Mucosal Immune Responses Predict Clinical Outcomes during Influenza Infection Independently of Age and Viral Load

Oshansky, Christine M.; Gartland, Andrew J.; Wong, Sook‐San; Jeevan, Trushar; Wang, David; Roddam, Philippa L.; Caniza, Miguela; Hertz, Tomer; DeVincenzo, John P.; Webby, Richard J.; Thomas, Paul G.

doi:10.1164/rccm.201309-1616oc

Cited by 157 publications

(221 citation statements)

References 34 publications

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“…This apparent discordance is also observed in studies examining whether CMV infection alters influenza vaccine responses and highlights the need for further investigation into interacting factors, such as age. The age of an individual is a unique factor in the context of CMV co-infection because it alters three aspects of infection control and immunity: (1) the normal aging of the immune system and age-associated effects independent of CMV status; (2) the chronic immune profile associated with CMV (e.g., memory inflation); and (3) potential independent associations with the etiologic agent of the secondary infection (e.g., younger individuals can have more severe influenza virus infection and exhibit hyperinflammatory immune responses) (Oshansky et al 2014;Wertheimer et al 2014;Furman et al 2015;Whiting et al 2015).…”

Section: Acute Co-infectionmentioning

confidence: 99%

A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness

Souquette¹,

Frere²,

Smithey³

et al. 2017

GeroScience

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Approximately 50% of individuals aged 6-49 years in the United States are infected with cytomegalovirus (CMV), with seroprevalence increasing with age, reaching 85-90% by 75-80 years according to Bate et al. (Clin Infect Dis 50 (11): 1439-1447 and Pawelec et al. (Curr Opin Immunol 24:507-511, 2012). Following primary infection, CMV establishes lifelong latency with periodic reactivation. Immunocompetent hosts experience largely asymptomatic infection, but CMV can cause serious illness in immunocompromised populations, such as transplant patients and the elderly. Control of CMV requires constant immune surveillance, and recent discoveries suggest this demand alters general features of the immune system in infected individuals. Here, we review recent advances in the understanding of the immune response to CMV and the role of CMV in immune aging and fitness, while highlighting the importance of potential confounding factors that influence CMV studies. Understanding how CMV contributes to shaping Bbaseline^immunity has important implications for a host's ability to mount effective responses to diverse infections and vaccination.

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Section: Acute Co-infectionmentioning

confidence: 99%

A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness

Souquette¹,

Frere²,

Smithey³

et al. 2017

GeroScience

Self Cite

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“…In general terms, high levels of proinflammatory cytokines have been associated with severe disease following infection with highly pathogenic influenza viruses (reviewed in reference 7). Moreover, specific cytokines have been correlated with disease severity in both human (8)(9)(10)(11)(12)(13) and animal (14)(15)(16) studies.…”

mentioning

confidence: 99%

Characterization of the Localized Immune Response in the Respiratory Tract of Ferrets following Infection with Influenza A and B Viruses

Carolan

Rockman

Borg

et al. 2016

J Virol

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The burden of infection with seasonal influenza viruses is significant. Each year is typically characterized by the dominance of one (sub)type or lineage of influenza A or B virus, respectively. The incidence of disease varies annually, and while this may be attributed to a particular virus strain or subtype, the impacts of prior immunity, population differences, and variations in clinical assessment are also important. To improve our understanding of the impacts of seasonal influenza viruses, we directly compared clinical symptoms, virus shedding, and expression of cytokines, chemokines, and immune mediators in the upper respiratory tract (URT) of ferrets infected with contemporary A(H1N1)pdm09, A(H3N2), or influenza B virus. Gene expression in the lower respiratory tract (LRT) was also assessed. Clinical symptoms were minimal. Overall cytokine/chemokine profiles in the URT were consistent in pattern and magnitude between animals infected with influenza A and B viruses, and peak expression levels of interleukin-1␣ (IL-1␣), IL-1␤, IL-6, IL-12p40, alpha interferon (IFN-␣), IFN-␤, and tumor necrosis factor alpha (TNF-␣) mRNAs correlated with peak levels of viral shedding. MCP1 and IFN-␥ were expressed after the virus peak. Granzymes A and B and IL-10 reached peak expression as the virus was cleared and seroconversion was detected. Cytokine/chemokine gene expression in the LRT following A(H1N1)pdm09 virus infection reflected the observations seen for the URT but was delayed 2 or 3 days, as was virus replication. These data indicate that disease severities and localized immune responses following infection with seasonal influenza A and B viruses are similar, suggesting that other factors are likely to modulate the incidence and impact of seasonal influenza. IMPORTANCEBoth influenza A and B viruses cocirculate in the human population, and annual influenza seasons are typically dominated by an influenza A virus subtype or an influenza B virus lineage. Surveillance data indicate that the burden of disease is higher in some seasons, yet it is unclear whether this is due to specific virus strains or to other factors, such as cross-reactive immunity or clinical definitions of influenza. We directly compared disease severities and localized inflammatory responses to different seasonal influenza virus strains, including the 2009 pandemic strain, in healthy naive ferrets. We found that the disease severities and the cytokine and chemokine responses were similar irrespective of the seasonal strain or the location of the infection in the respiratory tract. This suggests that factors other than the immune response to a particular virus (sub)type contribute to the variable impact of influenza virus infection in a population. Morbidity and mortality associated with human influenza virus infection are significant worldwide. Influenza is caused by three virus types (A, B, and C), among which types A and B are responsible for most of the diagnosed cases of seasonal influenza. Influenza A viruses attract the greatest attentio...

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“…The timing of monocyte appearance in the upper airways coincides with the decline of viral replication, suggesting that this population may contribute to the eradication of H1N1 and recovery of infant airways. Although we did not immunophenotype the monocytes in our model, these cells may be similar to a monocyte population recently identified in the nasal lavage fluid of influenza-infected pediatric patients, which was thought to suppress mucosal cytokine inflammation (51). Recent reports suggest a higher pathogenic potential for pandemic than for seasonal H1N1.…”

Section: Discussionmentioning

confidence: 68%

Enhanced Viral Replication and Modulated Innate Immune Responses in Infant Airway Epithelium following H1N1 Infection

Clay

Gerriets

Wang

et al. 2014

J Virol

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Influenza is the cause of significant morbidity and mortality in pediatric populations. The contribution of pulmonary host defense mechanisms to viral respiratory infection susceptibility in very young children is poorly understood. As a surrogate to compare mucosal immune responses of infant and adult lungs, rhesus monkey primary airway epithelial cell cultures were infected with pandemic influenza A/H1N1 virus in vitro. Virus replication, cytokine secretion, cell viability, and type I interferon (IFN) pathway PCR array profiles were evaluated for both infant and adult cultures. In comparison with adult cultures, infant cultures showed significantly increased levels of H1N1 replication, reduced alpha interferon (IFN-␣) protein synthesis, and no difference in cell death following infection. Age-dependent differences in expression levels of multiple genes associated with the type I IFN pathway were observed in H1N1-infected cultures. To investigate the pulmonary and systemic responses to H1N1 infection in early life, infant monkeys were inoculated with H1N1 by upper airway administration. Animals were monitored for virus and parameters of inflammation over a 14-day period. High H1N1 titers were recovered from airways at day 1, with viral RNA remaining detectable until day 9 postinfection. Despite viral clearance, bronchiolitis and alveolitis persisted at day 14 postinfection; histopathological analysis revealed alveolar septal thickening and intermittent type II pneumocyte hyperplasia. Our overall findings are consistent with the known susceptibility of pediatric populations to respiratory virus infection and suggest that intrinsic developmental differences in airway epithelial cell immune function may contribute to the limited efficacy of host defense during early childhood. IMPORTANCETo the best of our knowledge, this study represents the first report of intrinsic developmental differences in infant airway epithelial cells that may contribute to the increased susceptibility of the host to respiratory virus infections. Despite the global burden of influenza, there are currently no vaccine formulations approved for children <6 months of age. Given the challenges of conducting experimental studies involving pediatric patients, rhesus monkeys are an ideal laboratory animal model to investigate the maturation of pulmonary mucosal immune mechanisms during early life because they are most similar to those of humans with regard to postnatal maturation of the lung structure and the immune system. Thus, our findings are highly relevant to translational medicine, and these data may ultimately lead to novel approaches that enhance airway immunity in very young children.

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Mucosal Immune Responses Predict Clinical Outcomes during Influenza Infection Independently of Age and Viral Load

Cited by 157 publications

References 34 publications

A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness

A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness

Characterization of the Localized Immune Response in the Respiratory Tract of Ferrets following Infection with Influenza A and B Viruses

Enhanced Viral Replication and Modulated Innate Immune Responses in Infant Airway Epithelium following H1N1 Infection

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