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Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes.

ABSTRACT: Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. The mechanism of illness associated with severe disease in this age group is not well understood. Here we find preexisting serum antibodies that cross-react with, but do not protect against, 2009 H1N1 influenza virus in middle-aged adults. Nonprotective antibody is associated with immune complex-mediated disease after infection. We detected high titers of serum antibody of low avidity for H1-2009 antigen, and low-avidity pulmonary immune complexes against the same protein, in severely ill individuals. Moreover, C4d deposition--a marker of complement activation mediated by immune complexes--was present in lung sections of fatal cases. Archived lung sections from middle-aged adults with confirmed fatal influenza 1957 H2N2 infection revealed a similar mechanism of illness. These observations provide a previously unknown biological mechanism for the unusual age distribution of severe cases during influenza pandemics.

SUBMITTER: Monsalvo AC

PROVIDER: S-EPMC3034774 | biostudies-other | 2011 Feb

REPOSITORIES: biostudies-other

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Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes.

Monsalvo Ana Clara AC Batalle Juan P JP Lopez M Florencia MF Krause Jens C JC Klemenc Jennifer J Hernandez Johanna Zea JZ Maskin Bernardo B Bugna Jimena J Rubinstein Carlos C Aguilar Leandro L Dalurzo Liliana L Libster Romina R Savy Vilma V Baumeister Elsa E Aguilar Liliana L Cabral Graciela G Font Julia J Solari Liliana L Weller Kevin P KP Johnson Joyce J Echavarria Marcela M Edwards Kathryn M KM Chappell James D JD Crowe James E JE Williams John V JV Melendi Guillermina A GA Polack Fernando P FP

Nature medicine 20101205 2

Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. The mechanism of illness associated with severe disease in this age group is not well understood. Here we find preexisting serum antibodies that cross-react with, but do not protect against, 2009 H1N1 influenza virus in middle-aged adults. Nonprotective antibody is associated with immune complex-mediated disease after infection. We detected high titers of serum antibody of low avidity f ...[more]

PMID: 21131958

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Project description:In June 2009, the World Health Organization declared the first influenza pandemic of the 21st century, due to the emergence and rapid spread of new swine origin H1N1 influenza A virus. In contrast to seasonal influenza infections, which typically cause morbidity and mortality in the elderly, this virus caused severe infection in young adults and not the elderly. This phenomenon was attributed to the presence of cross-neutralizing antibodies acquired by older individuals from previous exposure to swine origin influenza. However, this hypothesis could not be empirically tested using clinical data. To address this question, we investigated viral replication and the development of the immune response in naï12 years old) and aged (20 to 24 years old) female rhesus macaques infected with A/California/04/2009 (H1N1), one of the circulating pandemic strains in 2009. We compared viral loads as well as the kinetics and magnitude of the adaptive immune response in peripheral blood and bronchoalveolar lavage samples (BAL) collected longitudinally for 99 days post-infection. Although, adult animals exhibited earlier T cell responses in peripheral blood, aged animals generated a robust T cell response with comparable kinetics and magnitude as those observed in young animals in BAL. Moreover, aged animals generated a higher hemagglutination inhibition titer compared to young animals. We also measured the concentration of several cytokines in BAL supernatant. With the exception of IL-8, which was higher in aged animals, we found no differences in IFNa, IFNb, TNFa, IL-1r, IL-6, IL-15, IL-17, or MCP1 levels. Finally, we compared gene expression infection using microarray analysis of BAL samples taken on days 0, 4, 7, 10, and 14 pi. Our analyses revealed that the largest difference in host response between aged and young animals was detected day 4 post-infection, with significant enrichment for genes associated with inflammation, the innate immune response, and T cell activation in aged animals. The ability of aged animals to generate a robust immune response, especially antibody response, following infection with 2009 H1N1 virus could explain the lack of morbidity normally observed with seasonal influenza viruses in this vulnerable population.

Dataset Information

Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes.

Publications

Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes.

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