Role of eosinophils in respiratory syncytial virus infection

Eosinophils recruited to the lungs, in response to respiratory syncytial virus (RSV) infection, have been associated with, the pathophysiological sequel of infection and more recently, with accelerated virus clearance. Heparan sulfates (HS), on the cell surface, are utilised by RSV to initiate infection, making HS a potential therapeutics target. As there is no effective RSV vaccine currently available, controlling RSV has remained a formidable challenge. The aims of this thesis were to investigate: (1) in vitro RSV effect on eosinophil morphology and eosinophil antiviral activity against RSV; (2) in vivo eosinophil antiviral activity expressed by four distinct mouse models following RSV infection and re-infection; and (3) the efficacy of HS mimetics treatment on RSV infection in vitro and in vivo. Firstly, transmission electron microscopy analysis, major basic protein and eosinophil peroxidase assays, eosinophil chemotaxis and RSV kinetics assays were used to examine aim 1. In vitro findings indicated human RSV pathogen inability to infect murine eosinophils however; eosinophil exposure to RSV antigen or RSV infected HEp-2 supernatant resulted in eosinophil activation, degranulation and chemotaxis. Secondly, four genetically modified BALB/s strains were infected and re-infected. Analysis of bronchoalveolar lavage (BALF), blood and lung histology was used to elucidate aim 2. These in vivo results revealed significant eosinophil mediated reduction in viral load following RSV primary infection of IL-5 Tg and IL-5 Tg Rag 2-/- BALB/c. However, following the RSV re-infection, eosinophils in addition to NK cells and type 2 innate lymphoid cells (ILC) were unable to provide the same antiviral protection in both, Rag 2-/- and IL-5 Tg Rag 2-/- BALB/c mice. Results of CD4+ cell adoptive transfer demonstrated a significant reduction of viral load recovered from IL-5 Tg Rag 2-/- BALB/c mice re-infected with RSV. Lastly, the antiviral potential of 53 HS mimetics was tested in vitro under four clinically relevant conditions. Following the in vitro findings, six HS mimetics were tested in vivo as a post RSV infection treatment and as a prophylactic treatment of RSV infection. Results revealed the first HS mimetic study examining and reporting on 53 HS mimetics RSV antiviral activity in vitro followed by HS mimetics effect on viral load reduction in vivo. Moreover, HS 228 was found to be the best performing compound, both, as post RSV infection HS treatment and prophylactic treatment of RSV infection, while reducing RSV disease pathology in vivo. Taken together, the findings of this thesis identify that RSV induced eosinophil activation results in targeted eosinophil response in vitro and in vivo; however, that eosinophil recruitment and activation following RSV re-infection appears to be dependent on stimulation by RSV-specific memory Th2 cells and/or sufficient cellular response involving NK cells and/or type 2 ILCs. In addition, exhaustive HS mimetics analysis has resulted in a comprehensive list of potential antiviral compounds that could be targeted for RSV therapeutic development. Furthermore, HS mimetics tested were found to activate an immune response even in the absence of viral infection, suggesting their potential in pre-emptive immune activation and modulation

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

Shared heritability and functional enrichment across six solid cancers

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis

The Role of Eosinophils in Viral Infections

Respiratory viruses are a leading cause of severe respiratory infections normally seen in infants and children. As there is currently no known vaccine against major respiratory viruses, the pressure is on the innate immune cells to clear these infections more efficiently. For a long time, the role of eosinophils in the pathogenesis and pathophysiology of respiratory virus infections has been examined and opinions seem very diverse. Eosinophils became the main research focus in 1960 following unsuccessful respiratory syncytial virus (RSV) vaccination trial. Vaccine contained formalin-inactivated RSV, triggering the recruitment of eosinophils to the lung tissue, which resulted in several deaths and severe tissue damage. Ever since, eosinophil role in viral infections has been investigated and numerous studies have shown that these cells have the potential to play beneficial role in the clearance on the viral infections. In this review, we have summarised the findings of studies that examined the role of eosinophils in respiratory virus infections involving viruses such as Respiratory Syncytial virus (RSV), Rhinovirus, Pneumonia virus of mice (PVM) as well as their role as antigen presenting cells (APCs) in viral infections. This review will show that the challenge is to ensure that the benefits of the eosinophilic leukocytes are harnessed to effect successful therapeutic intervention and this remains the main challenge in achieving successful vaccine against respiratory virus infections

Molecular and cellular mechanisms in the viral exacerbation of asthma

The aetiology of asthma associated with viral infection is complex. The dynamics that contribute to disease pathogenesis are multifactorial and involve overlapping molecular and cellular mechanisms, particularly the immune response to respiratory virus infection or allergen sensitization. This review summarizes the evidence associated with factors that may contribute to the development or exacerbation of asthma including age, host factors, genetic polymorphisms, altered immune responses, and aspects of viral antigen expression. This review also provides an important perspective of key events linked to the development of asthmatic disease and related pulmonary inflammation from human and animal studies, and discusses their relationship as targets for disease intervention strategies

Dual proinflammatory and antiviral properties of pulmonary eosinophils in respiratory syncytial virus vaccine-enhanced disease

Human respiratory syncytial virus (RSV) is a major cause of morbidity and severe lower respiratory tract disease in the elderly and very young, with some infants developing bronchiolitis, recurrent wheezing, and asthma following infection. Previous studies in humans and animal models have shown that vaccination with formalin-inactivated RSV (FI-RSV) leads to prominent airway eosinophilic inflammation following RSV challenge; however, the roles of pulmonary eosinophilia in the antiviral response and in disease pathogenesis are inadequately understood. In vivo studies in mice with eotaxin and/or interleukin 5 (IL-5) deficiency showed that FI-RSV vaccination did not lead to enhanced pulmonary disease, where following challenge there were reduced pulmonary eosinophilia, inflammation, Th2-type cytokine responses, and altered chemokine (TARC and CCL17) responses. In contrast to wild-type mice, RSV was recovered at high titers from the lungs of eotaxin- and/or IL-5-deficient mice. Adoptive transfer of eosinophils to FI-RSV-immunized eotaxin- and IL-5-deficient (double-deficient) mice challenged with RSV was associated with potent viral clearance that was mediated at least partly through nitric oxide. These studies show that pulmonary eosinophilia has dual outcomes: one linked to RSV-induced airway inflammation and pulmonary pathology and one with innate features that contribute to a reduction in the viral load. IMPORTANCE This study is critical to understanding the mechanisms attributable to RSV vaccine-enhanced disease. This study addresses the hypothesis that IL-5 and eotaxin are critical in pulmonary eosinophil response related to FI-RSV vaccine-enhanced disease. The findings suggest that in addition to mediating tissue pathology, eosinophils within a Th2 environment also have antiviral activity.This work was supported by Australian National Health and Medical Research Council (NHMRC) grants (399701 and 1047250) to S.M. Y.-C.S. is the recipient of an Australian NHMRC Peter Doherty Training Fellowship. S.M. is the recipient of an Australian NHMRC Senior Research Fellowship (1059167)

Dual proinflammatory and antiviral properties of pulmonary eosinophils in respiratory syncytial virus vaccine-enhanced disease

Human respiratory syncytial virus (RSV) is a major cause of morbidity and severe lower respiratory tract disease in the elderly and very young, with some infants developing bronchiolitis, recurrent wheezing, and asthma following infection. Previous studies in humans and animal models have shown that vaccination with formalin-inactivated RSV (FI-RSV) leads to prominent airway eosinophilic inflammation following RSV challenge; however, the roles of pulmonary eosinophilia in the antiviral response and in disease pathogenesis are inadequately understood. <i>In vivo</i> studies in mice with eotaxin and/or interleukin 5 (IL-5) deficiency showed that FI-RSV vaccination did not lead to enhanced pulmonary disease, where following challenge there were reduced pulmonary eosinophilia, inflammation, Th2-type cytokine responses, and altered chemokine (TARC and CCL17) responses. In contrast to wild-type mice, RSV was recovered at high titers from the lungs of eotaxin- and/or IL-5-deficient mice. Adoptive transfer of eosinophils to FI-RSV-immunized eotaxin- and IL-5-deficient (double-deficient) mice challenged with RSV was associated with potent viral clearance that was mediated at least partly through nitric oxide. These studies show that pulmonary eosinophilia has dual outcomes: one linked to RSV-induced airway inflammation and pulmonary pathology and one with innate features that contribute to a reduction in the viral load

Shared heritability and functional enrichment across six solid cancers

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10−8), breast and ovarian cancer (rg = 0.24, p = 7 × 10−5), breast and lung cancer (rg = 0.18, p =1.5 × 10−6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10−4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis