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

Mjokane, Nozethu; Maliehe, Maphori; Folorunso, Olufemi Samuel; Ogundeji, Adepemi O.; Gcilitshana, Onele; Albertyn, Jacobus; Pohl, Carolina H.; Sebolai, Olihile M.

doi:10.3390/cells11030437

Cited by 7 publications

(6 citation statements)

References 51 publications

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“…We don't know if a LP had been performed on the 8 dead patients not treated with amphotericin B+ flucytosine, Cryptococcus would have been found in CSF. Some authors investigated the role of cryptococcal protease during SARS-CoV-2 infection, suggesting the possible role of protease, ureases, phospholipases released by Cryptococcus in activating the SARS-CoV-2 S protein leading to hyper-inflammatory response [49]. This could explain the high mortality we found in our review.…”

Section: N Resultsmentioning

confidence: 70%

Invasive cryptococcal disease in COVID-19: systematic review of the literature and analysis

Pipitone¹,

Spicola²,

Abbott

et al. 2023

Infez Med

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During the Coronavirus Disease 2019 (COVID-19) pandemic, an increasing number of fungal infections associated with SARS-CoV-2 infection have been reported. Among them, cryptococcosis could be a lifethreatening disease. We performed a Systematic Review (PRISMA Statement) of cryptococcosis and CO-VID-19 co-infection, case report/series were included: a total of 34 cases were found, then we added our case report. We collected patients' data and performed a statistical analysis comparing two groups of patients sorted by outcome: "dead" and "alive". Three cases were excluded for lack of information. To compare categorical data, we used a Fisher-exact test (a=0.05). To compare quantitative variables a U Mann-Whitney test was used (a=0.05), with a 95% Confidence Interval. A total of 32 co-infected patients were included in the statistical analysis. Mortality rate was 17/32 (53.1%): these patients were included in "dead" group, and 15/32 (46.9%) patients survived and were included in "alive" group. Overall, males were 25/32 (78.1%), the median age was 60 years (IQR 53-70) with non-statistically significant difference between groups (p=0.149 and p=0.911, respectively). Three variables were associated with mortality: ARDS, ICU admission and inadequate treatment. Overall, 21 out of 24 (87.5%) patients were in ARDS with a statistically significant difference among two groups (p=0.028). ICU admission for COVID-19 was observed in 18/26 (69.2%), more frequently among dead group (p=0.034). Finally, 15/32 (46.9%) patients had adequate treatment (amphotericin B + flucytosine for invasive cryptococcosis) mostly among alive patients (p=0.039). In conclusion, mortality due to cryptococcal infection among COVID-19 patients remains high but an early diagnosis and appropriate treatment could reduce mortality.

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Section: N Resultsmentioning

confidence: 70%

Invasive cryptococcal disease in COVID-19: systematic review of the literature and analysis

Pipitone¹,

Spicola²,

Abbott

et al. 2023

Infez Med

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“…These syndromes are the and Cryptococcus spp. is the possible role of proteases produced by the fungus as facilitating agents of viral infection through the activation of the SARS-CoV-2 spike protein (MJOKANE et al, 2021;MJOKANE et al, 2022). Although this evidence is only proven in vitro experiments, the worsening of the general condition of patients with long-term COVID-19 in co-infection by the two pathogens may be related to this physiochemical process.…”

Section: Resultsmentioning

confidence: 99%

Secondary infection by Cryptococcus spp. in HIV-negative patients in the context of Covid-19

Norberg,

Manhães

et al. 2023

Interdisciplinarity and Innovation in Scientific Research

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Cryptococcosis is an infectious disease with worldwide distribution caused by fungi of the genus Cryptococcus, especially by the species C. neoformans and C. gattii. Cryptococcus infections begin with the inhalation of fungal particles that reach the lungs and can spread through hematogenous, especially in hosts with deficiencies in the cellular immune system. The acute respiratory syndrome in COVID-19 promotes a decrease in the efficiency of the immune system, either due to exhaustion resulting from the exacerbated response or due to immunosuppression in treatment with corticosteroids to contain the cytokine cascade in COVID-19, facilitating the appearance of opportunistic fungal infections in patients who develop severe cases of the virus due to SARS-CoV-2. The objective of this research is to conduct a review of clinical cases of cryptococcosis in co-infection with SARS-CoV-2 or the appearance of this mycosis in the post-COVID-19 convalescence period in HIV-uninfected individuals, analyzing the risk factors and circumstances associated with the relationship between cryptococcosis and COVID-19. Although cryptococcosis is a relatively rare infection among patients with COVID-19 and in the convalescence period of the disease, this opportunistic mycosis may be responsible for a mortality rate that is considered high (greater than 55%). Susceptibility to Cryptococcus spp. infection in the context of COVID-19 disease and treatment is strongly associated with corticosteroid use and pre-existing multiple comorbidities. It is not possible to determine the degree to which cryptococcosis is responsible for mortality in co-infection or infection during the COVID-19 convalescence period. The development of secondary infection by Cryptococcus spp. is indicative of a poor prognosis for the patient.

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“…The idea of a fungal protease activating a viral substrate has been shown before. In their work, Mjokane and co-workers showed that the fungus Cryptococcus neoformans secretes protease(s) that can activate the spike protein of SARS-CoV-2 [ 35 ]. As a mimetic peptide may not fold in a similar manner as a full-length peptide, it was imperative to show if the A. fumigatus supernatant contained a protease(s) that could transduce a laboratory cell line following the activation of the SARS-CoV-2 spike protein.…”

Section: Discussionmentioning

confidence: 99%

“… A. fumigatus alkaline protease 1 (PDB ID: AFUA_4G11800) Serine-based Aspergillus fumigatus Help to disrupt the host structural barriers [ 14 ]. Suggested to act on the furin cleavage site within the S1/S2 site [ 35 ]. …”

Section: Methodsmentioning

confidence: 99%

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,

Akintemi,

Sabiu

et al. 2024

Virol J

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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.

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

Cited by 7 publications

References 51 publications

Invasive cryptococcal disease in COVID-19: systematic review of the literature and analysis

Invasive cryptococcal disease in COVID-19: systematic review of the literature and analysis

Secondary infection by Cryptococcus spp. in HIV-negative patients in the context of Covid-19

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

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