Chemokine-mediated recruitment of NK cells is a critical host defense mechanism in invasive aspergillosis

Abstract

Invasive aspergillosis is a severe pneumonia that is usually fatal despite currently available therapy. The disease disproportionately afflicts immunocompromised patients, indicating the critical importance of the immune status of the host in this infection, but the defense mechanisms against this pathogen remain incompletely understood. In the current study, we hypothesized that the chemokine ligand monocyte chemotactic protein-1, also designated CC chemokine ligand-2 (MCP-1/CCL2) is necessary for effective host defense against invasive aspergillosis in immunocompromised hosts. We found a rapid and marked induction of MCP-1/CCL2 in the lungs of neutropenic mice with invasive aspergillosis. Neutralizing MCP-1/CCL2 resulted in twofold greater mortality and greater than threefold increase in pathogen burden in the lungs. Neutralization of MCP-1/CCL2 also resulted in reduced recruitment of NK cells to the lungs at early time points, but did not affect the number of other leukocyte effector cells in the lungs. Ab-mediated depletion of NK cells similarly resulted in impaired defenses against the infection, resulting in a greater than twofold increase in mortality and impaired clearance of the pathogen from the lungs. These data establish MCP-1/CCL2–mediated recruitment of NK cells to the lungs as a critical early host defense mechanism in invasive aspergillosis and demonstrate NK cells to be an important and previously unrecognized effector cell in this infection

Remission of chronic fungal asthma in the absence of CCR8

“…Both CCL2 and its receptor have been shown to have an important role in the immune response to A fumigatus, limiting the allergic remodeling responses during chronic fungal asthma. [27][28][29] Finally, the increased presence of mDCs in the CCR8 2/2 group may also enhance the clearance of fungus as this cell population is critical in the antifungal response. 18,30,31 Thus, several immune-related protein and cellular elements seemed to combine to enhance the clearance of fungal material from the lungs of mice lacking CCR8, and future studies in this model will address the relative importance of these elements during the progression of fungal asthma in these mice.…”

Re-evaluation of the involvement of NK cells and C-type lectin-like NK receptors in modulation of immune responses by multivalent GlcNAc-terminated oligosaccharides

“…Chemokine receptors for CCL2, CXCL3, and CX 3 CL1 are known to be involved in NK cell migration. There is evidence for CCL2/CCR2-dependent recruitment of NK cells during tumor metastasis and fungal infection [33]. CCL2 can induce NK cell-mediated eradication of metastatic tumors [34].…”

Challenges and Prospects of Adoptive Immunotherapy in Prevention and Treatment of Opportunistic Mycoses in Hematologic Transplant Recipients

“…It is well known that in addition to the killing of tumor cells, NK cells play a crucial role in combating infections from a variety of pathogens [33]. For example, in mice with pulmonary aspergillosis, the chemokinemediated recruitment of NK cells was demonstrated as an important antifungal host defense mechanism, and the transfer of activated NK cells resulted in greater pathogen clearance [34,35]. We recently presented our data demonstrating that unstimulated and IL-2 pre-stimulated human NK cells kill A. fumigatus hyphae, but do not affect resting conidia.…”