First Line of Defense: Innate Cell-Mediated Control of Pulmonary Aspergillosis

Abstract

Mycotic infections and their effect on the human condition have been widely overlooked and poorly surveilled by many health organizations even though mortality rates have increased in recent years. The increased usage of immunosuppressive and myeloablative therapies for the treatment of malignant as well as non-malignant diseases has contributed significantly to the increased incidence of fungal infections. Invasive fungal infections have been found to be responsible for at least 1.5 million deaths worldwide. About 90% of these deaths can be attributed to Cryptococcus, Candida, Aspergillus, and Pneumocystis. A better understanding of how the host immune system contains fungal infection is likely to facilitate the development of much needed novel antifungal therapies. Innate cells are responsible for the rapid recognition and containment of fungal infections and have been found to play essential roles in defense against multiple fungal pathogens. In this review we summarize our current understanding of host-fungi interactions with a focus on mechanisms of innate cell-mediated recognition and control of pulmonary aspergillosis.

Interleukin 1α Is Critical for Resistance against Highly Virulent Aspergillus fumigatus Isolates

“…If this primary barrier is bypassed, airway epithelial cells and lung-resident macrophages comprise the first line of defense against inhaled conidia, while neutrophils and inflammatory monocytes are then sequentially recruited to the site to prevent fungal growth (16,17). Defining the immunological events that are necessary for A. fumigatus conidia to be cleared from the lungs without excessive and immune-mediated lung damage is a critical step toward understanding how the response is altered in different immunocompromised populations.…”

Immune responses to invasive aspergillosis: new understanding and therapeutic opportunities

“…Ly6C hi monocytesand theirmonocyte-derived dendriticcell derivatives also condition the lung inflammatory environment to boost neutrophil conidial killing [14], though the precise mechanisms that underlie this intercellular crosstalk remain to be defined. Other myeloid cell populations, including alveolar macrophages, plasmacytoid dendritic cells, natural killer (NK) cells, innate NK T cells, and eosinophils contribute to fungal clearance, yet none are essential to prevent invasive aspergillosis in otherwise immune competent mice [3,17–20]. …”

“…A. fumigatus conidial swelling and germination triggers inflammatory responses via morphotype-specific exposure of β-glucans and other ligands that activate the C-type lectin receptor dectin-1 (encoded by the Clec7A gene) and dectin-2 ( Clec4N in mice, CLEC6A in humans) [3,18,43,44]. These spleen tyrosine kinase-coupled receptors activate caspase recruitment domain-containing protein 9 (CARD9) that forms a trimeric complex with BCL1 and MALT10 to activate canonical NF-κB subunits, resulting in the transcription of proinflammatory cytokines, including il1b , il6 , il12 , cxcl1 , cxcl2 , and tnf (reviewed in detail in [45,46]).…”

“…Invasive aspergillosis begins with inhalation or, occasionally, traumatic inoculation of conidia (vegetative spores) formed by Aspergillus species members [1–3]. Although the vast majority of these encounters conclude with asymptomatic clearance, humans with quantitative or qualitative myeloid cell defects are susceptible to invasive aspergillosis.…”

Host Response to Pulmonary Fungal Infections: a Highlight on Cell-Driven Immunity to Cryptococcus Species and Aspergillus fumigatus

“…In this review, we will summarize recent advances in our understanding of the role of specific immune cells in the control of infection with these two clinically important fungal species, with a primary focus on innate immunity. For more in-depth discussions on other relevant aspects of host immunity to fungi please see recent reviews [19, 20]. …”