title: Fatal outcome of pandemic H1N1 2009 influenza virus infection is associated with immunopathology and impaired lung repair, not enhanced viral burden, in pregnant mice.
abstract: Pandemic A (H1N1) 2009 influenza virus (pH1N1) infection in pregnant women can be severe. The mechanisms that affect infection outcome in this population are not well understood. To address this, pregnant and nonpregnant BALB/c mice were inoculated with the wild-type pH1N1 strain A/California/04/09. To determine whether innate immune responses are associated with severe infection, we measured the innate cells trafficking into the lungs of pregnant versus nonpregnant animals. Increased infiltration of pulmonary neutrophils and macrophages strongly correlated with an elevated mortality in pregnant mice. In agreement with this, the product of nitric oxide (nitrite) and several cytokines associated with recruitment and/or function of these cells were increased in the lungs of pregnant animals. Surprisingly, increased mortality in pregnant mice was not associated with higher virus load because equivalent virus titers and immunohistochemical staining were observed in the nasal cavities or lungs of all mice. To determine whether exacerbated inflammatory responses and elevated cellularity resulted in lung injury, epithelial regeneration was measured. The lungs of pregnant mice exhibited reduced epithelial regeneration, suggesting impaired lung repair. Despite these immunologic alterations, pregnant animals demonstrated equivalent percentages of pulmonary influenza virus-specific CD8(+) T lymphocytes, although they displayed elevated levels of T-regulator lymphocytes (Tregs) in the lung. Also, pregnant mice mounted equal antibody titers in response to virus or immunization with a monovalent inactivated pH1N1 A/California/07/09 vaccine. Therefore, immunopathology likely caused by elevated cellular recruitment is an implicated mechanism of severe pH1N1 infection in pregnant mice.
authors.affiliation: Department of Infectious Diseases, Division of Virology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 330, Memphis, TN 38105, USA.
authors.forename: Glendie
authors.initials: G
authors.lastname: Marcelin
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Aldridge
authors.forename: Susu
authors.initials: S
authors.lastname: Duan
authors.forename: Hazem E
authors.initials: HE
authors.lastname: Ghoneim
authors.forename: Jerold
authors.initials: J
authors.lastname: Rehg
authors.forename: Henju
authors.initials: H
authors.lastname: Marjuki
authors.forename: Adrianus C M
authors.initials: AC
authors.lastname: Boon
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: McCullers
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Webby
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology* / Q000472:pathogenicity*; D008168:Lung / Q000737:chemistry / Q000276:immunology* / Q000473:pathology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology; D009569:Nitric Oxide / Q000032:analysis; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000401:mortality* / Q000473:pathology / Q000821:virology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000821:virology; D012376:Rodent Diseases / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000821:virology; D019562:Viral Load
chemical_list: D016207:Cytokines; D009569:Nitric Oxide