title: Mck2-dependent infection of alveolar macrophages promotes replication of MCMV in nodular inflammatory foci of the neonatal lung.
abstract: Infection with cytomegalovirus (CMV) shows a worldwide high prevalence with only immunocompromised individuals or newborns to become symptomatic. The host's constitution and the pathogen's virulence determine whether disease occurs after infection. Mouse CMV (MCMV) is an appreciated pathogen for in vivo investigation of host-pathogen interactions. It has recently been reported that a single base pair deletion can spontaneously occur in the open reading frame of MCMV-encoded chemokine 2 (MCK2), preventing the expression of the full-length gene product. To study the consequences of this mutation, we compared the Mck2-defective reporter virus MCMV-3D with the newly generated repaired Mck2(+) mutant MCMV-3DR. Compared with MCMV-3D, neonatal mice infected with MCMV-3DR showed severe viral disease after lung infection. Viral disease coincided with high viral activity in multiple organs and increased virus replication in previously described nodular inflammatory foci (NIF) in the lung. Notably, MCMV-3DR showed tropism for alveolar macrophages in vitro and in vivo, whereas MCMV-3D did not infect this cell type. Moreover, in vivo depletion of alveolar macrophages reduced MCMV-3DR replication in the lung. We proposed an Mck2-mediated mechanism by which MCMV exploits alveolar macrophages to increase replication upon first encounter with the host's lung mucosa.
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: F R
authors.initials: FR
authors.lastname: Stahl
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: K A
authors.initials: KA
authors.lastname: Keyser
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Heller
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Bischoff
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Halle
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Messerle
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Förster
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism*; D006566:Herpesviridae Infections / Q000821:virology*; D007249:Inflammation / Q000821:virology*; D008168:Lung / Q000473:pathology*; D008171:Lung Diseases / Q000821:virology*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000472:pathogenicity / Q000502:physiology*; D017384:Sequence Deletion / Q000235:genetics; D003074:Solitary Pulmonary Nodule / Q000821:virology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D056189:Viral Tropism / Q000235:genetics; D014774:Virulence / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: D019742:Chemokines, CC; C121663:MCK-2 protein, Mouse cytomegalovirus 1; D014764:Viral Proteins