Genomic and phenotypic analysis of COVID-19-associated pulmonary aspergillosis isolates ofAspergillus fumigatus

Abstract

The ongoing global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) first described from Wuhan, China. A subset of COVID-19 patients has been reported to have acquired secondary infections by microbial pathogens, such as fungal opportunistic pathogens from the genus Aspergillus. To gain insight into COVID-19 associated pulmonary aspergillosis (CAPA), we analyzed the genomes and characterized the phenotypic profiles of four CAPA isolates of Aspergillus fumigatus obtained from patients treated in the area of North Rhine-Westphalia, Germany. By examining the mutational spectrum of single nucleotide polymorphisms, insertion-deletion polymorphisms, and copy number variants among 206 genes known to modulate A. fumigatus virulence, we found that CAPA isolate genomes do not exhibit major differences from the genome of the Af293 reference strain. By examining virulence in an invertebrate moth model, growth in the presence of osmotic, cell wall, and oxidative stressors, and the minimum inhibitory concentration of antifungal drugs, we found that CAPA isolates were generally, but not always, similar to A. fumigatus reference strains Af293 and CEA17. Notably, CAPA isolate D had more putative loss of function mutations in genes known to increase virulence when deleted (e.g., in the FLEA gene, which encodes a lectin recognized by macrophages). Moreover, CAPA isolate D was significantly more virulent than the other three CAPA isolates and the A. fumigatus reference strains tested. These findings expand our understanding of the genomic and phenotypic characteristics of isolates that cause CAPA.

An evolutionary genomic approach reveals both conserved and species-specific genetic elements related to human disease in closely relatedAspergillusfungi

“…To test the validity of the conserved and species-specific pathogenicity models of virulence, we searched the 18 Aspergillus genomes for pathogen-or A. fumigatus-specific genes using both candidate and unbiased approaches. The candidate approach consisted of determining the presence or absence pattern of 206 virulence-related genes (Steenwyk, Mead, de Castro, et al 2020) that our gene family analysis placed into 189 gene families. The number of gene members in each family ranged from 259 (in the gene family containing the transporter abcC -Afu1g14330 (Paul et al 2013)) to six (in the gene family containing the terpene cyclase fma-TC -Afu8g00520 -from the fumagillin biosynthetic gene cluster (Guruceaga et al 2018)).…”

“…To date, studies addressing this question have focused on comparing A. fumigatus to one or a few select species (Fedorova et al 2008;Wiedner et al 2013;Mead et al 2019;Knowles et al 2020;. Many individual genes and pathways are known to contribute to A. fumigatus virulence (Abad et al 2010;Bignell et al 2016;Brown and Goldman 2016;Steenwyk, Mead, de Castro, et al 2020), but if they are present or function in the same manner in other section Fumigati species, including in non-pathogens, has rarely been studied (Knowles et al 2020;). Genes associated with pathogenicity could be shared or absent amongst all pathogens, including A. fumigatus, following a "conserved pathogenicity" model, or be uniquely present (or absent) in each pathogen ("species-specific pathogenicity" model) (Rokas et al 2020).…”

Diatomaceous earth/zinc oxide micro-composite assisted antibiotics in fungal therapy

“…The recent BBC report showing that those who have been cared in intensive care unit (ICU) of severe COVID-19 are vulnerable to deadly infections [ 1 – 4 ]. In comparison with the death rate of COVID-19 (about 2.1%, calculate by 28th June, 2021), the high fatality rate of these Invasive Aspergillosis infection (IAI, such as mycosis: 70%, candida: 25%, aspergillus: 30 ~ 90%) has sent people into another serious pandemic [ 5 , 6 ]. Nowadays, resistance to and the toxicity of antibiotics are a concern due to the rising incidence of microbial infections with serious side effects in world healthcare settings [ 7 , 8 ].…”

(E)-3-[4-(1H-Imidazol-1-yl)phenyl]-1-(4-methylphenyl)prop-2-en-1-one

“…These numbers will only continue to grow if factors such as limited drug therapies, antifungal resistant strains [7,8], and the influx of individuals with compromised immune systems continue. In addition, recent literature illustrates respiratory viruses such as influenza and coronavirus disease 2019 (COVID-19) have led to new classifications of pulmonary aspergillosis, making matters more urgent [9][10][11][12].…”

“…There seems to be an appreciable prevalence of CAPA (20-30%), especially in mechanically ventilated or severely ill individuals [11]. In particular, one study discovered co-infections of Aspergillus in 26% of those with severe ammonia and 40% in those with acute respiratory distress syndrome engendered by COVID-19 [12]. These factors demonstrate that it is imperative to discover new treatments for the evolving disease pulmonary aspergillosis.…”