Susceptibility to Acute Mouse Adenovirus Type 1 Respiratory Infection and Establishment of Protective Immunity in Neonatal Mice

Abstract

There is an incomplete understanding of the differences between neonatal immune responses that contribute to the increased susceptibility of neonates to some viral infections. We tested the hypothesis that neonates are more susceptible than adults to mouse adenovirus type 1 (MAV-1) respiratory infection and are impaired in the ability to generate a protective immune response against a second infection. Following intranasal infection, lung viral loads were greater in neonates than in adults during the acute phase but the virus was cleared from the lungs of neonates as efficiently as it was from adult lungs. Lung gamma interferon (IFN-␥) responses were blunted and delayed in neonates, and lung viral loads were higher in adult IFN-␥ ؊/؊ mice than in IFN-␥ ؉/؉ controls. However, administration of recombinant IFN-␥ to neonates had no effect on lung viral loads. Recruitment of inflammatory cells to the airways was impaired in neonates. CD4 and CD8 T cell responses were similar in the lungs of neonates and adults, although a transient increase in regulatory T cells occurred only in the lungs of infected neonates. Infection of neonates led to protection against reinfection later in life that was associated with increased effector memory CD8 T cells in the lungs. We conclude that neonates are more susceptible than adults to acute MAV-1 respiratory infection but are capable of generating protective immune responses.

Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

“…IFN-␥ and Pfn play antagonistic roles during chronic myocarditis caused by Trypanosoma cruzi, with Pfn ϩ CD8 ϩ T cells implicated in causing tissue damage and IFN-␥ ϩ CD8 ϩ T cells preventing tissue damage (41). In the current study, we identified robust induction of IFN-␥ in the heart after MAV-1 infection, consistent with previous studies showing induction of IFN-␥ in MAV-1-infected lungs (25,26). During acute MAV-1 respiratory infection of adult mice, CD4 ϩ and CD8 ϩ T cells are the primary producers of IFN-␥ in the lung (24).…”

“…4D), and TNF-␣ (Fig. 4E) were upregulated in the hearts of infected adult mice, but the magnitudes of these responses were substantially lower than and the kinetics were delayed compared to those in neonates, in contrast to our previous findings in the lungs (26). We detected marked increases in the expression of both IL-1␤ (Fig.…”

“…inoculation (26). Similarly, IFN-␥ does not appear to be critical for control of MAV-1 replication in the hearts of neonatal mice, since IFN-␥ depletion did not lead to increased viral replication in the heart.…”

“…Cytokine gene expression was quantified using reverse transcriptase qPCR (RT-qPCR) as previously described (25,26). First, 2.5 g of RNA was reverse transcribed using Moloney murine leukemia virus (MMLV) reverse transcriptase (Invitrogen) in 20-l reaction mixtures according to the manufacturer's instructions.…”

“…MAV-1-induced cardiac disease is less pronounced in adult mice. We have previously described increased susceptibility to MAV-1 respiratory infection and blunted lung IFN-␥ responses in neonatal mice compared to adults (26). To determine whether this is also the case in the heart, we compared viral loads and inflammatory responses in the hearts of neonates and adult mice.…”