Platelets as Immune Cells in Infectious Diseases

Cornelia Speth; Jürgen Löffler; Sven Krappmann; Cornelia Lass-Flörl; Günter Rambach

Disclosures

Future Microbiol. 2013;8(11):1431-1451. 

In This Article

Platelets in Fungal Infections

With over 300 million people estimated to be infected by fungi worldwide, the socioeconomic burden caused by such pathogens has gained increasing attention and relevance. Fungal infections have become one of the major complications in distinct clinical settings over recent decades. Immunosuppressed patients are at particular risk of contracting fungus-associated diseases, a fact that demonstrates the opportunistic nature of most fungal infections. The pathogenic species Aspergillus, Cryptococcus and Pneumocystis were recognized to be major threats for the immunocompromised patients. The main entry site for these fungal pathogens are the lungs, and pulmonary infections may eventually develop into systemic, life-threatening diseases. Furthermore, infections with Candida species, which usually reside as commensals on mucosal compartments, may pose a serious problem for severely ill patients and cause bloodstream infections and septic candidemia.

Intravascular disease stages during fungal infections allow the interaction of platelets with the pathogen, and several studies have revealed the relevance of platelets in the outcome of fungal infections. In neutropenic patients the baseline platelet count is one predictive parameter for invasive aspergillosis[156] and thrombocytopenia in liver transplant recipients increases the risk for fungal infections.[157] Elevated numbers of platelet-derived microparticles, as found during severe sepsis caused by C. albicans,[158] further underline the relevance of these blood cells in fighting fungal infections. Recent insights in the host–pathogen interplay during fungal infections have revealed diverse relations between platelets and infectious fungal propagules.

Pathogenic Fungi Affect Platelet Activity, Aggregation & Functionality

Early studies focused on direct cellular interactions of Candida yeast cells or germ tubes with platelet cells, such as the adherence capacities of Candida spp. to fibrin–platelet matrices[159–161] or the positive influence of aggregated platelets on Candida cells adherence to endothelium.[162] Platelets are able to attach rapidly to fungal elements, cells or germlings of Candida species. For C. albicans, this binding of platelet cells is cation-dependent as demonstrated by reversion of the attachment by chelating agents.[163] Adhesion of platelets to Candida is accompanied by morphological changes of the platelets that subsequently flatten on the fungal cells.[164] Interestingly, whereas most Candida species exert stimulatory effects on platelets, C. albicans itself appears unable to promote their aggregation;[165] instead, an inhibition of ADP- and collagen-induced aggregation by C. albicans cells became evident in several studies, implying a putative influence on the second wave of aggregation.[166,167]

Furthermore, a direct and contact-dependent activation of platelets could be demonstrated for A. fumigatus. When platelets were exposed to resting or swollen conidia or hyphae, the exposition of CD62P on the platelet surface increased.[168] For other activation markers, such as CD63, RANTES or CD40L, differences between fungal morphotypes became apparent. Similarly, exposition of platelets to mucormycetes (formerly called zygomycetes) was demonstrated to trigger platelet stimulation.[169]

Such effects on platelets and their functions can be mediated by various fungal elements, including characteristic cell wall components and metabolic products. Cell wall fractions of C. albicans, such as a water soluble polysaccharide extract of C. albicans mainly consisting of β-glucan and mannan, induced aggregation of human platelets in a concentration-dependent manner.[170,171] In addition, antigens of A. fumigatus have been demonstrated to influence platelet aggregation in vitro, depending on the presence and deposition of complement factors.[172]

Beside cell wall components, fungi secrete a variety of soluble compounds that might also affect platelet activity. These secreted factors include proteases, via which fungi exert their osmotrophic nutrition style and degrade extracellular polymeric substrates, as well as complex secondary metabolites. Supernatants of A. fumigatus cultures were demonstrated to contain platelet-activating substances.[173] The culture filtrates induced the release of α- and dense granules as assessed by CD62P and CD63 exposure, respectively, in a time- or dose-dependent manner; further effects were phosphatidylserine exposure and budding of microparticles. Further analyses demonstrated that an A. fumigatus-derived serine protease and the mycotoxin gliotoxin contribute to this effect. In a further report, an inhibitory effect of gliotoxin on platelet aggregation had been described to act by impairment of fibrinogen binding in a dose-dependent manner.[166]

Platelets Affect Fungal Pathogens

In the interplay between fungal and host cells, fungi not only act on platelet function, but are also influenced by platelets. Three mechanisms were reported regarding how platelets can contribute to antifungal defense:

  • A direct antimycotic activity, mainly described for platelet-derived antimicrobial peptides;

  • An enhancement of effectiveness of antimycotic drugs by platelet-derived antimicrobial peptides;

  • Stimulation of the antifungal response of other immune cells.

Platelets that are exposed to aspergilli, Aspergillus-derived soluble factors or zygomycetes are able to delay germination and impair hyphal elongation.[168,169,173–175] Furthermore, platelets trigger a downmodulation of the A. fumigatusfks gene, which encodes 1,3-β-glucan synthase, a central enzyme of cell wall synthesis.[176]

These results imply a direct action of platelets on fungal cells, and intense studies confirmed the release of antimicrobial factors with antifungal potency. Some of the thrombocidins that are released from α-granules after stimulation had fungicidal activity against Candida species, Cryptococcus neoformans, A. fumigatus or mucormycetes.[177–179] It has been demonstrated in an experimental endocarditis model that this microbicidal action of platelets substantially supports the control of fungal infections.[180] When a C. albicans strain with resistance against the antimicrobial peptide tPMP was used to infect rabbits, higher fungal load and hematogenous dissemination to the spleen were observed. The CXC chemokine derivative TC-1 is another antimicrobial peptide stored in the α-granules of platelets and displays fungicidal activity against C. neoformans.[51] Serotonin does not belong to the classical antimicrobial peptides, but is also released after platelet activation and harbors some antifungal properties against the Aspergillus species A. fumigatus and A. terreus.[181] Being stored in dense granules of the platelets, serotonin is able to impair or attenuate hyphal growth and to affect fungal cell membrane integrity.

The mode of action of platelet-derived fungicidal proteins is unclear, but may be based on the collapse of cell wall integrity. Accordingly, enhanced effectiveness of antimycotic substances in the presence of platelets or thrombocidins has been observed and represents a second principle of platelet-associated antimicrobial effectiveness. Restricted adherence properties of C. albicans cells that had been treated with the ergosterol biosynthesis inhibitor fluconazole were augmented by incubation with the platelet microbicidal protein tPMP.[182,183] In addition, a potentially synergistic action of human platelets with antimycotics against several Aspergillus species has also been described.[176,184,185] Platelet-derived serotonin has also been reported to not only directly inhibit the elongation of fungal hyphae, but to also enhance the activity of amphotericin B against A. fumigatus.[186]

As a third mechanism, platelets can support and stimulate the antifungal capacity of other immune cells, mainly phagocytes. Activated platelets form aggregates with the pathogens, thus trapping and fixing the fungal elements and supporting elimination of the pathogen. Interaction of platelets with immune effector cells might also shape antifungal responses. Neutrophil degranulation or formation of NETs are influenced by platelets,[32,71,187] and both reactions are instrumental for the elimination of fungal pathogens.[188–191]

Interestingly, the predominantly pathogenic species C. albicans, by contrast to other Candida species, appears unable to promote aggregation of platelets. Instead, direct inhibition of C. albicans cells on platelet aggregation became evident in several studies. It might be postulated that C. albicans has developed mechanisms to evade the platelet-associated antimicrobial effect and that this platelet evasion correlates with pathogenicity in humans.

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