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- Title
Hematopoietic cell-mediated dissemination of murine cytomegalovirus is regulated by NK cells and immune evasion.
- Authors
Zhang, Shunchuan; Springer, Lauren E.; Rao, Han-Zhi; Espinosa Trethewy, Renee G.; Bishop, Lindsey M.; Hancock, Meaghan H.; Grey, Finn; Snyder, Christopher M.
- Abstract
Cytomegalovirus (CMV) causes clinically important diseases in immune compromised and immune immature individuals. Based largely on work in the mouse model of murine (M)CMV, there is a consensus that myeloid cells are important for disseminating CMV from the site of infection. In theory, such dissemination should expose CMV to cell-mediated immunity and thus necessitate evasion of T cells and NK cells. However, this hypothesis remains untested. We constructed a recombinant MCMV encoding target sites for the hematopoietic specific miRNA miR-142-3p in the essential viral gene IE3. This virus disseminated poorly to the salivary gland following intranasal or footpad infections but not following intraperitoneal infection in C57BL/6 mice, demonstrating that dissemination by hematopoietic cells is essential for specific routes of infection. Remarkably, depletion of NK cells or T cells restored dissemination of this virus in C57BL/6 mice after intranasal infection, while dissemination occurred normally in BALB/c mice, which lack strong NK cell control of MCMV. These data show that cell-mediated immunity is responsible for restricting MCMV to hematopoietic cell-mediated dissemination. Infected hematopoietic cells avoided cell-mediated immunity via three immune evasion genes that modulate class I MHC and NKG2D ligands (m04, m06 and m152). MCMV lacking these 3 genes spread poorly to the salivary gland unless NK cells were depleted, but also failed to replicate persistently in either the nasal mucosa or salivary gland unless CD8+ T cells were depleted. Surprisingly, CD8+ T cells primed after intranasal infection required CD4+ T cell help to expand and become functional. Together, our data suggest that MCMV can use both hematopoietic cell-dependent and -independent means of dissemination after intranasal infection and that cell mediated immune responses restrict dissemination to infected hematopoietic cells, which are protected from NK cells during dissemination by viral immune evasion. In contrast, viral replication within mucosal tissues depends on evasion of T cells. Author summary: Cytomegalovirus (CMV) is a common cause of disease in immune compromised individuals as well as a common cause of congenital infections leading to disease in newborns. The virus is thought to enter primarily via mucosal barrier tissues, such as the oral and nasal mucosa. However, it is not clear how the virus escapes these barrier tissues to reach distant sites. In this study, we used a mouse model of CMV infection. Our data illustrate a complex balance between the immune system and viral infection of "myeloid cells", which are most commonly thought to carry the virus around the body after infection. In particular, our data suggest that robust immune responses at the site of infection force the virus to rely on myeloid cells to escape the site of infection. Moreover, viral genes designed to evade these immune responses were needed to protect the virus during and after its spread to distant sites. Together, this work sheds light on the mechanisms of immune control and viral survival during CMV infection of mucosal tissues and spread to distant sites of the body.
- Subjects
KILLER cells; ORAL mucosa; CYTOMEGALOVIRUS diseases; MUCOUS membranes; RESPIRATORY mucosa; CELLULAR immunity; T cells
- Publication
PLoS Pathogens, 2021, Vol 17, Issue 1, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1009255