Scientists Launch Global Push to Outmaneuver a Fungus That Kills More Than Half Its Victims

Mucormycosis, a rare but devastating fungal infection that kills more than half of the people it strikes, is the target of a newly highlighted multidisciplinary research program described in PLOS Pathogens. The article, written by Sebastian Wurster, Adam G. Stewart, Dimitrios P. Kontoyiannis and colleagues on behalf of the MUCOR-ADVANCE consortium, reviews the major milestones in mucormycosis research during the 2020s and introduces the NIAID-funded program project that aims to translate those discoveries into better outcomes for patients.

Mucormycosis is caused by Mucorales molds and primarily affects immunocompromised individuals, including people with diabetes, patients with cancer, and recipients of solid organ or hematopoietic cell transplants. It can also be a devastating complication of severe trauma or burns, particularly in the context of natural disasters and war-related injuries. The infection is emerging worldwide and is hyper-endemic in South Asia. It drew global attention when more than 50,000 cases of Covid-19-associated mucormycosis strained already overburdened hospital systems in India. The most common manifestations are invasive sino-orbital infection in diabetic patients, pulmonary infection in patients with hematologic cancer, and cutaneous disease, usually seen in patients with trauma.

Regardless of the initial manifestation, mucormycosis is highly angioinvasive and can disseminate rapidly. The average treatment cost per patient in the United States exceeds six figures. Despite aggressive antifungal therapy with liposomal amphotericin B and/or Mucorales-active triazoles, often combined with surgical debridement, mortality rates exceed 50 percent and can approach 100 percent in patients with disseminated disease, persistent neutropenia, or brain involvement. The severity and global burden of the disease have earned it a place on both the World Health Organization’s Fungal Priority Pathogens List and the U.S. National Institute of Allergy and Infectious Diseases’ Biodefense and Emerging Infectious Diseases List, underscoring what the authors describe as an urgent need for breakthroughs in translational research.

Key challenges in managing mucormycosis include delayed diagnosis, the lack of prognostic risk stratification biomarkers, and limited therapeutic options, compounded by limited knowledge of Mucorales pathogenicity and host defense. Because early treatment markedly improves therapeutic outcomes even in highly immunosuppressed hosts, the authors argue that culture-independent diagnostic modalities for early detection would enable precision surveillance strategies and treatment of localized disease in high-risk patients. Such diagnostics would also allow assessment of disease burden and identification of early treatment failure. Prognostic models informed by clinical risk factors, routine clinical parameters, surrogates of fungal burden, and innovative immune biomarkers could facilitate individualized, risk-adapted treatment strategies. Because current antifungal drug treatments often fail, future combination therapies targeting elimination of the pathogen, neutralization of toxins, and boosting of host defenses hold promise, informed by translational research on fungal virulence, host defenses, and metabolic factors.

Diagnosis remains a major bottleneck. Obstacles include the inability to obtain a suitable microbiological specimen, delayed results and insensitivity of conventional culture-based methods, and poor specificity of histological examination. Molecular-based assays are well positioned to address these challenges. Given the high angioinvasion and early dissemination of Mucorales, molecular detection of circulating Mucorales DNA may be particularly promising. A recently published meta-analysis reported a pooled sensitivity of 97.5 percent and a pooled specificity of 95.8 percent for polymerase chain reaction testing on bronchoalveolar lavage fluid, although high methodological heterogeneity, including differences in DNA extraction, gene targets, and PCR platforms, results in variable diagnostic yield. Quantitative PCR assays have also been developed that may help identify severe, high-burden disease and monitor response to therapy. PCR-based approaches have shown promise in enabling early preemptive therapy, positively affecting outcome in some patient cohorts at high risk, such as burn patients.

Detection of cell-free fungal DNA in plasma offers another potential fast and non-invasive diagnostic route, with one study citing a sensitivity of 85.1 percent and a specificity of 92.9 percent; the diagnostic yield increased greatly when immunosuppression and disseminated disease were present. To improve accessibility and turnaround time, point-of-care platforms are being developed. These include loop-mediated isothermal amplification, a cost-effective assay that does not require sophisticated equipment and showed promising performance on both clinical and preclinical specimens. In addition, a lateral-flow device detecting an extracellular polysaccharide antigen specific to Mucorales fungi has recently been developed; early experience in archived biospecimens suggests sensitivity and specificity around 75 percent, indicating potential as an affordable point-of-care test for rapid diagnosis.

Recent discoveries have also identified specific molecular events that allow Mucorales to bypass human defenses, opening new avenues for precision diagnostics and targeted immunotherapies. The glucose-regulated protein 78 kDa receptor on endothelial and nasal epithelial cells and the integrin/epidermal growth factor receptor activation cascade on lung epithelial cells were identified as primary entryways for Mucorales. The fungal spore coat proteins known as CotH bind to GRP78 and integrins, triggering host cell endocytosis and subsequent damage. The CotH3/GRP78 interaction is significantly upregulated in states of hyperglycemia and ketoacidosis, providing a molecular explanation for the extreme vulnerability of diabetic patients to mucormycosis. Translating this discovery toward therapy, a murine monoclonal antibody and its humanized version, VX-01, targeting a conserved epitope among CotH proteins universally present in Mucorales, was shown to protect against mucormycosis in preclinical models by blocking Mucorales-mediated tissue invasion. Targeting angioinvasion is likely to enhance antifungal drug delivery to the site of infection and may explain the in vivo synergy seen with VX-01 and antifungal drugs. Beyond passive immunization, these surface proteins may also represent attractive candidates for recombinant vaccines.

The discovery of mucoricin, a ricin-like toxin, has revealed the mechanism behind the rapid vascular permeability and extensive tissue necrosis that often renders antifungal drugs unable to reach the site of infection. Mucoricin can also bind to the Mucorales cell wall and create a molecular trap that induces neutrophil apoptosis and disrupts effective responses by neutrophil clusters, a process known as neutrophil swarming, leading to invasive infection. Preclinical studies suggest that anti-toxin therapy may slow tissue necrosis, preserve the microvasculature, and improve antifungal drug delivery, effects that could also enhance protective immune responses. On the host side, a recent landmark study identified albumin as a master regulator of a novel metabolic host defense mechanism against Mucorales that prevents invasive disease by modulating fungal pathogenicity. Albumin elicits selective antifungal activity by shuttling, solubilizing, protecting, and releasing physiological free fatty acids, which are taken up by fungal cells and inhibit protein synthesis and virulence. Preexposure of germinating spores to albumin enhances neutrophil swarming and prevents invasive disease by inhibiting mucoricin expression. In patients with very low albumin levels, oxidation of albumin-bound free fatty acids results in loss of their antifungal properties, allowing unrestricted Mucorales growth. Consequently, hypoalbuminemia emerged as an independent predictor of mortality in mucormycosis patients across three global patient cohorts, suggesting that immuno-metabolic interventions such as restoration of albumin levels in high-risk patients could enhance host resilience.

Hypoxia-inducible factor 1-alpha was identified as another centerpiece of the host-pathogen interface, playing two opposing roles in airway epithelial cells during Mucorales infection: while promoting fungal invasion into host cells, infection-induced activation of HIF1α also contributes to proinflammatory responses. Blockade of HIF1α may therefore attenuate both fungal invasion of airway epithelia and exuberant inflammation, although more preclinical evidence is needed in diverse host backgrounds, since HIF1α was required for protection in other pulmonary mold infection models. Meanwhile, immunostimulatory agents are being evaluated to help immunocompromised hosts clear the infection. Cytokines such as IFN-γ and hematopoietic growth factors such as G-CSF and GM-CSF are already used as salvage immunotherapy in patients with severe fungal infections, and recent preclinical research showed that prophylactic GM-CSF may prevent mucoricin-induced apoptotic death of neutrophils, enhance neutrophil swarming, and thereby protect against invasive mucormycosis. Both preclinical and clinical data indicate that immuno-inhibitory checkpoint pathways are upregulated rapidly after infection with Mucorales and contribute to a dysfunctional immune environment with induction of exhaustion markers, suppression of T-cell signaling, and impairment of innate immune effector responses. Blocking these pathways with checkpoint inhibitors, a proven type of cancer immunotherapy, can enhance host defense and promote fungal elimination in experimental mucormycosis, and despite likely publication bias, several case reports support salvage use in patients whose mucormycosis was irresponsive to antifungal therapy. Preclinical data suggest that early combination therapy with antifungals and immunomodulators may be most effective in intercepting infection-induced immune dysregulation.

MUCOR-ADVANCE, described in the article as a multidisciplinary research unit dedicated to transforming the bench-to-bedside pipeline for mucormycosis management, is funded through NIAID grant P01AI186818 and includes synergistic research projects focused on fungal biology and host biology and regenerative medicine at The Lundquist Institute, and translational immunobiology at MD Anderson Cancer Center. A Genomics/Transcriptomics Core at the University of Maryland provides advanced sequencing and bioinformatics capabilities for data-driven discoveries and biomarker development, while a Clinical Core at MD Anderson prospectively collects patient data, Mucorales isolates, and diverse host-derived biospecimens from mucormycosis patients and relevant control groups, including patients with pulmonary aspergillosis, bacterial pneumonia, and high-risk patients with no infections. In addition to preclinical validation in mouse models mirroring various risk factors for mucormycosis, including diabetic ketoacidosis, glucocorticosteroid immunosuppression, neutropenia, and active leukemia, such biorepositories are intended to inform, prioritize, and cross-validate diagnostic, therapeutic, and risk stratification strategies. In concert with the broader mucormycosis research community and scientific societies such as the recently founded International Immunotherapy Society for Fungal Diseases, the consortium ultimately aims to inch closer to early and individualized precision management of mucormycosis through coordinated advances in discovery science, risk stratification, diagnosis, prognostic biomarkers, pathogen- and host-targeted therapeutics, and regenerative medicine. Beyond mucormycosis, the authors suggest that this multidisciplinary approach may serve as a blueprint for future studies of other rare mycotic diseases and opportunistic infections.

Subject of Research: Mucormycosis research and the NIAID-funded MUCOR-ADVANCE consortium

Article Title: MUCOR-ADVANCE: Uniting multidisciplinary science to defeat a deadly fungus

Article References: Wurster, S., Stewart, A. G., Gu, Y., Youssef, E. G., John, T. M., Uppuluri, P., Chamilos, G., Filler, S., Bruno, V., Ibrahim, A. S., Kontoyiannis, D. P., & on behalf of the MUCOR-ADVANCE consortium (2026). MUCOR-ADVANCE: Uniting multidisciplinary science to defeat a deadly fungus. PLOS Pathogens, 22(10), e1014736. https://doi.org/10.1371/journal.ppat.1014736

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014736

Keywords: mucormycosis, Mucorales, fungal infection, MUCOR-ADVANCE, NIAID, diagnostics, PCR, VX-01, mucoricin, albumin, immunotherapy, PLOS Pathogens