IL-33 promotes the egress of group 2 innate lymphoid cells from the bone marrow

Group 2 innate lymphoid cells (ILC2s) are effector cells within the mucosa and key participants in type 2 immune responses in the context of allergic inflammation and infection. ILC2s develop in the bone marrow from common lymphoid progenitor cells, but little is known about how ILC2s egress from the bone marrow for hematogenous trafficking. In this study, we identified a critical role for IL-33, a hallmark peripheral ILC2-activating cytokine, in promoting the egress of ILC2 lineage cells from the bone marrow. Mice lacking IL-33 signaling had normal development of ILC2s but retained significantly more ILC2 progenitors in the bone marrow via augmented expression of CXCR4. Intravenous injection of IL-33 or pulmonary fungal allergen challenge mobilized ILC2 progenitors to exit the bone marrow. Finally, IL-33 enhanced ILC2 trafficking to the lungs in a parabiosis mouse model of tissue disruption and repopulation. Collectively, these data demonstrate that IL-33 plays a critical role in promoting ILC2 egress from the bone marrow

Respiratory syncytial virus infection activates IL-13–producing group 2 innate lymphoid cells through thymic stromal lymphopoietin

BACKGROUND: Respiratory syncytial virus (RSV) is a major health care burden with a particularly high worldwide morbidity and mortality rate among infants. Data suggest that severe RSV-associated illness is in part caused by immunopathology associated with a robust type 2 response. OBJECTIVE: We sought to determine the capacity of RSV infection to stimulate group 2 innate lymphoid cells (ILC2s) and the associated mechanism in a murine model. METHODS: Wild-type (WT) BALB/c, thymic stromal lymphopoietin receptor (TSLPR) knockout (KO), or WT mice receiving an anti-TSLP neutralizing antibody were infected with the RSV strain 01/2-20. During the first 4 to 6 days of infection, lungs were collected for evaluation of viral load, protein concentration, airway mucus, airway reactivity, or ILC2 numbers. Results were confirmed with 2 additional RSV clinical isolates, 12/11-19 and 12/12-6, with known human pathogenic potential. RESULTS: RSV induced a 3-fold increase in the number of IL-13-producing ILC2s at day 4 after infection, with a concurrent increase in total lung IL-13 levels. Both thymic stromal lymphopoietin (TSLP) and IL-33 levels were increased 12 hours after infection. TSLPR KO mice did not mount an IL-13-producing ILC2 response to RSV infection. Additionally, neutralization of TSLP significantly attenuated the RSV-induced IL-13-producing ILC2 response. TSLPR KO mice displayed reduced lung IL-13 protein levels, decreased airway mucus and reactivity, attenuated weight loss, and similar viral loads as WT mice. Both 12/11-19 and 12/12-6 similarly induced IL-13-producing ILC2s through a TSLP-dependent mechanism. CONCLUSION: These data demonstrate that multiple pathogenic strains of RSV induce IL-13-producing ILC2 proliferation and activation through a TSLP-dependent mechanism in a murine model and suggest the potential therapeutic targeting of TSLP during severe RSV infection

Evolving Concepts in how Viruses Impact Asthma

Over the past decade, there have been substantial advances in our understanding about how viral infections regulate asthma. Important lessons have been learned from birth cohort studies examining viral infections and subsequent asthma and from understanding the relationships between host genetics and viral infections, the contributions of respiratory viral infections to patterns of immune development, the impact of environmental exposure on the severity of viral infections, and how the viral genome influences host immune responses to viral infections. Further, there has been major progress in our knowledge about how bacteria regulate host immune responses in asthma pathogenesis. In this article, we also examine the dynamics of bacterial colonization of the respiratory tract during viral upper respiratory tract infection, in addition to the relationship of the gut and respiratory microbiomes with respiratory viral infections. Finally, we focus on potential interventions that could decrease virus-induced wheezing and asthma. There are emerging therapeutic options to decrease the severity of wheezing exacerbations caused by respiratory viral infections. Primary prevention is a major goal, and a strategy toward this end is considered

Wheezing Exacerbations in Early Childhood: Evaluation, Treatment, and Recent Advances Relevant to the Genesis of Asthma

Children who begin wheezing during early childhood are frequently seen by health care providers in primary care, in hospitals, and in emergency departments, and by allergists and pulmonologists. When a young child, such as the 2 year-old patient presented here, is evaluated for wheezing, a frequent challenge for clinicians is to determine whether the symptoms represent transient, viral-induced wheezing or whether sufficient risk factors are present to suspect that the child may experience recurrent wheezing and develop asthma. Most factors that influence prognosis are not mutually exclusive, are interrelated (ie, cofactors), and often represent gene-environment interactions. Many of these risk factors have been, and continue to be, investigated in prospective studies to decipher their relative importance with the goal of developing new therapies and interventions in the future. The etiologies of wheezing in young children, diagnostic methods, treatment, prognostic factors, and potential targets for prevention of the development of asthma are discussed. (C) 2014 American Academy of Allergy, Asthma & Immunolog

Effective infection of pup and adult mice with RSV line 19.

<p>Adult (8–9 wks old) and pup (2–4 days old) BALB/cJ mice received a HD/HV inoculum of RSV line 19 or cell lysate. Serial viral titers were determined by standard H&E plaque assay (A). Daily weights were measured in adults (B) and pups (C). For linear regression analysis, pup data are representative of 3 separate experiments with 15 pups per group. For viral titers and adult weights, data are representative of 3 experiments and points represent data for at least 5 mice per group ± SD. *, Significant compared with mock groups at p<0.05.</p

Inhaled rIFNγ reduces viral load in RSV-infected neonatal BALB/cJ mice.

<p>On 1, 3, 5, and 7 dpi pups received 16 ng/g of i.n. rIFNγ or diluent only. (A) Daily weight change compared to weight prior to infection was plotted; (B) IFNγ was measured from BALF by Luminex assay. Viral titers were measured from left lung lobes by H&E plaque assay on 2, 3, 4, 5, and 7 dpi. RSV titers were analyzed by a 2-way ANOVA and graphically represented with a line graph (C) and by paired t-test, which is graphically represented by a bar graph (D). Mean values ± SD are depicted, and statistical difference was defined as a <i>P</i> value .05 for differences between mock-infected animals at the same time point (*); data are representative of two separate experiments.</p

Inhaled rIFNγ increases CAM activation in RSV-infected neonatal BALB/cJ mice.

<p>Pup (2–4 days old) BALB/cJ mice received a HD/HV inoculum of RSV line 19 followed by 16 ng/g of i.n. rIFNγ (RSV/rIFNγ+) or diluent only (RSV/rIFNγ−) on 1, 3, 5, and 7 dpi. Control groups were mock-infected with cell lysate followed by 16 ng/g of i.n. rIFNγ (mock/rIFNγ+) or diluent only (mock/rIFNγ −) on 1, 3, 5, and 7 dpi. Cells were isolated from BALF on 4, 7, and 10 dpi and percent CD11b− CD11c+ (nonlymphocyte gate) (A), CD11b+CD11c+ (nonlymphocyte gate) (D), and MHC II, MR, CD86, and CCR7 (gated on CD11b− CD11c+ cells) (B, C, E, F) were determined by flow cytometry. Points represent data for ≥5 mice per group ± SD. (†) indicates <i>P</i><0.05 for comparisons between RSV/rIFNγ+ and RSV/rIFNγ−; (‡) indicates p<0.05 for comparisons between mock/rIFNγ+ and mock/rIFNγ−; (*) indicates p<0.05 for comparisons between RSV/rIFNγ+ and mock/rIFNγ+.</p