Mucormycosis and COVID-19-Associated Mucormycosis: Insights of a Deadly but Neglected Mycosis

Abstract

The ongoing COVID-19 pandemic has quickly become a health threat worldwide, with high mortality and morbidity among patients with comorbidities. This viral infection promotes the perfect setting in patients for the development of opportunistic infections, such as those caused by fungi. Mucormycosis, a rare but deadly fungal infection, has recently increased its incidence, especially in endemic areas, since the onset of the pandemic. COVID-19-associated mucormycosis is an important complication of the pandemic because it is a mycosis hard to diagnose and treat, causing concern among COVID-19-infected patients and even in the already recovered population. The risk factors for the development of mucormycosis in these patients are related to the damage caused by the SARS-CoV-2 itself, the patient's overstimulated immune response, and the therapy used to treat COVID-19, causing alterations such as hyperglycemia, acidosis, endothelial and lung damage, and immunosuppression. In this review, the molecular aspects of mucormycosis and the main risk factors for the development of COVID-19-associated mucormycosis are explained to understand this virus-fungi-host interaction and highlight the importance of this neglected mycosis.

Keywords: ACE2; CAM; COVID-19; GRP-78; SARS-CoV-2; corticosteroids; cytokine storm; hyperglycemia; immunosuppression; iron overload; mucormycosis.

Figure 1

Schematic diagram representing the environment promoted by COVID-19 that predisposes the development of mucormycosis. The use of corticosteroids for COVID treatment and the dysregulation of ACE2 caused by SARS-CoV-2 create a hyperglycemic status in the patient, which causes overexpression of GRP-78, acidosis, and immunosuppression, this last also promoted by corticosteroid use, acidosis, and the COVID-19 itself. GRP-78 overexpression and acidosis are closely related since the presence of one promotes the development of the other, both causing iron overload; this last is also promoted by the cytokine storm observed during COVID-19. ACE2 dysregulation is related to the development of endothelial damage, thrombosis, angiogenesis, and altered pulmonary function, which can also be caused by the SARS-CoV-2 replication and the cytokine storm. Iron overload, GRP-78 overexpression, immunosuppression, endothelial damage, thrombosis, angiogenesis, and altered pulmonary function are directly related to mucormycosis development during COVID-19. Double black arrow: a risk factor for COVID-19 and mucormycosis infection. Dotted black lines: alterations directly caused by SARS-CoV-2 and COVID-19. Dotted red, blue, green, and purple lines: alterations caused by COVID-19. Purple, green, and brown lines: factors directly related to the development of mucormycosis.