Abstract
ABSTRACTHerpesviruses have coevolved with their hosts over hundreds of millions of years and exploit fundamental features of their biology. Cytomegaloviruses (CMVs) colonize blood-borne myeloid cells, and it has been hypothesized that systemic dissemination arises from infected stem cells in bone marrow. However, poor CMV transfer by stem cell transplantation argues against this being the main reservoir. To identify alternative pathways for CMV spread, we tracked murine CMV (MCMV) colonization after mucosal entry. We show that following intranasal MCMV infection, lung CD11c+ dendritic cells (DC) migrated sequentially to lymph nodes (LN), blood, and then salivary glands. Replication-deficient virus followed the same route, and thus, DC infected peripherally traversed LN to enter the blood. Given that DC are thought to die locally following their arrival and integration into LN, recirculation into blood represents a new pathway. We examined host and viral factors that facilitated this LN traverse. We show that MCMV-infected DC exited LN by a distinct route to lymphocytes, entering high endothelial venules and bypassing the efferent lymph. LN exit required CD44 and the viral M33 chemokine receptor, without which infected DC accumulated in LN and systemic spread was greatly reduced. Taken together, our studies provide the first demonstration of virus-driven DC recirculation. As viruses follow host-defined pathways, high endothelial venules may normally allow DC to pass from LN back into blood.
Highlights
Herpesviruses have coevolved with their hosts over hundreds of millions of years and exploit fundamental features of their biology
Imaging dissected organs established that thoracic signals were from the lungs and that cervical signals were from the salivary glands (SG)
Lung signals obscured those of the mediastinal lymph nodes (LN) (MLN), but dissection revealed MLN infection before SG infection (Fig. 1C and D)
Summary
Herpesviruses have coevolved with their hosts over hundreds of millions of years and exploit fundamental features of their biology. Cytomegaloviruses (CMVs) colonize blood-borne myeloid cells, and it has been hypothesized that systemic dissemination arises from infected stem cells in bone marrow. HCMV and murine CMV (MCMV) both infect blood-borne myeloid cells. We show that MCMV-infected dendritic cells in the lungs reach the blood via lymph nodes, surprisingly migrating into high endothelial venules. Human CMV (HCMV) infects 1% of live births and commonly causes fetal damage This reflects its capacity to spread systemically in immunocompetent hosts [1]. Blood monocytes and dendritic cells (DC) harbor viral genomes at steady state They are hypothesized to derive from infected bone marrow stem cells [2]. CMVs can infect myeloid cells in peripheral tissues, and such cells can migrate to lymph nodes (LN) They are thought not to rejoin the circulation. No alternative fate has been identified for the many myeloid cells that enter afferent lymphatics [6]
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