Platelets are critical for survival and tissue integrity during murine pulmonary Aspergillus fumigatus infection

Abstract

Beyond their canonical roles in hemostasis and thrombosis, platelets function in the innate immune response by interacting directly with pathogens and by regulating the recruitment and activation of immune effector cells. Thrombocytopenia often coincides with neutropenia in patients with hematologic malignancies and in allogeneic hematopoietic cell transplant recipients, patient groups at high risk for invasive fungal infections. While neutropenia is well established as a major clinical risk factor for invasive fungal infections, the role of platelets in host defense against human fungal pathogens remains understudied. Here, we examined the role of platelets in murine Aspergillus fumigatus infection using two complementary approaches to induce thrombocytopenia without concurrent neutropenia. Thrombocytopenic mice were highly susceptible to A. fumigatus challenge and rapidly succumbed to infection. Although platelets regulated early conidial phagocytosis by neutrophils in a spleen tyrosine kinase (Syk)-dependent manner, platelet-regulated conidial phagocytosis was dispensable for host survival. Instead, our data indicated that platelets primarily function to maintain hemostasis and lung integrity in response to exposed fungal antigens, since thrombocytopenic mice exhibited severe hemorrhage into the airways in response to fungal challenge in the absence of overt angioinvasion. Challenge with swollen, heat-killed, conidia was lethal in thrombocytopenic hosts and could be reversed by platelet transfusion, consistent with the model that fungus-induced inflammation in platelet-depleted mice was sufficient to induce lethal hemorrhage. These data provide new insights into the role of platelets in the anti-Aspergillus host response and expand their role to host defense against filamentous molds.

Risk Factors for Invasive Aspergillosis in Patients Admitted to the Intensive Care Unit With Coronavirus Disease 2019: A Multicenter Retrospective Study

“…Platelets have versatile antifungal immune functions, and thrombocytopenic hosts are highly susceptible to IPA and can rapidly succumb to infection (27)(28)(29). To the best of our knowledge no study has investigated the correlation between thrombocytopenia in COVID-19 patients and IPA susceptibility.…”

“…In the present study thrombocytopenia was an independent risk factor for CAPA, but the underlying mechanisms are not clear. Mechanisms of IPA-related thrombocytopenia have been suggested (27)(28)(29). One is that when infected with Aspergillus spp.…”

“…One is that when infected with Aspergillus spp. the galactosaminogalactan secreted by the pathogen is deposited on the surfaces of platelets, inducing their activation and resulting in fungal damage ( 27 , 29 , 30 ). Another is that the altered platelet surface triggers a complement cascade reaction that attracts and activates phagocytes to eliminate the invading Aspergillus spp.…”

Aspergillus-Derived Galactosaminogalactan Triggers Complement Activation on Human Platelets

“…Data of mouse models indicate that platelets represent a key factor to maintain hemostasis and lung integrity in response to exposed fungal antigens. Thrombocytopenic mice exhibited severe hemorrhage into the airways in response to A. fumigatus challenge ( 30 ). Since platelets are versatile antifungal immune weapons ( 10 , 11 ), their shutoff via the body's own complement cascade represents a perfidious mechanism of fungal immune evasion.…”

Dysregulation of Key Proteinases in Aspergillus fumigatus Induced by Blood Platelets

“…The interplay between platelets and Aspergillus has been shown to be a multifactorial process (10). Human platelets exhibit specific features of classic cell-mediated immunity and play important roles in antifungal host defense in IA by preventing germination, hyphal elongation, viability (11,12), and increased susceptibility to antifungal drugs in vitro (13)(14)(15)(16). During exposure to Aspergillus, platelets interact directly with hyphae, aggregate, surround the fungus, and release stored serotonin from their dense granules within 30 min (13).…”