Surviving Deadly Lung Infections: Innate Host Tolerance Mechanisms in the Pulmonary System

Abstract

Much research on infectious diseases focuses on clearing the pathogen through the use of antimicrobial drugs, the immune response, or a combination of both. Rapid clearance of pathogens allows for a quick return to a healthy state and increased survival. Pathogen-targeted approaches to combating infection have inherent limitations, including their pathogen-specific nature, the potential for antimicrobial resistance, and poor vaccine efficacy, among others. Another way to survive an infection is to tolerate the alterations to homeostasis that occur during a disease state through a process called host tolerance or resilience, which is independent from pathogen burden. Alterations in homeostasis during infection are numerous and include tissue damage, increased inflammation, metabolic changes, temperature changes, and changes in respiration. Given its importance and sensitivity, the lung is a good system for understanding host tolerance to infectious disease. Pneumonia is the leading cause of death for children under five worldwide. One reason for this is because when the pulmonary system is altered dramatically it greatly impacts the overall health and survival of a patient. Targeting host pathways involved in maintenance of pulmonary host tolerance during infection could provide an alternative therapeutic avenue that may be broadly applicable across a variety of pathologies. In this review, we will summarize recent findings on tolerance to host lung infection. We will focus on the involvement of innate immune responses in tolerance and how an initial viral lung infection may alter tolerance mechanisms in leukocytic, epithelial, and endothelial compartments to a subsequent bacterial infection. By understanding tolerance mechanisms in the lung we can better address treatment options for deadly pulmonary infections.

Electronic Nicotine Delivery System Aerosol-induced Cell Death and Dysfunction in Macrophages and Lung Epithelial Cells

“…Macrophages in the lung have many functions including clearing pathogens, dead cells, and other debris (27). They also play important roles in mediating tissue repair processes (31). Alveolar macrophages are a self-renewing population; however, they can be replenished by infiltrating bone marrow-derived monocytes and macrophages (32,33).…”

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“…The drugs would probably work better if given in combination rather than by themselves [ 8 ]. For a severe infection like pandemic influenza, treatment with these drugs could improve an adult's tolerance of infection [ 44 – 47 ] and might improve survival. The drugs might also have similar effects in children who develop life-threatening illness.…”

oprC Impairs Host Defense by Increasing the Quorum-Sensing-Mediated Virulence of Pseudomonas aeruginosa

“…Critically, our results demonstrated reduced mortality, lung barrier damage, and inflammatory responses in mice infected by the oprC deletion mutant. It was established that lung barrier integrity plays a critical role in homeostasis and immunity against pathogen invasion (55,56). Once pathogen invades the host, the PRR will recognize the specific PAMP of the pathogen.…”

“…Here, our results demonstrate that oprC regulates the critical QS virulence signals, leading to a reduction in inflammasome activation, whereas exacerbated inflammatory responses profoundly impact cell viability, lung barrier integrity, tissue injury, and ultimately survival. Lung epithelial barrier is one of the critical mechanisms in preserving homeostasis and protecting immunity against pathogen invasion (55). We proposed a model for the OprC-mediated virulence regulation and host immune response to P. aeruginosa infection (Figure 7).…”