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Contributions of CD8 T cells to the pathogenesis of mouse adenovirus type 1 respiratory infection.

ABSTRACT: CD8 T cells are key components of the immune response to viruses, but their roles in the pathogenesis of adenovirus respiratory infection have not been characterized. We used mouse adenovirus type 1 (MAV-1) to define CD8 T cell contributions to the pathogenesis of adenovirus respiratory infection. CD8 T cell deficiency in ?2m-/- mice had no effect on peak viral replication in lungs, but clearance of virus was delayed in ?2m-/- mice. Virus-induced weight loss and increases in bronchoalveolar lavage fluid total protein, IFN-?, TNF-?, IL-10, CCL2, and CCL5 concentrations were less in ?2m-/- mice than in controls. CD8 T cell depletion had similar effects on virus clearance, weight loss, and inflammation. Deficiency of IFN-? or perforin had no effect on viral replication or inflammation, but perforin-deficient mice were partially protected from weight loss. CD8 T cells promote MAV-1-induced pulmonary inflammation via a mechanism that is independent of direct antiviral effects.

SUBMITTER: Molloy CT

PROVIDER: S-EPMC5493992 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Contributions of CD8 T cells to the pathogenesis of mouse adenovirus type 1 respiratory infection.

Molloy Caitlyn T CT Andonian Jennifer S JS Seltzer Harrison M HM Procario Megan C MC Watson Michael E ME Weinberg Jason B JB

Virology 20170411

CD8 T cells are key components of the immune response to viruses, but their roles in the pathogenesis of adenovirus respiratory infection have not been characterized. We used mouse adenovirus type 1 (MAV-1) to define CD8 T cell contributions to the pathogenesis of adenovirus respiratory infection. CD8 T cell deficiency in β2m<sup>-/-</sup> mice had no effect on peak viral replication in lungs, but clearance of virus was delayed in β2m<sup>-/-</sup> mice. Virus-induced weight loss and increases i ...[more]

PMID: 28410483

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Project description:Virus entry into host cells is a complex process that is largely regulated by access to specific cellular receptors. Human adenoviruses (HAdVs) and many other viruses use cell adhesion molecules such as the coxsackievirus and adenovirus receptor (CAR) for attachment to and entry into target cells. These molecules are rarely expressed on the apical side of polarized epithelial cells, which raises the question of how adenoviruses-and other viruses that engage cell adhesion molecules-enter polarized cells from the apical side to initiate infection. We have previously shown that species C HAdVs utilize lactoferrin-a common innate immune component secreted to respiratory mucosa-for infection via unknown mechanisms. Using a series of biochemical, cellular, and molecular biology approaches, we mapped this effect to the proteolytically cleavable, positively charged, N-terminal 49 residues of human lactoferrin (hLF) known as human lactoferricin (hLfcin). Lactoferricin (Lfcin) binds to the hexon protein on the viral capsid and anchors the virus to an unknown receptor structure of target cells, resulting in infection. These findings suggest that HAdVs use distinct cell entry mechanisms at different stages of infection. To initiate infection, entry is likely to occur at the apical side of polarized epithelial cells, largely by means of hLF and hLfcin bridging HAdV capsids via hexons to as-yet-unknown receptors; when infection is established, progeny virions released from the basolateral side enter neighboring cells by means of hLF/hLfcin and CAR in parallel.IMPORTANCE Many viruses enter target cells using cell adhesion molecules as receptors. Paradoxically, these molecules are abundant on the lateral and basolateral side of intact, polarized, epithelial target cells, but absent on the apical side that must be penetrated by incoming viruses to initiate infection. Our study provides a model whereby viruses use different mechanisms to infect polarized epithelial cells depending on which side of the cell-apical or lateral/basolateral-is attacked. This study may also be useful to understand the biology of other viruses that use cell adhesion molecules as receptors.

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Contributions of CD8 T cells to the pathogenesis of mouse adenovirus type 1 respiratory infection.

Publications

Contributions of CD8 T cells to the pathogenesis of mouse adenovirus type 1 respiratory infection.

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