Inducible Bronchus-Associated Lymphoid Tissue Elicited by a Protein Cage Nanoparticle Enhances Protection in Mice against Diverse Respiratory Viruses

Abstract

BackgroundDestruction of the architectural and subsequently the functional integrity of the lung following pulmonary viral infections is attributable to both the extent of pathogen replication and to the host-generated inflammation associated with the recruitment of immune responses. The presence of antigenically disparate pulmonary viruses and the emergence of novel viruses assures the recurrence of lung damage with infection and resolution of each primary viral infection. Thus, there is a need to develop safe broad spectrum immunoprophylactic strategies capable of enhancing protective immune responses in the lung but which limits immune-mediated lung damage. The immunoprophylactic strategy described here utilizes a protein cage nanoparticle (PCN) to significantly accelerate clearance of diverse respiratory viruses after primary infection and also results in a host immune response that causes less lung damage.Methodology/Principal FindingsMice pre-treated with PCN, independent of any specific viral antigens, were protected against both sub-lethal and lethal doses of two different influenza viruses, a mouse-adapted SARS-coronavirus, or mouse pneumovirus. Treatment with PCN significantly increased survival and was marked by enhanced viral clearance, accelerated induction of viral-specific antibody production, and significant decreases in morbidity and lung damage. The enhanced protection appears to be dependent upon the prior development of inducible bronchus-associated lymphoid tissue (iBALT) in the lung in response to the PCN treatment and to be mediated through CD4+ T cell and B cell dependent mechanisms.Conclusions/SignificanceThe immunoprophylactic strategy described utilizes an infection-independent induction of naturally occurring iBALT prior to infection by a pulmonary viral pathogen. This strategy non-specifically enhances primary immunity to respiratory viruses and is not restricted by the antigen specificities inherent in typical vaccination strategies. PCN treatment is asymptomatic in its application and importantly, ameliorates the damaging inflammation normally associated with the recruitment of immune responses into the lung.

Regulatory T Cells Prevent Inducible BALT Formation by Dampening Neutrophilic Inflammation

“…Strikingly, LPS exposure in neonatal and weanling mice significantly diminished viral burden in response to acute Pneumovirus infection later in life, and decreased the magnitude of sloughing of the airway epithelium, consistent with a protective role for iBALT. Our findings are in agreement with previous reports demonstrating that BALT can confer protection against various respiratory viruses and limit immunopathology (3)(4)(5). Although the mechanistic basis for this phenomenon remains to be definitively elucidated, we observed that the increased presence of iBALT was associated with increased expression of the neutrophil chemokines CCL3 and CXCL10, a heightened neutrophilia, and elevated IFN-g expression.…”

“…This is somewhat surprising as neutrophils are one of the first inflammatory cells to be recruited to the site of sterile or infectious inflammation, can migrate from the inflammatory site to the draining lymph nodes, and are increasingly recognized as modulators of adaptive immunity (42)(43)(44). Indeed, neutrophils have been observed to infiltrate the iBALT area (12,45) as well as other TLOs (46,47), and are recruited in response to other TLR ligands or infectious pathogens shown to initiate iBALT formation in various animal species (4,48). Perhaps most significantly, neutrophilic inflammation is a common feature of diseases in which iBALTs are prevalent, including COPD, rheumatoid arthritis, asthma, idiopathic pulmonary fibrosis, tuberculosis, and hypersensitivity pneumonitis.…”

“…iBALT develop postnatally, are evident in many autoimmune/inflammatory disorders (e.g., rheumatoid arthritis, Sjogren's disease, chronic obstructive pulmonary disease [COPD]), and may contribute to immunopathology through the production of autoantibodies or allergen-specific Abs (1,2). In contrast, iBALT can limit immunopathology and can contribute to host defense against respiratory pathogens (3,4) via the creation of a local niche to facilitate immune cell crosstalk and accelerated T cell priming (5). Thus, understanding the processes that underlie iBALT formation may offer strategies to limit immunopathology or enhance protective immunity (6,7).…”

ApoE-Deficient Mice on Cholate-Containing High-Fat Diet Reveal a Pathology Similar to Lung Sarcoidosis

“…36 It has been shown that iBALT can functionally replace the function of conventional lymphoid organs and its size and cell composition varies widely. 37,38 Thus, the appearance of iBALT in our experiment might be related to the observed hypertrophy and fibrotic changes in thymus.…”

Humoral Immunity and the Development of Obliterative Bronchiolitis after Lung Transplantation

“…However, the lung is able to mount its own immune responses in situ, without secondary lymphoid tissues (11,12). This is attributable to the development of inducible bronchus-associated lymphoid tissue (iBALT), which contains a full complement of antigen-presenting cells (i.e., B and T cells) that are able to induce local humoral and cellular immunity (13,14). As such, the lung may function as a "lymph node with alveoli" (15).…”