Research Article: Type 1 Interferons and NK Cells Limit Murine Cytomegalovirus Escape from the Lymph Node Subcapsular Sinus

Date Published: December 7, 2016

Publisher: Public Library of Science

Author(s): Helen E. Farrell, Kimberley Bruce, Clara Lawler, Rhonda D. Cardin, Nicholas J. Davis-Poynter, Philip G. Stevenson, Laurent Coscoy.

http://doi.org/10.1371/journal.ppat.1006069

Abstract

Cytomegaloviruses (CMVs) establish chronic, systemic infections. Peripheral infection spreads via lymph nodes, which are also a focus of host defence. Thus, this is a point at which systemic infection spread might be restricted. Subcapsular sinus macrophages (SSM) captured murine CMV (MCMV) from the afferent lymph and poorly supported its replication. Blocking the type I interferon (IFN-I) receptor (IFNAR) increased MCMV infection of SSM and of the fibroblastic reticular cells (FRC) lining the subcapsular sinus, and accelerated viral spread to the spleen. Little splenic virus derived from SSM, arguing that they mainly induce an anti-viral state in the otherwise susceptible FRC. NK cells also limited infection, killing infected FRC and causing tissue damage. They acted independently of IFN-I, as IFNAR blockade increased NK cell recruitment, and NK cell depletion increased infection in IFNAR-blocked mice. Thus SSM restricted MCMV infection primarily though IFN-I, with NK cells providing a second line of defence. The capacity of innate immunity to restrict MCMV escape from the subcapsular sinus suggested that enhancing its recruitment might improve infection control.

Partial Text

Human CMV is a ubiquitous pathogen that causes birth defects and harms immunocompromised hosts [1]. Although adaptive immunity normally prevents disease, adaptive immune priming has not prevented infection establishment [2], suggesting that this presents a qualitatively distinct challenge, requiring possibly different immune effectors. Analysing early human infection is made difficult by CMV transmission being sporadic and largely asymptomatic. However CMV infections long pre-date human speciation [3], so different host / virus pairs are likely to share common themes and analogous animal infections can yield key insights. MCMV has particular value for understanding how CMVs work in vivo, as its host provides the standard model of mammalian cell biology. MCMV exploits myeloid cells to spread [4, 5], and live imaging shows peripheral to systemic spread via lymph nodes (LN) [6], so LN myeloid cells are likely to be a key target for limiting systemic infection.

LN survey extracellular fluid returning to the blood. SSM remove particulate antigens such as viruses. However viruses that replicate in SSM, or bypass them by infecting FRC, mandate additional defences. MCMV, like HCMV, has a broad tropism, encompassing fibroblasts, macrophages and endothelial cells, and lymph-borne MCMV directly infected both SSM and FRC. Thus, the need to contain this infection preceded adaptive immunity. Containment depended primarily on IFN-I, which restricted SSM and FRC infections despite viral IFN-I evasion [42]. Innate immunity is inherently polylithic, and IFN-I was not the sole SSM-based defence: NK cell recruitment was also important. Nor were SSM the sole IFN-I producers at the subcapsular sinus: pDC also contributed. But IFN-I and SSM were major players, and boosting their engagement provides a potential route to better infection control.

 

Source:

http://doi.org/10.1371/journal.ppat.1006069

 

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