Necrotizing Mucormycosis of Wounds Following Combat Injuries, Natural Disasters, Burns, and Other Trauma

Walsh, Thomas J.; Hospenthal, Duane R.; Petraitis, Vidmantas; Kontoyiannis, Dimitrios P.

doi:10.3390/jof5030057

Cited by 47 publications

(68 citation statements)

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“…As the causative agent of the meningitis outbreak, E. rostratum was identified 1 month after the first meningitis case was reported, when the CDC announced that E. rostratum was recovered from unopened vials of steroid injections [42]. Similar problems occurred with necrotizing mucormycosis, a devastating complication of wounds caused by Apophysomyces sp., Saksenaea sp., and Lichtheimia [43]. Late laboratory diagnosis of cases of necrotizing mucormycosis caused by Apophysomyces trapeziformis resulted in 5 deaths in Missouri in 2011 [44].…”

Section: The Need For Improved Diagnosis Of Fungal Infectionsmentioning

confidence: 99%

Fungal diseases as neglected pathogens: A wake-up call to public health officials

2020

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Fungal diseases: A real threat to public healthHuman fungal diseases differ fundamentally from other infections in diverse ways. As eukaryotic pathogens, fungi share many similarities with their host cells, which impairs the development of antifungal compounds. Fungal tropism is highly variable, as pathogens infect a wide range of cell types. A single fungal pathogen can infect multiple tissues in the same patient (depending on the host's immunological status) and can undergo morphogenic shifts during infection. Fungi are still underappreciated as major pathogens by both the public and public health officials. Diseases caused by protozoa, bacteria, and viruses have been recognized as important public health issues for centuries. For instance, syphilis, influenza, and Chagas disease have been documented for over 100 years [1], while invasive mycoses were only widely acknowledged as medically important pathogens in the 1980s [2]. Viral diseases of major population impact (such as smallpox, influenza and-more recentlydengue, Zika, Chikungunya, and coronavirus) have affected millions of people with significant effects on human health in developed, developing, and less developed nations [3,4]. These conditions have boosted the generation of knowledge, which has led to the eradication of smallpox [5], the wide availability of effective vaccines [6], and the development of diagnostic and preventive tools against influenza [7] and, more recently, Zika [8]. Bacterial diseases have profoundly impacted human health at different times in history, and although the phenomenon of antimicrobial resistance is a matter of extreme concern, there are several effective tools for the prevention, treatment, and diagnosis of bacterial infections [9]. Human parasitosis have been recognized to negatively impact public health in different parts of the globe for decades, which has stimulated the ongoing development of vaccines, new drugs, and diagnostic tests for malaria, sleeping sickness, leishmaniasis, filariasis, and Chagas disease [10]. Fungal infections, however, are part of a different scenario. These diseases, for most of recorded history as well as the majority of the last century, have been rare or had a low impact on human health.The increase in the number of immunocompromised patients, some of whom are highly susceptible to fungal infections, has totally changed this picture. The invasive diseases caused by fungi, the so-called systemic mycoses, profoundly impact human health. Moreover, the Global Action Fund for Fungal Infections (GAFFI) also highlights the devastating impact of focal fungal diseases in individuals who often have intact immune systems. GAFFI estimates that more than 1 million eyes go blind each year due to fungal keratitis [11]. Nearly one billion people have skin mycoses, which makes this disease only slightly less common on the planet than headaches and dental caries. Fungal spores contribute to significant reactive airway diseases in over 10 million individuals. In total, the GAFFI estimates that over 300 mi...

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Section: The Need For Improved Diagnosis Of Fungal Infectionsmentioning

confidence: 99%

Fungal diseases as neglected pathogens: A wake-up call to public health officials

2020

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“…Interestingly, the increase in virulence after TSC was particularly pronounced in A. trapeziformis , with a 26 % 7-day survival rate of infected flies compared with 64 % for flies infected with static spores (p < 0.001, Fig. 1A ), concordant with the dominance of A. trapeziformis after high-energy trauma (1, 10, 27). However, as it is challenging to obtain large quantities of Apophysomyces spores, we used R. arrhizus as a model organism for further investigations of TSC-induced pathogenicity.…”

Section: Resultsmentioning

confidence: 58%

“…While this was a pathogen-centered study, future investigations would also need to characterize the impact of TSC on fungal interactions with the diverse innate and adaptive immune cell repertoire of mammalian hosts, the local inflammatory environment in infected myocutaneous tissue, and biochemical parameters of wound healing. In addition, comparative studies in immunocompetent and immunosuppressed animals would be needed to account for trauma-induced immune paralysis (1, 52–53).…”

Section: Discussionmentioning

confidence: 99%

“…Necrotizing myocutaneous invasive mold infections following severe trauma represent a life-threatening disease with high morbidity and mortality (1–4). A variety of molds have been implicated as causative agents, with fungi belonging to the order Mucorales predominating as the most common and devastating cause (3–4).…”

Section: Introductionmentioning

confidence: 99%

“…These emerging fungal pathogens affect an expanding population of hosts and are characterized by innate resistance to many antifungals, broad geographic and environmental distribution, and high virulence (5–8). While immunocompromised patients are at highest risk for the development of mucormycosis (5–8), immunocompetent individuals are prone to necrotizing myocutaneous mucormycosis (NMM) when incurring penetrating trauma (2, 9–12), combat-related wounds (13–15), or burn injuries (1).…”

Section: Introductionmentioning

confidence: 99%

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Tornadic shear stress induces a transient, calcineurin-dependent hyper-virulent phenotype in Mucorales molds

Wurster

Tatara

Albert

et al. 2020

Preprint

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6Trauma-related necrotizing myocutaneous mucormycosis (NMM) has a high morbidity and mortality in 2 7 victims of combat-related injuries, geo-meteorological disasters, and severe burns. Inspired by the obser-2 8 vation that several recent clusters of NMM have been associated with extreme mechanical forces (e.g. 2 9during tornados), we studied the impact of mechanical stress on Mucoralean biology and virulence in a 3 0 Drosophila melanogaster infection model. In contrast to other experimental procedures to exert mechani-3 1 cal stress, tornadic shear challenge (TSC) by magnetic stirring induced a hyper-virulent phenotype in sev-3 2 eral clinically relevant Mucorales species but not in Aspergillus or Fusarium. Whereas fungal growth 3 3 rates, morphogenesis, and susceptibility to noxious environments or phagocytes were not altered by TSC, 3 4 soluble factors released in the supernatant of shear-challenged R. arrhizus spores rendered static spores 3 5 hyper-virulent. Consistent with a rapid decay of TSC-induced hyper-virulence, minimal transcriptional 3 6 changes were revealed by comparative RNA sequencing analysis of static and shear-challenged Rhizopus 3 7 arrhizus. However, inhibition of the calcineurin/heat shock protein 90 (hsp90) stress response circuitry by 3 8 cyclosporine A (CsA) and tanespimycin abrogated the increased pathogenicity of R. arrhizus spores fol-3 9 lowing TSC. Similarly, calcineurin loss-of-function mutants of Mucor circinelloides displayed no in-4 0 creased virulence capacity in flies after undergoing TSC. Collectively, these results establish that TSC 4 1 induces hyper-virulence specifically in Mucorales and point out the calcineurin/hsp90 pathway as a key 4 2 orchestrator of this phenotype. Our findings invite future studies of topical calcineurin inhibitor treatment 4 3 of wounds as an adjunct mitigation strategy for NMM following high-energy trauma. 4 4 3 Significance 4 5 Given the limited efficacy of current medical treatments in trauma-related necrotizing mucormycosis, 4 6there is a dire need to better understand the Mucoralean pathophysiology in order to develop novel strate-4 7 gies to counteract fungal tissue invasion following severe trauma. Here, we describe that tornadic shear 4 8 stress challenge transiently induces a hyper-virulent phenotype in various pathogenic Mucorales species 4 9

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Larone's Medically Important Fungi

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Necrotizing Mucormycosis of Wounds Following Combat Injuries, Natural Disasters, Burns, and Other Trauma

Cited by 47 publications

References 50 publications

Fungal diseases as neglected pathogens: A wake-up call to public health officials

Fungal diseases as neglected pathogens: A wake-up call to public health officials

Tornadic shear stress induces a transient, calcineurin-dependent hyper-virulent phenotype in Mucorales molds

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