How a Plant-Killing Fungus Turns Deadly in Humans

Fusarium oxysporum is best known as a scourge of agriculture, a soilborne fungus that devastates tomato, banana, and countless other crops through wilt diseases. Yet the same species complex has quietly emerged as a formidable human pathogen. The World Health Organization now lists Fusarium among the high-priority fungal agents responsible for invasive fungal disease, and a new educational review published in PLOS Pathogens by Jeffrey Coleman of Auburn University, Neta Shlezinger of the Hebrew University of Jerusalem, and Li-Jun Ma of the University of Massachusetts-Amherst synthesizes what is known about why certain lineages of this fungus can infect people. Their analysis arrives at a critical moment: as the population of immunocompromised patients grows, invasive fusariosis is becoming more common, and the fungus’s intrinsic resistance to many first-line antifungal drugs makes these infections exceptionally difficult to treat.

The clinical burden is concentrated in a surprisingly narrow slice of an enormous genus. Fusarium is currently divided into 23 species complexes, but only a handful cause human disease, and two of them, the F. solani species complex and the F. oxysporum species complex, account for roughly 80 percent of all clinical Fusarium infections. Within the F. oxysporum species complex, at least 26 sequence types have been recovered from patients, yet a single lineage, sequence type 33, dominates worldwide and is frequently traced to plumbing systems, including hospital water distribution networks. That a genetically diverse group of fungi should funnel through one dominant clinical lineage is itself a clue: it implies that specific genetic factors carried by that lineage may underpin the ability to infect mammalian hosts.

The spectrum of disease is broad. In immunocompetent individuals, Fusarium infections tend to be superficial, such as nail infections termed onychomycosis, or keratitis, an inflammation of the cornea for which Fusarium is among the most common fungal causes. The fungus can form complex biofilms on contact lenses, and it was responsible for a multistate outbreak of contact lens-associated keratitis in the United States. In vulnerable patients, however, the stakes rise dramatically. People with hematological malignancies, profound neutropenia, or transplants, particularly hematopoietic stem cell transplant recipients, face life-threatening invasive or disseminated fusariosis. Most invasive infections are thought to begin when airborne spores are inhaled into the lungs, germinate, and colonize alveolar tissue, though breaks in the skin from trauma, burns, ulcers, or catheters offer an alternative portal of entry.

Treatment is hampered by the fungus’s built-in drug arsenal. Fusarium genomes carry three copies of CYP51, also known as ERG11, the gene encoding cytochrome P450 sterol 14α-demethylase, the target of azole antifungals. This expanded copy number likely contributes to resistance, and expression studies show that drug exposure upregulates ergosterol biosynthesis genes, membrane biosynthetic pathways, and multiple efflux pumps. An ABC transporter that expels antifungal agents and an NADPH-cytochrome P450 reductase that fuels ergosterol biosynthesis have both been directly shown to increase resistance. The result is intrinsic resistance to echinocandins and several triazoles, which helps explain the high mortality of fusariosis in susceptible patient populations.

The most compelling mechanistic story emerging from genomics concerns genome compartmentalization. F. oxysporum genomes are partitioned into a core genome, containing genes conserved across the species complex and essential for cellular life, and an accessory genome of rapidly evolving, nonessential genes. In plant-pathogenic isolates, host-specific virulence factors are enriched in the accessory genome, often organized into entire accessory chromosomes or subtelomeric regions. These chromosomes are remarkably fluid: they can be laterally transferred between isolates, conferring new virulence, or spontaneously lost, abolishing host-specific pathogenicity. Clinical isolates follow the same pattern. A fusariosis patient isolate carries four accessory chromosomes absent from plant pathogens, and its 5.3-megabase accessory genome encodes 812 putative genes enriched for metal ion and cation transport and responses to extracellular stimuli.

Several genes within that accessory genome stand out. Among them is a homolog of human ceruloplasmin, the major copper-carrying protein of blood, which may help the fungus subvert host nutritional immunity by manipulating copper and iron availability. Even more striking is an expansion of PacC homologs, transcription factors that govern the fungal response to ambient pH. PacC mutants are significantly reduced in virulence in mouse models, and extra copies of the gene could give the fungus an advantage under the alkaline conditions of mammalian tissues. Notably, the paralogous PacC copies are flanked by transposable elements, and experimental evolution studies show that stress induces transposable element activity in these fungi, driving fitness gains. A roughly 140-kilobase region of this accessory genome, including one PacC paralog, is partially conserved in a separate clinical isolate from a keratitis patient, hinting at shared loci that contribute to mammalian pathogenesis.

Phenotypes mirror genotypes. Compared with plant-derived strains, clinical isolates display increased thermotolerance, an obvious adaptation to the mammalian body. In a mouse keratitis model, a clinical keratitis strain caused severe corneal colonization, and both the fusariosis and keratitis strains showed enhanced virulence relative to a plant pathogen in immunocompromised mice, measured by survival, tissue damage, and cytotoxicity to host cells. Experimental work has also confirmed specific virulence factors, most encoded in the core genome. The secreted protein Fpr1, a member of the CAP protein superfamily, is induced when the fungus is grown in human blood and in vivo, and is required for full virulence, possibly promoting tissue invasion or immune evasion. Its induction depends on the MAP kinase Fmk1, and while fmk1 mutants alone retain virulence, a double mutant lacking the G-protein beta subunit fgb1 is significantly attenuated, showing that multiple signaling pathways coordinate mammalian infection.

Regulation and metabolism emerge as recurring themes. The velvet complex, composed of VeA, VelB, VelC, and LaeA, controls development, conidiation, chromatin architecture, and secondary metabolism; VeA and LaeA are required for full virulence on both tomato plants and in immunosuppressed mice, and fusaric acid biosynthesis is abolished in the corresponding mutants. Mutation of FUB1, the polyketide synthase gene essential for fusaric acid production, also reduces virulence, though less severely, implying additional velvet-controlled factors are at play. Prime candidates are the siderophores ferricrocin and triacetylfusarinine C, whose iron-scavenging role is a well-established virulence mechanism in medically important fungi. Deleting HapX, the bZIP transcription factor regulating iron homeostasis, renders the fungus avirulent and unable to colonize kidneys and lungs, while copper handling also matters: mutants of the copper transporter CrpF are paradoxically more virulent, and the metallothionein Mt1 aids survival inside macrophages. Recent work adds sterol metabolism to the list, with clinical isolates showing altered ergosterol homeostasis and increased extracellular ergosterol release that promotes macrophage killing through caspase-1-dependent pyroptosis while suppressing chemokine production and neutrophil recruitment.

Studying these mechanisms has required a growing toolbox of infection models. Systemic fusariosis models use intravenous infection of neutropenic mice, in which the fungus produces its durable chlamydospores within tissues, while pulmonary models based on intranasal or intratracheal inoculation produce rapid, lethal respiratory disease. A contact lens-associated keratitis model showed that hyphae preincubated on a lens can establish corneal infection within 24 hours. Ex vivo systems complement these: live-cell microscopy of macrophages challenged with F. oxysporum germlings revealed engulfment kinetics comparable to those reported for Candida albicans, but with continued hyphal growth lysing the phagocyte from within and even arresting macrophage cytokinesis, producing multinucleated cells linked by fungal hyphae. Free-living amoebae such as Acanthamoeba castellanii offer an ecological angle, since F. solani survives amoebal internalization and co-culture can enhance fungal growth and cytopathic activity, supporting the idea that environmental predators select for traits that later resist mammalian phagocytes. The greater wax moth Galleria mellonella provides a whole-organism intermediate: the same F. oxysporum isolate kills tomato plants, immunosuppressed mice, and Galleria larvae, and mutants attenuated in mice are similarly weakened in larvae, validating the insect as a screen for mammalian virulence determinants and antifungal efficacy.

Considerable questions remain. Researchers do not yet know whether more distantly related clinical sequence types share the accessory genes seen in the dominant lineages, or whether mammalian infectivity has arisen repeatedly through convergent evolution. The community is converging on reference strains, including the fusariosis isolate NRRL 32931, the keratitis strain MRL8996, and the sequence type 33 isolate FoCI-2, but broader genotyping will be needed to capture the diversity of this dynamic pathogen. A unified nomenclature built on core-genome orthologs could link annotations across genome projects, and dissecting the contribution of individual accessory genes is a wide-open frontier. With immunocompromised populations expanding and antifungal options limited, understanding how a plant pathogen became a human threat may prove essential to developing the anti-Fusaria drugs that patients urgently need.

Subject of Research: Virulence determinants of the fungus Fusarium oxysporum in human clinical infections

Article Title: Virulence determinants of Fusarium oxysporum for clinical infections

Article References: Coleman, J. J., Shlezinger, N., & Ma, L.-J. (2026). Virulence determinants of Fusarium oxysporum for clinical infections. PLOS Pathogens, 22(10), e1014630. https://doi.org/10.1371/journal.ppat.1014630

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014630

Keywords: Fusarium oxysporum, fusariosis, fungal pathogenesis, accessory genome, virulence factors, antifungal resistance, fungal keratitis, immunocompromised patients, Galleria mellonella, macrophages, siderophores, PLOS Pathogens