Host and Pathogen Communication in the Respiratory Tract: Mechanisms and Models of a Complex Signaling Microenvironment

Abstract

Chronic lung diseases are a leading cause of morbidity and mortality across the globe, encompassing a diverse range of conditions from infections with pathogenic microorganisms to underlying genetic disorders. The respiratory tract represents an active interface with the external environment having the primary immune function of resisting pathogen intrusion and maintaining homeostasis in response to the myriad of stimuli encountered within its microenvironment. To perform these vital functions and prevent lung disorders, a chemical and biological cross-talk occurs in the complex milieu of the lung that mediates and regulates the numerous cellular processes contributing to lung health. In this review, we will focus on the role of cross-talk in chronic lung infections, and discuss how different cell types and signaling pathways contribute to the chronicity of infection(s) and prevent effective immune clearance of pathogens. In the lung microenvironment, pathogens have developed the capacity to evade mucosal immunity using different mechanisms or virulence factors, leading to colonization and infection of the host; such mechanisms include the release of soluble and volatile factors, as well as contact dependent (juxtracrine) interactions. We explore the diverse modes of communication between the host and pathogen in the lung tissue milieu in the context of chronic lung infections. Lastly, we review current methods and approaches used to model and study these host-pathogen interactions in vitro, and the role of these technological platforms in advancing our knowledge about chronic lung diseases.

Keywords: in vitro models; juxtacrine signaling; pulmonary cross-talk; soluble factors; volatile signaling.

Figure 1

The lung microenvironment is home to a complex signaling network that interprets factors from various sources simultaneously. Signaling phenomena includes the exchange of soluble, volatile, and physical signals between cells of the host immune system, microbes, and host tissue components at varying spatiotemporal concentrations. Translating this complex quagmire of signals requires a broad perspective to see the role of each type of communication in the context of host-pathogen, pathogen-pathogen, and host-host signaling.

Figure 2

The exchange of soluble factors through paracrine signaling generates context-dependent effects. The secretion of proinflammatory factor IFNγ by T cells induces antimicrobial functions (e.g., autophagy) and signaling (e.g., HIF1α-mediated NO production) in M. tuberculosis-infected macrophages, while increasing the virulence of P. aeruginosa through OprF-binding and downstream induction of virulence factor PA-I. The secretion of IFNγ is decreased by interaction with C. neoformans virulence factor GXM, which decreases secretion of inflammatory factors (TNFα) while increasing secretion of anti-inflammatory factors IL-4 and IL-10. OprF, outer membrane porin F; PA-I, type I P. aeruginosa lectin; HIF1α, hypoxia inducible factor-1 α; NO, nitric oxide; GXM, glucuronoxylomannan.

Figure 3

Pathogens leverage host cytoskeletal components for movement within and between host cells in response to host-initiated physical interactions. Actin-mediated movement of B. pseudomallei is vital for pathogen survival and movement subsequent to phagosomal escape, as proteins BimA and BimC enable actin repolymerization in an Arp2/3-independent manner and the ability to protrude and infect proximal cells. Similarly, actin localization to the phagosome is an important component of C. neoformans phagocytosis and containment, as actin undergoes an Arp2/3-dependent rapid polymerization (“flash”) in response to C. neoformans permeabilization of the phagosome; disruption of the phagosome and C. neoformans extrusion into neighboring cells or extracellularly is an actin-dependent process that results in vacuole formation. Arp2/3, actin-related proteins 2/3; BimA, Burkholderia intracellular motility A; BimC, Burkholderia intracellular motility C.

Figure 4

Volatile signaling in the lung microenvironment supports commensal and pathogenic microbial populations against diverse challenges and stimuli. Pulmonary pathogens S. aureus and P. aeruginosa secrete biogenic ammonia (NH₃) and hydrogen sulfide (H₂S) which offers protection against pharmacological interventions such as TCN and reactive oxygen species induced by GM, AP, or NA, respectively, to persist in the lung microenvironment. Further, the secretion of DMS from P. aeruginosa has been found to promote A. fumigatus growth, and the bidirectional exchange of volatile factors between the two pathogens leads to increased secretion of proinflammatory factors GM-CSF, IL-8, IL-6, IFNγ, and IL-1β from a lung tissue model of infection. TCN, tetracycline; GM, gentamicin; AP, ampicillin; NA, nalidixic acid; DMS, dimethyl sulfide.