseptically collected 120 bird dropping samples from 15 representative city sites. In the laboratory, samples were assessed with regards to location, weighed, and standardized to a mass of 1 g before suspension in 10 mL phosphate buffer saline. Samples were first screened usingCalcofluor-white stain as it is a rapid technique for the detection of fungi via binding to cell wall components such as chitin. After this, positive Calcofluor samples were serologically assayed for the cryptococcal antigen (CrAg). To confirm assay data, CrAg positive samples were then cultured on bird seed agar and resulting colonies were assessed using Indian ink. Results: We determined that 10/15 locations were positive for the CrAg. Pathogenic cells were identified on bird seed agar as brown colonies. When examined using microscopy, brown colony cells exhibited characteristic thick capsules representative of cryptococcal cells. Conclusion: This is the first proximate analysis showing the ecological distribution of cryptococcal cells in Bloemfontein. This is important as associated infections are acquired from the environment. Similarly, given the threat posed by cryptococcal cells to immunocompromised individuals, local authorities must initiate measures curbing the spread of these cells.
Language	English
Publishing date	2021-10-25
Publishing country	India
Document type	Journal Article
ZDB-ID	2456277-4
ISSN	2231-0916 ; 0972-8988
ISSN (online)	2231-0916
ISSN	0972-8988
DOI	10.14202/vetworld.2021.2739-2744
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Article ; Online: The Repurposing of Acetylsalicylic Acid as a Photosensitiser to Inactivate the Growth of Cryptococcal Cells

Adepemi O. Ogundeji / Nozethu Mjokane / Olufemi S. Folorunso / Carolina H. Pohl / Martin M. Nyaga / Olihile M. Sebolai

Pharmaceuticals, Vol 14, Iss 404, p

2021 Volume 404

Abstract	Photodynamic treatment (PDT) is often successful when used against aerobic microbes, given their natural susceptibility to oxidative damage. To this end, the current study aimed to explore the photodynamic action of acetylsalicylic acid (ASA; aspirin, which is commonly used to treat non-infectious ailments), when administered to respiring cryptococcal cells. The treatment of cryptococcal cells, i.e., exposure to 0.5 or 1 mM of ASA in the presence of ultraviolet light (UVL) for 10 min, resulted in a significant ( p < 0.05) reduction in the growth of tested cells when compared to non-treated (non-Rx) cells, i.e., no ASA and no UVL. The treated cells were also characterised by diseased mitochondria, which is crucial for the survival of respiring cells, as observed by a significant ( p < 0.05) loss of mitochondrial membrane potential (ΔΨM) and significant ( p < 0.05) accumulation of reactive oxygen species (ROS) when compared to non-Rx cells. Moreover, the photolytic products of acetylsalicylic acid altered the ultrastructural appearance of treated cells as well as limited the expression levels of the capsular-associated gene, CAP64, when compared to non-Rx cells. The results of the study highlight the potential use of ASA as a photosensitiser that is effective for controlling the growth of cryptococcal cells. Potentially, this treatment can also be used as an adjuvant, to complement and support the usage of current anti-microbial agents.
Keywords	acetylsalicylic acid (ASA ; aspirin) ; capsule ; CAP64 ; Cryptococcus ; membrane potential (ΔΨM) ; photodynamic treatment ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
Subject code	630
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cryptococcal Protease(s) and the Activation of SARS-CoV-2 Spike (S) Protein

Nozethu Mjokane / Maphori Maliehe / Olufemi S. Folorunso / Adepemi O. Ogundeji / Onele M. N. Gcilitshana / Jacobus Albertyn / Carolina H. Pohl / Olihile M. Sebolai

Cells, Vol 11, Iss 437, p

2022 Volume 437

Abstract	In this contribution, we report on the possibility that cryptococcal protease(s) could activate the SARS-CoV-2 spike (S) protein. The S protein is documented to have a unique four-amino-acid sequence (underlined, S PRRA R↓S) at the interface between the S1 and S2 sites, that serves as a cleavage site for the human protease, furin. We compared the biochemical efficiency of cryptococcal protease(s) and furin to mediate the proteolytic cleavage of the S1/S2 site in a fluorogenic peptide. We show that cryptococcal protease(s) processes this site in a manner comparable to the efficiency of furin ( p > 0.581). We conclude the paper by discussing the impact of these findings in the context of a SARS-CoV-2 disease manifesting while there is an underlying cryptococcal infection.
Keywords	cryptococcal infection ; Cryptococcus ; Cryptococcus neoformans ; fluorogenic peptide ; furin ; protease ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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