Uncovering mechanisms of innate resistance against viral infection amongst Irish women exposed to hepatitis C virus via contaminated anti-D immunoglobulin
M. W. Robinson1, C. Keane1, M. Needham1, G. Roche1, C. Gardiner1, D. Houlihan2, and C. O’Farrelly1,3
1 School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland 2 Liver Unit, St. Vincent’s University Hospital, Dublin 4, Ireland 3 School of Medicine, Trinity College Dublin, Dublin 2, Ireland
Understanding the immune mechanisms confering resistance against viral infection is vital for future therapeutic and vaccination strategies targeting hepatitis C virus (HCV). Studies of resistance to viral infection in humans are hampered by a lack of suitable cohorts with defined pathogen exposure and no documented evidence of infection. In Ireland individuals exposed to HCV through contaminated anti-D immunoglobulin provide a unique opportunity to study mechanisms of innate resistance in a well-defined human cohort.
Hundreds of Irish women received documented high-risk batches of contaminated anti-D immunoglobulin and yet subsequently tested negative for any evidence of previous infection. We hypothesise that these exposed seronegative (ESN) individuals have enhanced innate immune function capable of providing innate resistance against HCV infection. The aim of this study was to profile innate immune responses in a pilot group of ESN individuals who received contaminated anti-D immunoglobulin.
To explore potential mechanisms of viral resistance, we profiled innate immune function in ESN recipients of contaminated anti-D immunoglobulin (n = 16) and matched healthy controls (n = 9). Initial screening assays assessed circulating cytokine levels and immune cell responsiveness to interferon (IFN)α, in addition to targeted assays focusing on natural killer (NK) cell function.
Analysis of intracellular signalling following IFNα stimulation identified enhanced signalling exclusively in NK cells of ESN individuals compared to matched unexposed controls (mean MFI fold change 2.81 vs 1.96, P-value = 0.003). Circulating proinflammatory cytokine levels were largely comparable to matched unexposed controls with the exception of interleukin (IL)8 and IL18, which were elevated in exposed seronegative individuals. At a functional level CD56dim NK cells from exposed seronegative individuals had stronger IFNγ responses following IL2/IL12/IL18 pre-activation and 721.221 target cell stimulation compared to matched unexposed controls (mean % IFNγ[+] CD56dim NK cells 50.9 vs 31.8, P-value = 0.046).
Our results describe a general enhancement of NK cell activity in ESN individuals that provides insights into the mechanisms of enhanced innate immune cell function. This work highlights the potential of Irish women who received contaminated anti-D immunoglobulin for discovering novel mechanisms that confer innate resistance to viral infection.