Competition between influenza A virus subtypes through heterosubtypic immunity modulates re-infection and antibody dynamics in the mallard duck

Abstract

Our overall hypothesis is that host population immunity directed at multiple antigens will influence the prevalence, diversity and evolution of influenza A virus (IAV) in avian populations where the vast subtype diversity is maintained. To investigate how initial infection influences the outcome of later infections with homologous or heterologous IAV subtypes and how viruses interact through host immune responses, we carried out experimental infections in mallard ducks (Anas platyrhynchos). Mallards were pre-challenged with an H3N8 low-pathogenic IAV and were divided into six groups. At five weeks post H3N8 inoculation, each group was challenged with a different IAV subtype (H4N5, H10N7, H6N2, H12N5) or the same H3N8. Two additional pre-challenged groups were inoculated with the homologous H3N8 virus at weeks 11 and 15 after pre-challenge to evaluate the duration of protection. The results showed that mallards were still resistant to re-infection after 15 weeks. There was a significant reduction in shedding for all pre-challenged groups compared to controls and the outcome of the heterologous challenges varied according to hemagglutinin (HA) phylogenetic relatedness between the viruses used. There was a boost in the H3 antibody titer after re-infection with H4N5, which is consistent with original antigenic sin or antigenic seniority and suggest a putative strategy of virus evasion. These results imply competition between related subtypes that could regulate IAV subtype population dynamics in nature. Collectively, we provide new insights into within-host IAV complex interactions as drivers of IAV antigenic diversity that could allow the circulation of multiple subtypes in wild ducks.

As the Duck Flies—Estimating the Dispersal of Low-Pathogenic Avian Influenza Viruses by Migrating Mallards

“…This is a simplification of the course of an individual's infection with LPAIV. Yet, individual variation in time to clearing infections is substantial (e.g., Latorre-Margalef et al, 2009;Tolf et al, 2013), and dependent on previous exposure to the same or other strains or subtypes of LPAIV (e.g., Costa et al, 2010;Verhagen et al, 2015;Latorre-Margalef et al, 2017). We thus think that using a simplified process was justified, and does not overestimate time to recovery.…”

Development of an influenza virus protein microarray to measure the humoral response to influenza virus infection in mallards

“…In contrast to sequential inoculation with H3N8, inoculation of H3N8-infected animals with H4N5 led to a dramatic change in antibody repertoire, including a strongly boosted response to H3 and a broadening of the reactivity to other group 2 HAs, with a proportion of the response being driven by antibodies to the conserved stalk of HA. Interestingly, it has been shown that the degree of protection of mallard ducks after a secondary infection with a different virus subtype correlates to the similarity between HAs 5 and may be the result of reactivity of anti-stalk antibodies. The induction of broadly reactive anti-stalk antibodies has been reported in mice and humans that were sequentially exposed to different HA subtypes of the same group 30 , 32 , 33 , 36 , 37 , 38 , 39 (for example, H1 and H5), but this phenomenon has not been reported so far in avian species.…”

“…Mallard ( Anas platyrhynchos ) sera used in the study were available from a previously published study. 5 All work was approved by the University of Georgia Animal Care and Use Committee under AUP number A2013 05–021. Mallards were raised in captivity at the Animal Resources College of Veterinary medicine at the University of Georgia, and confirmed to be naive to influenza virus by nucleoprotein ELISA.…”

“… 3 , 4 The mechanisms underlying these seasonal patterns are not known, but one possibility is that they are driven by the induction of humoral cross protective immunity after early infections. 5 , 6 Given the capacity for influenza viruses to spread via migratory avian hosts, as observed when H5N8 spread across North America in 2015, 7 it is important to study the mechanics underlying these seasonal dynamics. This is specifically interesting in light of cross-reactivity/cross-protection within group 1 (H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17 and H18) and group 2 (H3, H4, H7, H10, H14 and H15) hemagglutinnin (HA) expressing viruses by stalk-reactive monoclonal antibodies isolated from humans and mice.…”

The roles of migratory and resident birds in local avian influenza infection dynamics

“…In our effort to construct relatively simple models allowing for comprehensive testing of a set of hypothesised drivers for local AIV infection dynamics, we had to make a considerable number of assumptions. Possibly the most important one is that we ignored the existence of viral subtypes, and that AIV infection might elicit subtype specific immunity against further infections (Latorre‐Margalef et al., ). However, ducks may show limited immune responses to AIV infection contrasting findings from, for example, chickens (Kida et al., ) and can quickly be reinfected with the same AIV subtype (Chaise et al., ) providing support for our simplifying approach to ignore potential antigenic variation in AIV infected mallards.…”