Infectious pneumonias are a leading cause of death worldwide, particularly among immunocompromised patients. Therapeutic stimulation of the lungs’ intrinsic defenses with a unique combination of inhaled Toll-like receptor agonists broadly protects mice against otherwise lethal pneumonias. As the survival benefit persists despite cytotoxic chemotherapy-related neutropenia, the cells required for protection were investigated. The inducibility of resistance was tested in mice with deficiencies of leukocyte lineages due to genetic deletions and in wild type mice with leukocyte populations significantly reduced by antibodies or toxins. Surprisingly, these serial reductions in leukocyte lineages did not appreciably impair inducible resistance, but targeted disruption of Toll-like receptor signaling in the lung epithelium resulted in complete abrogation of the protective effect. Isolated lung epithelial cells were also induced to kill pathogens in the absence of leukocytes. Proteomic and gene expression analyses of isolated epithelial cells and whole lungs revealed highly congruent antimicrobial responses. Taken together, these data indicate that lung epithelial cells are necessary and sufficient effectors of inducible resistance. These findings challenge conventional paradigms about the role of epithelia in antimicrobial defense and offer a novel potential intervention to protect patients with impaired leukocyte-mediated immunity from fatal pneumonias.

Viral pneumonias cause profound worldwide morbidity, necessitating novel strategies to prevent and treat these potentially lethal infections. Stimulation of intrinsic lung defenses via inhalation of synergistically acting Toll-like receptor (TLR) agonists protects mice broadly against pneumonia, including otherwise-lethal viral infections, providing a potential opportunity to mitigate infectious threats. As intact lung epithelial TLR signaling is required for the inducible resistance and as these cells are the principal targets of many respiratory viruses, the capacity of lung epithelial cells to be therapeutically manipulated to function as autonomous antiviral effectors was investigated. Our work revealed that mouse and human lung epithelial cells could be stimulated to generate robust antiviral responses that both reduce viral burden and enhance survival of isolated cells and intact animals. The antiviral protection required concurrent induction of epithelial reactive oxygen species (ROS) from both mitochondrial and dual oxidase sources, although neither type I interferon enrichment nor type I interferon signaling was required for the inducible protection. Taken together, these findings establish the sufficiency of lung epithelial cells to generate therapeutically inducible antiviral responses, reveal novel antiviral roles for ROS, provide mechanistic insights into inducible resistance, and may provide an opportunity to protect patients from viral pneumonia during periods of peak vulnerability.

Synopsis Fungal pneumonias cause unacceptable morbidity among patients with hematologic malignancies (HM) and recipients of hematopoietic stem cell transplantation (HSCT). The high incidence of fungal pneumonias in HM/HSCT populations arises from their frequently severe, complex and persistent immune dysfunction caused by both the underlying disease and its treatment. The cytopenias, treatment toxicities and other immune derangements that make HM/HSCT patients susceptible to fungal pneumonia frequently also complicate its diagnosis by impeding generation of classically recognizable host response patterns and increase the intensity and duration of required antifungal therapy. This manuscript addresses the host factors that contribute to susceptibility, summarizes diagnostic recommendations, and reviews current guidelines for management of fungal pneumonia in HM/HSCT patients.

The survival in matched cohorts did not show adverse outcomes with prior PCI at 1, 3, 5, 7, and 10 years. Prior PCI does not adversely impact survival after CABG.

In the published version of this article, the name of author Gabriela Martinez Zayas was misspelled. This erratum serves to correct the spelling.