Paediatrics (RCH) - Research Publications

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    Neonatal BCG vaccination is associated with a long-term DNA methylation signature in circulating monocytes
    Bannister, S ; Kim, B ; Dominguez-Andres, J ; Kilic, G ; Ansell, BRE ; Neeland, MR ; Moorlag, SJCFM ; Matzaraki, V ; Vlahos, A ; Shepherd, R ; Germano, S ; Bahlo, M ; Messina, NL ; Saffery, R ; Netea, MG ; Curtis, N ; Novakovic, B (AMER ASSOC ADVANCEMENT SCIENCE, 2022-08-05)
    Trained immunity describes the capacity of innate immune cells to develop heterologous memory in response to certain exogenous exposures. This phenomenon mediates, at least in part, the beneficial off-target effects of the BCG vaccine. Using an in vitro model of trained immunity, we show that BCG exposure induces a persistent change in active histone modifications, DNA methylation, transcription, and adenosine-to-inosine RNA modification in human monocytes. By profiling DNA methylation of circulating monocytes from infants in the MIS BAIR clinical trial, we identify a BCG-associated DNA methylation signature that persisted more than 12 months after neonatal BCG vaccination. Genes associated with this epigenetic signature are involved in viral response pathways, consistent with the reported off-target protection against viral infections in neonates, adults, and the elderly. Our findings indicate that the off-target effects of BCG in infants are accompanied by epigenetic remodeling of circulating monocytes that lasts more than 1 year.
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    Virology and immune dynamics reveal high household transmission of ancestral SARS-CoV-2 strain
    Tosif, S ; Haycroft, ER ; Sarkar, S ; Toh, ZQ ; Lien, AHD ; Donato, CM ; Selva, KJ ; Hoq, M ; Overmars, I ; Nguyen, J ; Lee, L-Y ; Clifford, V ; Daley, A ; Mordant, FL ; McVernon, J ; Mulholland, K ; Marcato, AJ ; Smith, MZ ; Curtis, N ; McNab, S ; Saffery, R ; Kedzierska, K ; Subarrao, K ; Burgner, D ; Steer, A ; Bines, JE ; Sutton, P ; Licciardi, P ; Chung, AW ; Neeland, MR ; Crawford, NW (WILEY, 2022-07)
    BACKGROUND: Household studies are crucial for understanding the transmission of SARS-CoV-2 infection, which may be underestimated from PCR testing of respiratory samples alone. We aim to combine the assessment of household mitigation measures; nasopharyngeal, saliva, and stool PCR testing; along with mucosal and systemic SARS-CoV-2-specific antibodies, to comprehensively characterize SARS-CoV-2 infection and transmission in households. METHODS: Between March and September 2020, we obtained samples from 92 participants in 26 households in Melbourne, Australia, in a 4-week period following the onset of infection with ancestral SARS-CoV-2 variants. RESULTS: The secondary attack rate was 36% (24/66) when using nasopharyngeal swab (NPS) PCR positivity alone. However, when respiratory and nonrespiratory samples were combined with antibody responses in blood and saliva, the secondary attack rate was 76% (50/66). SARS-CoV-2 viral load of the index case and household isolation measures were key factors that determine secondary transmission. In 27% (7/26) of households, all family members tested positive by NPS for SARS-CoV-2 and were characterized by lower respiratory Ct values than low transmission families (Median 22.62 vs. 32.91; IQR 17.06-28.67 vs. 30.37-34.24). High transmission families were associated with enhanced plasma antibody responses to multiple SARS-CoV-2 antigens and the presence of neutralizing antibodies. Three distinguishing saliva SARS-CoV-2 antibody features were identified according to age (IgA1 to Spike 1, IgA1 to nucleocapsid protein (NP)), suggesting that adults and children generate distinct mucosal antibody responses during the acute phase of infection. CONCLUSION: Utilizing respiratory and nonrespiratory PCR testing, along with the measurement of SARS-CoV-2-specific local and systemic antibodies, provides a more accurate assessment of infection within households and highlights some of the immunological differences in response between children and adults.
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    Children and Adults in a Household Cohort Study Have Robust Longitudinal Immune Responses Following SARS-CoV-2 Infection or Exposure
    Neeland, MR ; Bannister, S ; Clifford, V ; Nguyen, J ; Dohle, K ; Overmars, I ; Toh, ZQ ; Anderson, J ; Donato, CM ; Sarkar, S ; Do, LAH ; McCafferty, C ; Licciardi, PV ; Ignjatovic, V ; Monagle, P ; Bines, JE ; Mulholland, K ; Curtis, N ; McNab, S ; Steer, AC ; Burgner, DP ; Saffery, R ; Tosif, S ; Crawford, NW (FRONTIERS MEDIA SA, 2021-10-13)
    Children have reduced severity of COVID-19 compared to adults and typically have mild or asymptomatic disease. The immunological mechanisms underlying these age-related differences in clinical outcomes remain unexplained. Here, we quantify 23 immune cell populations in 141 samples from children and adults with mild COVID-19 and their PCR-negative close household contacts at acute and convalescent time points. Children with COVID-19 displayed marked reductions in myeloid cells during infection, most prominent in children under the age of five. Recovery from infection in both children and adults was characterised by the generation of CD8 TCM and CD4 TCM up to 9 weeks post infection. SARS-CoV-2-exposed close contacts also had immunological changes over time despite no evidence of confirmed SARS-CoV-2 infection on PCR testing. This included an increase in low-density neutrophils during convalescence in both exposed children and adults, as well as increases in CD8 TCM and CD4 TCM in exposed adults. In comparison to children with other common respiratory viral infections, those with COVID-19 had a greater change in innate and T cell-mediated immune responses over time. These findings provide new mechanistic insights into the immune response during and after recovery from COVID-19 in both children and adults.
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    Immune responses to SARS-CoV-2 in children of parents with symptomatic COVID-19
    Tosif, S ; Neeland, M ; Sutton, P ; Licciardi, P ; Sarkar, S ; Selva, K ; Do, LAH ; Donato, C ; Toh, ZQ ; Higgins, R ; de Sandt, CV ; Lemke, M ; Lee, C ; Shoffner, S ; Flanagan, K ; Arnold, K ; Mordant, F ; Mulholland, K ; Bines, J ; Dohle, K ; Pellicci, D ; Curtis, N ; McNab, S ; Steer, A ; Saffery, R ; Subbarao, K ; Chung, A ; Kedzierska, K ; Burgner, D ; Crawford, N ( 2020)
    Compared to adults, children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have mild or asymptomatic infection, but the underlying immunological differences remain unclear. We describe clinical features, virology, longitudinal cellular and cytokine immune profile, SARS-CoV-2-specific serology and salivary antibody responses in a family of two parents with PCR-confirmed symptomatic SARS-CoV-2 infection and their three children, who were repeatedly SARS-CoV-2 PCR negative. Cellular immune profiles and cytokine responses of all children were similar to their parents at all timepoints. All family members had salivary anti-SARS-CoV-2 antibodies detected, predominantly IgA, that coincided with symptom resolution in 3 of 4 symptomatic members. Plasma from both parents and one child had IgG antibody detected against the S1 protein and virus neutralising activity ranging from just detectable to robust titers. Using a systems serology approach, we show that all family members demonstrated higher levels of SARS-CoV-2-specific antibody features than healthy controls. These data indicate that children can mount an immune response to SARS-CoV-2 without virological evidence of infection. This raises the possibility that despite chronic exposure, immunity in children prevents establishment of SARS-CoV-2 infection. Relying on routine virological and serological testing may therefore not identify exposed children, with implications for epidemiological and clinical studies across the life-span.
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    Innate cell profiles during the acute and convalescent phase of SARS-CoV-2 infection in children
    Neeland, MR ; Bannister, S ; Clifford, V ; Dohle, K ; Mulholland, K ; Sutton, P ; Curtis, N ; Steer, AC ; Burgner, DP ; Crawford, NW ; Tosif, S ; Saffery, R (NATURE PORTFOLIO, 2021-02-17)
    Children have mild severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confirmed disease (COVID-19) compared to adults and the immunological mechanisms underlying this difference remain unclear. Here, we report acute and convalescent innate immune responses in 48 children and 70 adults infected with, or exposed to, SARS-CoV-2. We find clinically mild SARS-CoV-2 infection in children is characterised by reduced circulating subsets of monocytes (classical, intermediate, non-classical), dendritic cells and natural killer cells during the acute phase. In contrast, SARS-CoV-2-infected adults show reduced proportions of non-classical monocytes only. We also observe increased proportions of CD63+ activated neutrophils during the acute phase to SARS-CoV-2 in infected children. Children and adults exposed to SARS-CoV-2 but negative on PCR testing display increased proportions of low-density neutrophils that we observe up to 7 weeks post exposure. This study characterises the innate immune response during SARS-CoV-2 infection and household exposure in children.
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    Immune responses to SARS-CoV-2 in three children of parents with symptomatic COVID-19
    Tosif, S ; Neeland, MR ; Sutton, P ; Licciardi, PV ; Sarkar, S ; Selva, KJ ; Lien, AHD ; Donato, C ; Toh, ZQ ; Higgins, R ; Van de Sandt, C ; Lemke, MM ; Lee, CY ; Shoffner, SK ; Flanagan, KL ; Arnold, KB ; Mordant, FL ; Mulholland, K ; Bines, J ; Dohle, K ; Pellicci, DG ; Curtis, N ; McNab, S ; Steer, A ; Saffery, R ; Subbarao, K ; Chung, AW ; Kedzierska, K ; Burgner, DP ; Crawford, NW (NATURE PORTFOLIO, 2020-11-11)
    Compared to adults, children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have predominantly mild or asymptomatic infections, but the underlying immunological differences remain unclear. Here, we describe clinical features, virology, longitudinal cellular, and cytokine immune profile, SARS-CoV-2-specific serology and salivary antibody responses in a family of two parents with PCR-confirmed symptomatic SARS-CoV-2 infection and their three children, who tested repeatedly SARS-CoV-2 PCR negative. Cellular immune profiles and cytokine responses of all children are similar to their parents at all timepoints. All family members have salivary anti-SARS-CoV-2 antibodies detected, predominantly IgA, that coincide with symptom resolution in 3 of 4 symptomatic members. Plasma from both parents and one child have IgG antibody against the S1 protein and virus-neutralizing activity detected. Using a systems serology approach, we demonstrate higher levels of SARS-CoV-2-specific antibody features of these family members compared to healthy controls. These data indicate that children can mount an immune response to SARS-CoV-2 without virological confirmation of infection, raising the possibility that immunity in children can prevent the establishment of SARS-CoV-2 infection. Relying on routine virological and serological testing may not identify exposed children, with implications for epidemiological and clinical studies across the life-span.
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    A Potential Role for Epigenetically Mediated Trained Immunity in Food Allergy
    Imran, S ; Neeland, MR ; Shepherd, R ; Messina, N ; Perrett, KP ; Netea, MG ; Curtis, N ; Saffery, R ; Novakovic, B (CELL PRESS, 2020-06-26)
    The prevalence of IgE-mediated food allergy is increasing at a rapid pace in many countries. The association of high food allergy rates with Westernized lifestyles suggests the role of gene-environment interactions, potentially underpinned by epigenetic variation, in mediating this process. Recent studies have implicated innate immune system dysfunction in the development and persistence of food allergy. These responses are characterized by increased circulating frequency of innate immune cells and heightened inflammatory responses to bacterial stimulation in food allergic patients. These signatures mirror those described in trained immunity, whereby innate immune cells retain a "memory" of earlier microbial encounters, thus influencing subsequent immune responses. Here, we propose that a robust multi-omics approach that integrates immunological, transcriptomic, and epigenomic datasets, combined with well-phenotyped and longitudinal food allergy cohorts, can inform the potential role of trained immunity in food allergy.