Recovery from severe H7N9 disease is associated with diverse response mechanisms dominated by CD8+ T cells

Abstract

The avian origin A/H7N9 influenza virus causes high admission rates (>99%) and mortality (>30%), with ultimately favourable outcomes ranging from rapid recovery to prolonged hospitalization. Using a multicolour assay for monitoring adaptive and innate immunity, here we dissect the kinetic emergence of different effector mechanisms across the spectrum of H7N9 disease and recovery. We find that a diversity of response mechanisms contribute to resolution and survival. Patients discharged within 2–3 weeks have early prominent H7N9-specific CD8+ T-cell responses, while individuals with prolonged hospital stays have late recruitment of CD8+/CD4+ T cells and antibodies simultaneously (recovery by week 4), augmented even later by prominent NK cell responses (recovery >30 days). In contrast, those who succumbed have minimal influenza-specific immunity and little evidence of T-cell activation. Our study illustrates the importance of robust CD8+ T-cell memory for protection against severe influenza disease caused by newly emerging influenza A viruses.

Fc functional antibodies in humans with severe H7N9 and seasonal influenza

“…Severe human H7N9 infection has a high mortality rate (3) and leads to immune dysfunction on many levels, so we cannot assert that this observed reduction in HA-specific Fc functional Abs was causally related to their death (9)(10)(11). Previous work on this cohort showed that the CD8 + T cell response was also impaired in people who died from H7N9 infection (6) and that these subjects commonly had other comorbidities (7). There is a growing interest in passive transfer of anti-influenza Abs in severe influenza, with some efficacy observed in small human studies (43,44) and animal models (45).…”

“…Of the 4 subjects hospitalized with influenza B, 2 were infected with viruses from the Yamagata lineage, 1 was infected with a virus from the Victoria lineage, and 1 virus could not be sequenced (Supplemental Table 1 HI and FRA. HI and luciferase-based pseudovirus neutralization (with an HIV backbone carrying H7 and N9) assays with H7N9-infected sera were performed as previously described (6,7). HI assays with plasma/sera from subjects with seasonal influenza infections were carried out as described in Kristensen et al (35).…”

“…Neutralizing antibodies (Abs) (NAbs), T cells, and natural killer (NK) cell responses were associated with recovery in a cohort of 18 subjects with severe human H7N9 infection (6,7). In the absence of vaccination, partial immunity to seasonal influenza is driven by immune responses to repeated infections with related strains.…”

“…A Additional details on the H7N9-infected subjects are present in references (6,7). B One DISI subject acquired influenza after 4 days of hospitalization.…”

Differential Recognition of Influenza A Viruses by M158–66Epitope-Specific CD8+T Cells Is Determined by Extraepitopic Amino Acid Residues

“…The recognition of conserved proteins results in a high degree of cross-reactivity with antigenically distinct IAVs (13,14,16,17). Although CTLs do not afford sterilizing immunity, they contribute substantially to viral clearance and reduce the severity of infections with influenza viruses, including those with antigenically distinct HA or NA (18)(19)(20). However, the high mutation rate of influenza viruses and the selective pressure exerted by virus-specific CTLs drive the accumulation of amino acid substitutions that are associated with evasion from recognition by CTLs specific for some epitopes.…”