Mucormycosis pathogenesis: Beyond Rhizopus

KEYWORDS:

• mucormycosis
• murine
• Lictheimia
• pathogenesis
• Rhizopus

This article refers to:

Ketoacidosis alone does not predispose to mucormycosis by Lichtheimia in a murine pulmonary infection model

In the last two decades, extensive research has greatly expanded our knowledge of the pathogenesis of the deadly mold infection, mucormycosis.¹ Clinically, mucormycosis occurs in patients who have diabetes mellitus, defects in phagocytic function (e.g., neutropenia or glucocorticoid treatment), and/or elevated levels of free iron, which enhances fungal growth.

The original observation regarding the role of iron in pathogenesis of mucormycosis derived from patients with end-stage renal failure in the pre-erythropoeitin era. Such patients were regularly transfused due to the anemia of renal failure, and hence developed iron overload. Treatment of such patients with deferoxamine to lower their iron levels resulted in a high risk of rapidly fatal, disseminated mucormycosis.² It was then discovered that while deferoxamine is an iron chelator for the human host, it actually serves as a siderophore for fungi, directly delivering iron to the Mucorales.² Subsequently the availability of host iron has been found to be crucial to the ability of the Mucorales to cause infection.^3-5 Indeed, in the only randomized, controlled clinical trial ever conducted for the treatment of mucormycosis, higher baseline blood iron levels were predictive of higher risk of mortality.^6,7

Subsequent research into why diabetes mellitus predisposes to mucormycosis initially focused on the role of diabetic ketoacidosis (DKA).² Although less than half of diabetic patients who present with mucormycosis are in DKA,⁸ diabetic patients in DKA are at higher risk for having mucormycosis than those not in DKA. Pathogenesis research found that acidic conditions in the blood cause dissociation of iron from sequestering proteins, delivering free iron to the fungus.^1,2 Nevertheless, even absent acidosis, hyperglycemia increases the risk of mucormycosis by at least 4 likely mechanisms; 1) hyperglycation of iron-sequestering proteins, which disrupts the proteins’ ability to sequester iron, resulting in increased free iron levels in blood even without acidosis; 2) upregulation of a mammalian epithelial receptor (GRP78) that binds to Mucorales, enabling tissue penetration; 3) upregulation of a fungal protein, CotH, which binds to the mammalian receptor to initiate invasion into host tissue; and 4) inducing poorly characterized defects in phagocytic function.^1,2,9

Virtually all of the pathogenesis research conducted to date, which has dissected the above causal chain for mucormycosis, was conducted with fungi of the family Mucoraceae, genus Rhizopus, which is the most common genus to cause clinical infection. However, mucormycosis can be caused by fungi of many genera in the subphylum Mucormycotina, order Mucorales. The order Mucorales consists of at least 6 families, and while mucormycosis is most commonly caused by molds in the family Mucoraceae, clinical disease has been described to occur from fungi of each of the other families (e.g., Lichtheimaceae, Cunninghamellacea, Saksenaceae, Mortierellacea, etc).^10,11 Thus far, we have presumed similar pathogenesis of infection caused by non-Rhizopus species. However, evidence is preferred to presumption, and in this context, the findings by Schulze et al. are of considerable interest.¹²

They now report that fungi of the genus Lichtheimia, family Lichtheimiaceae, have similarities, but also some differences, compared with Rhizopus in the mouse model of infection. Not surprisingly, corticosteroid treatment was found to enhance susceptibility of mice to lung infections caused by L. corymbifera or L. ramosus. Corticosteroid-treated, infected mice died principally of necrotizing pneumonia, similar to clinical disease, and with some evidence of dissemination to internal organs. However, mice that were in DKA were not susceptible to lung infection caused by Lichtheimia species, in contrast to previous publications where DKA has been found to predispose to infection by Rhizopus spp.^1,2

Multiple strains of Lichtheimia were tested in the intranasal infection model of pneumonia, and not surprisingly, variations in virulence were found across the strains. Although not directly compared, the virulence of Lichtheimia appeared to be less than Rhizopus in that even with corticosteroid-treatment, fatal infection was not uniform, and a high inoculum of spores was necessary to cause fatal infection. Diminished virulence may in part explain why clinical infections are less commonly caused by Lichtheimia spp than Rhizopus spp Indeed survival of patients infected with Lichtheimia spp has been reported to be higher than for patients infected with Rhizopus.¹⁰ However, the nature of any putative virulence differences remain unclear. For example, whether Lichtheimia spp are less sensitive to free iron levels than Rhizopus spp, or more prone to immune clearance despite mild immune suppression, is unknown, and merits additional investigation.

Some caution is warranted in extrapolating the results in the DKA mouse model of lung mucormycosis to clinical disease. For example, despite the lack of lethality of Lichtheimia in the DKA lung infection model in mice, patients in DKA do develop infections caused by Lichtheimia. Thus DKA is still be a risk factor for clinical infection caused by Lichtheimia. Furthermore, patients in DKA almost always develop the rhino-orbital-cerebral form of mucormycosis, and rarely develop lung infection.² Thus another potential explanation for the lack of lethal outcome of infection by Lichtheimia in DKA mice is that the DKA simply doesn't predispose to lung infection, and that a model specific to rhino-orbital-cerebral infection might yield different results.

We are still learning about the pathogenesis of mucormycosis. The marked improvements in outcome of these infections seen in recent years largely has been due to the development of more effective antifungal strategies, as well as a focus on earlier diagnosis.^13,14 Most of what we know of pathogenesis stems from work focusing on Rhizopus spp Hopefully continued expansion of pathogenesis research, including infection caused by other species, including those outside the family Mucoraceae, will enable future therapeutic interventions designed to interrupt pathogenesis to further improve outcomes.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.