Contributions of E1A to mouse adenovirus type 1 pathogenesis following intranasal inoculation

Abstract

We investigated the role of mouse adenovirus type 1 (MAV-1) early region 1A (E1A) protein in adenovirus respiratory infection. Intranasal (i.n.) inoculation of mice with wild type (wt) virus induced chemokine and cellular inflammatory responses in the lung. We observed similar responses in mice infected with an E1A-null mutant virus at the same dose, although the magnitude of these responses was lower. Levels of viral hexon gene expression were lower in the lung following infection with E1A-null virus than with wt virus. When input doses were adjusted so that equivalent viral loads were present following infection with varying doses of wt and E1A-null virus, we observed equivalent chemokine upregulation in the lung. Dissemination to the brain occurred following i.n. inoculation with equal doses of wt or E1A-null virus, but viral gene expression and viral loads were lower and the magnitude of chemokine responses was lower in brains of E1A-null virus-infected mice. CD4 and CD8 T cells and neutrophils were recruited to the brains of mice infected with either wt or E1A-null virus. Together, these data suggest that MAV-1 E1A makes important contributions to viral replication in the lung and the brain following i.n. inoculation. However, E1A is not essential for the induction of inflammatory responses in the lung or for viral dissemination out of the lung.

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

“…Consistent with our previous reports (40,41), patchy areas of cellular inflammation developed in the lungs of infected adult mice beginning by 7 dpi (Fig. 4A, right columns).…”

“…Acute MAV-1 infection induces the expression of multiple cytokines and chemokines in the lungs of adult mice (40,41). To determine whether virus-induced cytokine production differs between neonates and adults, we measured protein and mRNA levels of representative Th1 (IFN-␥) and Th2 (IL-4) cytokines along with those of chemokines (CCL5 and CXCL1) that are typically induced in the lung by acute MAV-1 respiratory infection.…”

“…Because mice are not fully permissive hosts for human adenovirus replication (14,18), it is difficult to study human adenovirus pathogenesis in vivo. We have established mouse adenovirus type 1 (MAV-1, also known as MAdV-1) as a useful model to study the pathogenesis of adenovirus respiratory infection in the natural host of the virus (5,40,41).…”

Mouse Adenovirus Type 1-Induced Breakdown of the Blood-Brain Barrier

“…These chemokines function to recruit macrophages (CCL1, CCL2, and CXCL10), B cells (CCL1), and T cells (CCL5 and CXCL10) (reviewed in references 14 and 51), and CXCL10 also promotes T-cell adhesion to endothelial cells (58). These same four chemokines were also the major ones upregulated in brains of mice infected intranasally by MAV-1 (78). MBMEC expression of CCL1, CXCL10, and CCL5 mRNAs was increased after infection with pmE314 compared to mock infection but was lower than in cells infected with wt MAV-1.…”

“…Total RNA was isolated as described above and analyzed by RNase protection assay (RPA) as described previously (78). Chemokine RNA expression was measured using the mCK-5c riboprobe template (Pharmingen), and MAV-1 hexon RNA expression was measured with a custom probe set and normalized to L32 levels as described previously (24,79).…”