Influenza, but not SARS‐CoV‐2, infection induces a rapid interferon response that wanes with age and diminished tissue‐resident memory CD8⁺ T cells

Abstract

Older individuals exhibit a diminished ability to respond to and clear respiratory pathogens and, as such, experience a higher rate of lung infections with a higher mortality rate. It is unclear why respiratory pathogens impact older people disproportionately. Using human lung tissue from donors aged 22-68 years, we assessed how the immune cell landscape in lungs changes throughout life and investigated how these immune cells respond following in vitro exposure to influenza virus and SARS-CoV-2, two clinically relevant respiratory viruses. While the frequency of most immune cell subsets profiled in the human lung remained stable with age, memory CD8 + T cells declined, with the tissueresident memory (Trm) CD8 + T-cell subset being most susceptible to age-associated attrition. Infection of lung tissue with influenza virus resulted in an age-associated attenuation in the antiviral immune response, with aged donors producing less type I interferon (IFN), GM-CSF and IFNc, the latter correlated with a reduction of IFNc-producing memory CD8 + T cells. In contrast, irrespective of donor age, exposure of human lung cells to SARS-CoV-2, a pathogen for which all donors were immunologically na€ ıve, did not trigger activation of local immune cells and did not result in the induction of an early IFN response. Our findings show that the attrition of tissue-bound pathogen-specific Trm in the lung that occurs with advanced age, or their absence in immunologically na€ ıve individuals, results in a diminished early antiviral immune response which creates a window of opportunity for respiratory pathogens to gain a greater foothold.

ACE2-lentiviral transduction enables mouse SARS-CoV-2 infection and mapping of receptor interactions

“…A high level of cross-compensation is thus implicated, as is described in influenza infection [ 84 ]. In vitro experiments show that SARS-CoV-2 replication is sensitive to type I and III IFNs, although infection does not stimulate particularly high levels of IFN [ 85 , 103 , 104 ]. A number of SARS-CoV-2 encoded proteins inhibit IFN production and signaling [ 98 , 105 , 106 ].…”

Tissue resident memory T cells in the respiratory tract

“…Interestingly, recent evidence suggests the quality of the Trm re-call response can be influenced by the identity of the APC which triggers their reactivation, with presentation by hematopoietic APCs-regulating chemokine/cytokine production, and presentation by nonhematopoietic APCs-regulating proliferation 94 . Studies characterizing the immune cell landscape in lung tissue from human organ donors revealed that the human lung harbors a large pool of influenza-specific CD8 + Trm 51 , 93 , 95 – 97 . These cells were shown to be highly proliferative and polyfunctional, composed of a diverse TCRαβ repertoire, and a proportion were cross-reactive against multiple influenza strains 93 , 98 .…”

“…This attrition is consequential as animal studies clearly show that a loss of influenza-specific Trm in the parenchyma and airways correlates with waning cross-protective immunity 17 , 116 , 117 . Similarly, influenza-specific CD8 + Trm in human lung tissue wane with advanced age, and this resulted in a lag in the development of an antiviral response following influenza exposure 95 . The attrition of lung CD8 + Trm is not restricted to influenza-specific Trm cells, as similar findings are observed following Sendai virus 116 , 118 and RSV 101 infections in mice.…”

ACE2-lentiviral transduction enables mouse SARS-CoV-2 infection and mapping of receptor interactions

“…A high level of cross-compensation is thus implicated, as is described in influenza infection (71). In vitro experiments show that SARS-CoV-2 replication is sensitive to type I and III IFNs, although infection does not stimulate particularly high levels of IFN (72, 88, 89). A number of SARS-CoV-2 encoded proteins inhibit IFN production and signaling (83, 90, 91).…”