Role of Neutrophils in Preventing and Resolving Acute Fungal Sinusitis

Abstract

Acute fungal sinusitis (AFS) is a devastating disease of the paranasal sinuses afflicting immunocompromised individuals. Knowledge about this disease is limited to clinical observations because there are no animal models in which to study the pathogenesis of the infection. Our goal was to develop a murine model of AFS and examine the role of neutrophils in host defense within the nasal cavity. Female C57BL/6 mice were depleted of neutrophils using anti-Gr-1 monoclonal antibody from day ؊1 to day 5 postinfection to initiate a transient neutropenia within the mice. At day 0, Aspergillus fumigatus conidia were administered intranasally. The untreated Aspergillus-exposed group had significant neutrophil recruitment by day 3, but by day 7 the leukocyte numbers had returned to unexposed levels. There was not a significant influx of mononuclear cells at either time point. In contrast, beginning at day 3 postinfection and continuing through day 7, anti-Gr-1-treated mice had increased cellular recruitment consisting of banded neutrophils at day 3 and mature neutrophils at day 7. Hyphal masses developed only in the anti-Gr-1-treated mice (25 to 36%) but only during the period of treatment. When the treatment was discontinued, hyphal masses could no longer be detected in the nasal cavities of these mice. In contrast, cyclophosphamide treatment did not induce neutropenia, and the nasal cavity remained free of hyphal masses. These studies demonstrate the feasibility of using this model to study AFS and implicate neutrophils in protection of the sinuses against acute Aspergillus infection and in clearance of established hyphal masses.Acute fungal sinusitis (AFS), also known as fulminant sinusitis, is a rapid, invasive disease of the paranasal cavities. It develops primarily in immunocompromised individuals, such as bone marrow transplant and AIDS patients (5, 21). The infection is characterized by rapid hyphal transformation within the paranasal sinus cavities. This is followed by fungal invasion of the surrounding mucosa, musculature, vasculature, and, in severe cases, cranium. Patients who do not receive proper medical attention can suffer from bone and tissue loss and, if left untreated, death.Recent research about AFS has been limited to clinical observations because there are not currently animal models of this disease. Much of what is understood about the innate response to fungal infections in the nasal cavity is inferred from correlatives drawn from other tissue sites. For example, within the lungs, fungal conidium challenge stimulates leukocyte recruitment into the airspaces. The leukocytes, primarily macrophages and neutrophils, internalize resting or swollen conidia and use mechanisms such as respiratory burst to combat infections (2, 3, 10-12, 22, 24). It is believed that macrophages and neutrophils may have a similar response to fungi within the nasal cavity, although there have been no murine models that demonstrate this (18,20). Neutrophils help mediate the nasal inflammatory response in rodents coexposed to li...

Tracing Conidial Fate and Measuring Host Cell Antifungal Activity Using a Reporter of Microbial Viability in the Lung

“…The method has the potential to be combined with imaging technology to explore temporal, anatomic, and cellular aspects of conidiacidal activity in the lung (Looney et al, 2011). FLARE conidia could be administered at other physiologically relevant portals of infections, e.g., nasal sinuses or corneal tissues (Leal et al, 2010; Rodriguez et al, 2007), to probe tissue- or organ-specific host defense mechanisms.…”

Coevolution of TH1, TH2, and TH17 Responses during Repeated Pulmonary Exposure toAspergillus fumigatusConidia

“…Neutrophils, a major cell type during the early phases of the response, are well known to play a central role in the host defense against Aspergillus (5,29,43,44,64) and were seen at all stages of the response, particularly at early stages prior to the engagement of the adaptive response. Levels of lung eosinophils, serum IgE, and IL-4 Expansion of the regulatory T cell population is important for limiting disease, because T reg cells ultimately aid in the clearance of fungi by limiting T H 1 inflammation (17) or dampening T H 2 hypersensitivity reactions (8,16).…”

Resolution of invasive fungal sinusitis in immunocompromised patients: neutrophil count is crucial beside a combined medical and surgical approach

“…The fungi most frequently involved are Aspergillus and Zygomicetes. Prognosis is related to various factors, such as the speed of diagnosis and treatment, the type of fungal infection [3], dissemination to the central nervous system, and complete neutrophil recovery [4]. The scarce information in the literature on invasive fungal sinusitis in immunocompromised patients highlights the importance and efficacy of a combined surgical and medical approach [5].…”