Complement and fungal pathogens: an update

Abstract

Fungal infections are a serious complication in immunocompromised patients such as human immunodeficiency virus-infected individuals, patients with organ transplantations or with haematological neoplasia. The lethality of opportunistic fungal infection is high despite a growing arsenal of antimycotic drugs, implying the urgent need for supportive immunological therapies to strengthen the current inefficient antimicrobial defences of the immunocompromised host. Therefore, increasing effort has been directed to investigating the interplay between fungi and the host immunity and thus to find starting points for additional therapeutic approaches. In this article, we review the actual state of the art concerning the role of complement in the pathogenesis of fungal infections. Important aspects include the activation of the complement system by the fungal pathogen, the efficiency of the complement-associated antimicrobial functions and the arsenal of immune evasion strategies applied by the fungi. The twin functions of complement as an interactive player of the innate immunity and at the same time as a modulator of the adaptive immunity make this defence weapon a particularly interesting therapeutic candidate to mobilise a more effective immune response and to strengthen in one fell swoop a broad spectrum of different immune reactions. However, we also mention the 'Yin-Yang' nature of the complement system in fungal infections, as growing evidence assigns to complement a contributory part in the pathogenesis of fungus-induced allergic manifestations.

Aspergillus Nigerperitonitis in a peritoneal dialysis patient treated with eculizumab

“…9 Interestingly, invasive Aspergillosis has been reported in murine models with the same C5 and C5a defects. 6,8 Therefore, we suggest that the A. niger PD peritonitis in our patient is likely secondary to the altered host complement system as a result of chronic Eculizumab therapy. While the manufacturer has emphasized the importance of vaccination against Neisseria species, it is possible that the impairment of the complement cascade induced by this drug leads to susceptibility to infection by other organisms.…”

“…Melanin has been identified as the surface molecule responsible for the activation of the alternative pathway in A. Niger infection. 6,8 Fungi, owing to their thick cell wall, are resistant to the membrane attack complex (MAC) of the complement cascade. Opsonization with C3-derived fragments plays a major role for efficient phagocytosis, induction of oxidative burst, and destruction of fungi by monocytes.…”

“…Simultaneous activation of the innate immunity occurs through antigen presentation, costimulation of B lymphocytes with subsequent antigen memory retention by the immune system through activated complement products and their mediators of inflammation. 6,8 Dysregulation of the complement pathway is associated with various forms of glomerulonephritis and atypical hemolytic uremic syndromes (aHUS). Eculizumab is a monoclonal antibody against human complement component 5 (C5) and blocks cleavage of C5, thus inhibiting formation of C5a, C5b-9, and the membrane attack complex (MAC).…”

“…The high mortality has been attributed to the delayed diagnosis and the subsequent delay in surgical removal of the catheter largely due to a low index of suspicion from nonspecific symptoms or from drainage problems as a result of an Aspergillus mass in the catheter lumen. 6,7 The complement system comprises a group of proteins that, when activated, brings in a synergy between innate and adaptive immune systems providing a robust defense against microbes. This is ensured through opsonization, local inflammation and chemotaxis, cell lysis, and subsequent clearance of immune complexes all in a finely regulated way.…”

“…3 Risk factors for Aspergillus peritonitis include prolonged antibiotic therapy, corticosteroid therapy, recent bacterial peritonitis, recent hospitalization, and lupus. [3][4][5] The conidia of pathogenic Aspergillus species are extremely small (2-5 mm) 6 and entry into the peritoneal cavity has been reported to occur through the catheter intraluminally, periluminally, and rarely by the vaginal route. 5 The PD catheter is usually colonized, so catheter removal is necessary in addition to antifungal therapy.…”