Ketoacidosis alone does not predispose to mucormycosis byLichtheimiain a murine pulmonary infection model

Abstract

Mucormycosis is a rare fungal infection; however, the number of cases increased during the last decades. The main risk factors are immunosuppression and uncontrolled diabetes mellitus. Although Lichtheimia species represent a common cause of mucormycosis in Europe, virulence and pathogenesis of this genus has not been investigated in detail yet. Using murine pulmonary infection models, we found that immunosuppression is essential for establishment of infection. The disease was characterized by necrosis, angioinvasion, thrombosis, and the lethal course of infection was associated with systemic activation of platelets. Furthermore, dissemination to internal organs was frequently observed. While the virulence potential of individual L. corymbifera and L. ramosa isolates differed, pathogenicity of both species was comparable. Although ketoacidosis promoted Rhizopus infection in mice, it did not predispose mice to infection with Lichtheimia in the absence of additional immunosuppression. This might partially explain the dominance of Rhizopus as cause of mucormycosis in countries with high prevalence of ketoacidotic patients.

Recent Advances in the Pathogenesis of Mucormycoses

“…4,5 Although Mucorales share common and unique characteristics, fungi-specific differences in pathogenesis, virulence, and susceptibility to host immunity have been recorded, resulting in the observed differences in epidemiology, site of infection, disease severity, and outcomes. [6][7][8] Mucorales are considered opportunistic pathogens, requiring a breach in the immune system and occurring most frequently in patients with neutropenia, hematopoietic and solid organ transplantation, iron overload, uncontrolled diabetes mellitus (particularly in the presence of diabetic ketoacidosis [DKA]), or malnutrition or as breakthrough infections after prolonged exposure to antifungals. 1,[9][10][11] However, they are also encountered in immunocompetent persons with skin lesions, traumatic injuries, and burn injury.…”

The geographical region of origin determines the phagocytic vulnerability of Lichtheimia strains

“…, highlighted in lilac. Out of these three strains, two were investigated earlier, showing that FSU 9682 was virulent, whereas FSU 10164 was attenuated, based on tests in various infection models (Schwartze et al ., ; Schulze et al ., ). However, our analysis showed that the phagocytic measures of these two strains did not differ significantly.…”

“…The current study is the first attempt to understand the interplay between immune cells and L. ramosa in vitro . We previously tested the virulence of various species of Lichtheimia by using chicken embryo and mouse models as well, and we found that L. ramosa and L. corymbifera were comparable in this regard, which is consistent with our current phagocytosis results (Schwartze et al ., ; Schulze et al ., ).…”

“…Mucormycosis is caused by opportunistic Mucorales fungi that overcome the defensive system of predominantly immunocompromised patients (Ibrahim and Spellberg, ). Several studies characterized the virulence of Mucorales fungi and described their behaviour when confronting various immune cells or partaking in infection model studies (Schwartze et al ., , ; Kraibooj et al ., ; Kaerger et al ., ; Schulze et al ., ). Yet, the interplay of Mucorales fungi, especially Lichtheima species, with the innate immune system, for example, alveolar macrophages, is poorly understood.…”

“…As an example, Farmer's Lung Disease (FLD) is caused by Lichtheimia species that are inhaled from the environment, yet FLD remains a non-infectious disease (Bellanger et al, 2010). The disease typically begins like any invasive aspergillosis with the inhalation of airborne spores, which face alveolar macrophages as the first line of defence by the host's innate immune system in the alveolae of the lung (Levitz et al, 1986;Waldorf et al, 1989;Espinosa and Rivera, 2016;Schulze et al, 2017).…”