Vitamin D, in addition to its classical functions in bone homeostasis, has a modulatory and regulatory role in multiple processes, including host defense, inflammation, immunity, and epithelial repair. Patients with respiratory disease are frequently deficient in vitamin D, implying that supplementation might provide significant benefit to these patients. Respiratory viral infections are common and are the main trigger of acute exacerbations and hospitalization in children and adults with asthma and other airways diseases. Respiratory monocytes/macrophages and epithelial cells constitutively express the vitamin D receptor. Vitamin D, acting through this receptor, may be important in protection against respiratory infections. Whether the in vitro findings can be translated into a substantial in vivo benefit still remains uncertain. Here we review the in vitro data on the role of vitamin D in antiviral innate immunity, the data concerning the deficient levels of vitamin D in lung diseases, and the in vivo role of supplementation as protection against respiratory viral infections in healthy individuals and in patients with chronic respiratory diseases. Finally, we suggest ways of improving the effectiveness of vitamin D as an adjuvant in the prevention and treatment of acute respiratory infections.

By modulating the antiviral immune response via vitamin D receptor, the active form of vitamin D (1,25-dihydroxyvitamin D, calcitriol) could play a central role in protection against respiratory virus infections. This in vitro study tested the hypothesis that respiratory viruses modulate vitamin D receptor expression in human bronchial epithelial cells and this modulation affects the antiviral response to exogenous vitamin D. Human primary bronchial epithelial cells were infected with rhinoviruses and respiratory syncytial virus in the presence or absence of vitamin D. Expression of vitamin D receptor, 1α-hydroxylase (1α(OH)ase), 24-hydroxylase (24(OH)ase), innate interferons, interferon stimulated genes and cathelicidin were measured by quantitative polymerase chain reaction. The antiviral effect of vitamin D on rhinovirus replication was determined by measurement of virus load. A direct inactivation assay was used to determine the antiviral activity of cathelicidin. Both RV and RSV decreased vitamin D receptor and 24(OH)ase and, in addition, RSV increased 1α(OH)ase expression in epithelial cells. Vitamin D decreased rhinovirus replication and release, and increased rhinovirus-induced interferon stimulated genes and cathelicidin. Furthermore, cathelicidin had direct anti-rhinovirus activity. Despite lower vitamin D receptor levels in rhinovirus-infected epithelial cells, exogenous vitamin D increased antiviral defences most likely via cathelicidin and innate interferon pathways.

Respiratory syncytial virus (RSV) is a major cause of bronchiolitis in infants. It is also responsible for high morbidity and mortality in the elderly. Programmed death ligands (PD-Ls) on antigen-presenting cells interact with receptors on T cells to regulate immune responses. The programmed death receptor-ligand 1/programmed death receptor 1 (PD-L1-PD-1) pathway is inhibitory in chronic viral infections, but its role in acute viral infections is unclear. We hypothesized that bronchial epithelial cell (BEC) expression of PD-Ls would inhibit local effector CD8⁺ T cell function. We report that RSV infection of primary human BECs strongly induces PD-L1 expression. In a co-culture system of BECs with purified CD8⁺ T cells, we demonstrated that RSV-infected BECs increased CD8⁺ T cell activation, proliferation, and antiviral function. Blocking PD-L1 on RSV-infected BECs co-cultured with CD8⁺ T cells enhanced CD8⁺ T cell IFN-γ, IL-2, and granzyme B production. It also decreased the virus load of the BECs. Based on our findings, we believe therapeutic strategies that target the PD-L1-PD-1 pathway might increase antiviral immune responses to RSV and other acute virus infections.

Rhinovirus infections are the major cause of asthma exacerbations. We hypothesised that IL-15, a cytokine implicated in innate and acquired antiviral immunity, may be deficient in asthma and important in the pathogenesis of asthma exacerbations. We investigated regulation of IL-15 induction by rhinovirus in human macrophages in vitro, IL-15 levels in bronchoalveolar lavage (BAL) fluid and IL-15 induction by rhinovirus in BAL macrophages from asthmatic and control subjects, and related these to outcomes of infection in vivo. Rhinovirus induced IL-15 in macrophages was replication-, NF-κB- and α/β interferon-dependent. BAL macrophage IL-15 induction by rhinovirus was impaired in asthmatics and inversely related to lower respiratory symptom severity during experimental rhinovirus infection. IL-15 levels in BAL fluid were also decreased in asthmatics and inversely related with airway hyperresponsiveness and with virus load during in vivo rhinovirus infection. Deficient IL-15 production in asthma may be important in the pathogenesis of asthma exacerbations. We previously reported deficiency in interferon production in asthma, which correlated with disease severity and viral load during experimental rhinovirus infection. Here we show that macrophages produce IL-15 upon rhinovirus infection and that IFN-β plays an important role in IL-15 production. In asthmatic subjects, there is a deficiency in rhinovirus-induced production of IL-15 by macrophages, which indicates immunodeficiency in asthma is surprisingly broad, also involving IL-15, an important cytokine that bridges innate and acquired immunity. These results show that IFN-β therapy in asthma exacerbations could be effective not only due to direct anti-viral effects of IFN-β, but also by inducing IL-15 production. We also show induction of IFN-β and IL-15 to be NF-kB dependent, an important finding which has implications for NF-kB inhibitor drug development programmes as these drugs have potential to worsen rather than improve asthma exacerbation severity, by further enhancing deficiencies of IL-15 and IFN-β. This study investigating the role of IL-15 in rhinovirus infection and asthma has also major implications in other diseases, for example pandemic influenza, where asthma is a major risk factor for severe disease and death, and COPD and cystic fibrosis where IFN-β deficiency is also present.

It is a new and exciting time for acute lymphoblastic leukemia (ALL). While nearly 50 years ago, only one in nine children with ALL survived with chemotherapy, nowadays nearly 90% of children have a chance of long-term survival. Adults with ALL, as well as the special category of adolescents and young adult (AYA) patients, are catching up with the new developments seen in children, but still their prognosis is much worse. A plethora of factors are regarded as responsible for the differences in treatment response, such as age, ethnicity, disease biology, treatment regimens and toxicities, drug tolerance and resistance, minimal residual disease evaluation, hematopoietic stem cell transplantation timing and socio-economic factors. Taking these factors into account, bringing pediatric-like protocols to adult patient management and incorporating new agents into frontline treatment could be the key to improve the survival rates in adults and AYA.

Activation through different signaling pathways results in two functionally different types of macrophages, the pro‐inflammatory (M1) and the anti‐inflammatory (M2). The polarization of macrophages toward the pro‐inflammatory M1 phenotype is considered to be critical for efficient antiviral immune responses in the lung. Among the various cell types that are present in the asthmatic airways, macrophages have emerged as significant participants in disease pathogenesis, because of their activation during both the inflammatory and resolution phases, with an impact on disease progression. Polarized M1 and M2 macrophages are able to reversibly undergo functional redifferentiation into anti‐inflammatory or pro‐inflammatory macrophages, respectively, and therefore, macrophages mediate both processes. Recent studies have indicated a predominance of M2 macrophages in asthmatic airways. During a virus infection, it is likely that M2 macrophages would secrete higher amounts of the suppressor cytokine IL‐10, and less innate IFNs. However, the interactions between IL‐10 and innate IFNs during virus‐induced exacerbations of asthma have not been well studied. The possible role of IL‐10 as a therapy in allergic asthma has already been suggested, but the divergent roles of this suppressor molecule in the antiviral immune response raise concerns. This review attempts to shed light on macrophage IL‐10–IFNs interactions and discusses the role of IL‐10 in virus‐induced asthma exacerbations. Whereas IL‐10 is important in terminating pro‐inflammatory and antiviral immune responses, the presence of this immune regulatory cytokine at the beginning of virus infection could impair the response to viruses and play a role in virus‐induced asthma exacerbations. © 2014 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.