Agricultural Research Organization
- Volcani Institute
Research & Initiatives
Mycotoxins are natural toxic compounds produced by certain filamentous fungi that readily colonize foodstuffs such as fruits, cereals, nuts and spices. Exposure to certain mycotoxins (via ingestion, inhalation, skin contact etc.) may lead to acute poisoning (mycotoxicosis) with symptoms of severe illness appearing quickly. Others are linked to long-term chronic effects on health including immune deficiency and development of cancer.
Although the scientific community has identified and characterized several hundred mycotoxins to date, only a few have gained the most attention due to their severe effects on human and animal health and their widespread occurrences in food. The major groups of mycotoxins include aflatoxins, fumonisins, ochratoxins, trichothecenes, citrinin, patulin and zearalenone.
Mycotoxins belong to a larger group of organic compounds called specialized or secondary metabolites, because they are not directly involved in normal primary functions of the fungi, such as growth, development and reproduction. The reason for the synthesis of most mycotoxins is unknown as of yet. The accepted theory is that they offer a selective ecological advantage to the producing fungi by weakening the receiving host, fighting off competing microbes or serving as signaling molecules.
The genes encoding for the enzymatic activities to produce any mycotoxin are arranged in a contiguous fashion, usually in the same locus, termed a biosynthetic gene cluster (BGC). A typical BGC contains a backbone enzyme that acts on primary metabolites such as acyl-CoA or amino acids (more often than not a polyketide synthase or non-ribosomal peptide synthetase) and tailoring enzymes with diverse functions that "decorate" and alter the bioactivities of the final metabolite. Larger BGCs also frequently contain a cluster-specific transcription factor that functions as a positive regulator to induce expression of the remaining cluster genes, in addition to dedicated transporter(s) for trafficking and secretion of the toxin or its constituents.
The Aflatoxin Gene Cluster
Mycotoxin regulation by environmental and molecular factors
Regulation of mycotoxin biosynthesis is a complex process involving cluster-specific regulators, global transcriptional complexes and epigenetic modifications. A number of global transcription factors contribute to both positive and negative regulation of mycotoxin synthesis. These "broad domain" regulators are often responsive to the environmental state the fungus is subjected to, for instance carbon and nitrogen source, pH, ambient light and oxidative stress. Notable mentions include the carbon catabolite repressor CreA, the nitrogen metabolism regulator AreA, the pH responsive transcription factor PacC, the "velvet complex" master regulator LaeA and the epigenetic reader SntB.
In the lab, we aim to elucidate the intrinsic and extrinsic factors contributing to mycotoxin production in-vitro and in colonized hosts.
Four Transcription Factor Knockout Strains in Penicillium expansum Affecting Toxin Production and Virulence in Golden Delicious Apples
Aneuploidy as a resistance mechanism in filamentous fungi
Aneuploidy is defined as the presence of an abnormal number of chromosomes in a cell. That is, the occurrence of one or more extra or missing chromosomes leading to an unbalanced chromosome complement. Aneuploidy has been associated with drug resistance and tolerance in human pathogenic yeasts such as Candida albicans, Cryptococcus neoformans, Candida glabrata and Candida auris. Duplication of existing chromosomes or formation of new ones enable these yeasts to withstand many toxic compounds including anti-fungal drugs and endoplasmic reticulum stressors.
Aspergillus flavus is a pathogenic filamentous fungus that contaminates many important agricultural crops with significant quantities of aflatoxins. This fungus is also the second leading cause of human invasive aspergillosis, a disease that is particularly prevalent in immunocompromised individuals. Azole drugs are considered the most effective compounds to control Aspergillus infections both in clinical and agricultural settings. Emergence of azole resistance in Aspergillus spp. is typically associated with point mutations to the target-binding sites of cyp51 orthologues, overexpression of the amount of said genes or by altering the effective drug concentration using specialized membrane transporters termed efflux pumps.
We hypothesize that alternative molecular mechanisms, like aneuploidy, are also responsible for acquisition of azole resistance in filamentous fungi.
Complete and Partial Chromosome Duplication Events in Aspergillus flavus in Response to Voriconazole Stress
