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* Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112;
Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803; and
Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA 70112
Influenza infection remains a significant cause of pulmonary morbidity and mortality worldwide, with the highest hospitalization and mortality rates occurring in infants and elder adults. The mechanisms inducing this considerable morbidity and mortality are largely unknown. To address this question, we established a neonatal mouse model of influenza infection to test the hypothesis that the immaturity of the neonatal immune system is responsible for the severe pulmonary disease observed in infants. Seven-day-old mice were infected with influenza A virus (H1N1) and allowed to mature. As adults, these mice showed enhanced airway hyperreactivity, chronic pulmonary inflammation, and diffuse emphysematous-type lesions in the lungs. The adaptive immune responses of the neonates were much weaker than those of adults. This insufficiency appeared to be in both magnitude and functionality and was most apparent in the CD8+ T cell population. To determine the role of neonatal CD8+ T cells in disease outcome, adult, naive CD8+ T cells were adoptively transferred into neonates before infection. Neonatal mice receiving the adult CD8+ T cells had significantly lower pulmonary viral titers and greatly improved pulmonary function as adults (airway resistance similar to SHAM). Additional adoptive transfer studies using adult CD8+ T cells from IFN-
-deficient mice demonstrated the importance of IFN- from CD8+ T cells in controlling the infection and in determining disease outcome. Our data indicate that neonates are more vulnerable to severe infections due to immaturity of their immune system and emphasize the importance of vaccination in infants.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grants P20 RR020159 from the LSU/Tulane COBRE-CEIDR Program of the National Center for Research Resources and R01 ES015050 from the National Institutes of Environmental Health to S.A.C. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
2 Current address: Department of Respiratory Medicine, 2nd Affiliated Hospital, College of Medicine of Zhejiang University, Hangzhou, China.
3 Address correspondence and reprint requests to Dr. Stephania Cormier, Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido Street, MEB P7-1, New Orleans, LA 70112. E-mail address: scorm1{at}lsuhsc.edu
4 Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; RSV, respiratory syncytial virus; MeCh, methacholine; DI, destructive index; Lm, mean linear intercept; BALF, bronchoalveolar lavage fluid; dpi, days postinfection; hpi, hours postinfection; AM, alveolar macrophage.
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