The induction and consequences of Influenza A virus-induced cell death

Atkin-Smith, Georgia K.; Duan, Mubing; Chen, Weisan; Poon, Ivan K. H.

doi:10.1038/s41419-018-1035-6

Cited by 101 publications

(92 citation statements)

References 111 publications

(180 reference statements)

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“…This acute inflammation in response to influenza infection is mediated by lung monocytes and monocytederived dendritic cells that are involved in the detection and clearance of influenza virus and influenza pathogenesis in the lungs [80]. These innate immune cells are not only susceptible to influenza-induced apoptotic and necrotic cell death [81], influenza infection has a direct effect on monocytes which results in the downregulation of Th17-mediated immunity necessary for protection against secondary pneumococcal pneumonia [82]. This effect of influenza infection on the monocyte function necessary for the clearance of pneumococcus has recently been demonstrated in a human challenge model [83].…”

Section: Role Of Innate Immune Cells In Influenza Infectionmentioning

confidence: 99%

The immune response to influenza in older humans: beyond immune senescence

et al. 2020

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Despite widespread influenza vaccination programs, influenza remains a major cause of morbidity and mortality in older adults. Age-related changes in multiple aspects of the adaptive immune response to influenza have been well-documented including a decline in antibody responses to influenza vaccination and changes in the cellmediated response associated with immune senescence. This review will focus on T cell responses to influenza and influenza vaccination in older adults, and how increasing frailty or coexistence of multiple (≥2) chronic conditions contributes to the loss of vaccine effectiveness for the prevention of hospitalization. Further, dysregulation of the production of pro-and anti-inflammatory mediators contributes to a decline in the generation of an effective CD8 T cell response needed to clear influenza virus from the lungs. Current influenza vaccines provide only a weak stimulus to this arm of the adaptive immune response and rely on re-stimulation of CD8 T cell memory related to prior exposure to influenza virus. Efforts to improve vaccine effectiveness in older adults will be fruitless until CD8 responses take center stage.

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Section: Role Of Innate Immune Cells In Influenza Infectionmentioning

confidence: 99%

The immune response to influenza in older humans: beyond immune senescence

et al. 2020

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“…Therefore, the numbers of neutrophils at the infected lungs must be tightly tuned to maximize efficient viral clearance while minimizing immunopathology (10). In such settings, the initiation of neutrophil apoptosis and consequent reduction in neutrophil numbers may be advantageous to limit lung inflammation and bystander tissue injury (11). To this end, however, a direct link between excess neutrophil recruitment and/or survival and the extent of pulmonary inflammation during IAV infection remains unclear.…”

mentioning

confidence: 99%

BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection

Zhu

Zhang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Neutrophils are vital for antimicrobial defense; however, their role during viral infection is less clear. Furthermore, the molecular regulation of neutrophil fate and function at the viral infected sites is largely elusive. Here we report that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza A virus (IAV) infection. In contrast to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cre-transgenic, reporter, and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or lung macrophages, attenuated host inflammation and morbidity following IAV infection. Mechanistically, BCL6 bound to the neutrophil gene loci involved in cellular apoptosis in cells specifically at the site of infection. As such, BCL6 disruption resulted in increased expression of apoptotic genes in neutrophils in the respiratory tract, but not in the circulation or bone marrow. Consequently, BCL6 deficiency promoted tissue neutrophil apoptosis. Partial neutrophil depletion led to diminished pulmonary inflammation and decreased host morbidity. Our results reveal a previously unappreciated role of BCL6 in modulating neutrophil apoptosis at the site of infection for the regulation of host disease development following viral infection. Furthermore, our studies indicate that tissue-specific regulation of neutrophil survival modulates host inflammation and tissue immunopathology during acute respiratory viral infection.

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“…An alternative explanation comes from our Calu-3 model, in which we found that MIF increases cellular necrosis or delayed clearance of apoptotic cells during late stages of IAV infection and enhances viral replication. This may explain MIF's ability to enhance viral replication, as cells exhibiting increased late apoptotic and necrotic characteristics during late stages of infection have been a marker of enhanced IAV propagation (38,40).…”

Section: Discussionmentioning

confidence: 99%