Time to Detection of Cytomegalovirus (CMV) DNA in Blood Leukocytes Is a Predictor for the Development of CMV Disease in CMV-Seronegative Recipients of Allografts from CMV-Seropositive Donors following Liver Transplantation

Manez, Rafael; Kusne, Shimon; Rinaldo, Charles R.; Aguado, José María; George, Kirsten St.; Grossi, Paolo; Frye, Bonnie; Fung, John J.; Ehrlich, Garth D.

doi:10.1093/infdis/173.5.1072

Cited by 50 publications

(43 citation statements)

References 12 publications

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“…Monocytes are the primary mediator of this initial hematogenous dissemination of HCMV (25,26). In this study, we have demonstrated that the nuclear translocation pathway is cell type-dependent, and that receptor-ligand interactions during HCMV infection drive a unique nuclear translocation pathway in monocytes.…”

Section: Discussionmentioning

confidence: 72%

Viral binding-induced signaling drives a unique and extended intracellular trafficking pattern during infection of primary monocytes

Kim

Collins-McMillen

Caposio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We initiated experiments to examine the infection of monocytes postentry. New data show that human cytomegalovirus (HCMV) DNA is detected in the nucleus beginning only at 3 d postinfection in monocytes, compared with 30 min postinfection in fibroblasts and endothelial cells, suggesting that HCMV nuclear translocation in monocytes is distinct from that seen in other cell types. We now show that HCMV is initially retained in early endosomes and then moves sequentially to the trans-Golgi network (TGN) and recycling endosomes before nuclear translocation. HCMV is retained initially as a mature particle before deenvelopment in recycling endosomes. Disruption of the TGN significantly reduced nuclear translocation of viral DNA, and HCMV nuclear translocation in infected monocytes was observed only when correct gH/gL/UL128-131/integrin/c-Src signaling occurred. Taken together, our findings show that viral binding of the gH/gL/UL128-131 complex to integrins and the ensuing c-Src signaling drive a unique nuclear translocation pattern that promotes productive infection and avoids viral degradation, suggesting that it represents an additional viral evasion/survival strategy.monocytes | viral trafficking | gH/gL/UL128-131 complex | integrins | nuclear translocation pathway H uman cytomegalovirus (HCMV) infection usually results in an asymptomatic lifelong persistent infection in healthy individuals after primary infection (1, 2). Although HCMV infection rarely causes disease in immunocompetent individuals, it can cause severe/ fatal disease in immunocompromised patients, such as congenitally infected neonates, patients with AIDS, and transplant recipients (3-6). HCMV infection is also associated with the development of cardiovascular diseases, including atherosclerosis, restenosis, and transplant vascular sclerosis, as well as some cancers (7-10). This wide range of pathological complications results from viral spread to multiple organs and the broad cellular tropism displayed by HCMV following infection (11).Monocytes are a primary site of persistent HCMV infection, and HCMV-infected monocytes are believed to play a key role in the hematogenous dissemination of the virus to target organs following primary infection (12). For HCMV to infect primary monocytes, it must overcome several biological barriers to successfully mediate viral spread and persistence. For example, monocytes do not initially support de novo HCMV gene expression and viral replication (13), and they have a lifespan of only 1-3 d in circulation under normal homeostatic conditions (14, 15). Understanding how HCMV overcomes these biological barriers following infection may provide clues to the underlying causes of HCMV pathogenesis and persistence. Our laboratory has provided molecular evidence for how HCMV evolved to deal with these biological barriers (16)(17)(18)(19)(20)(21)(22).We have shown that the biological changes in HCMV-infected monocytes are triggered by the binding of gB to EGFR (19) and binding of the gH/gL/UL128-131 complex to β1 and β3 integri...

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Section: Discussionmentioning

confidence: 72%

Viral binding-induced signaling drives a unique and extended intracellular trafficking pattern during infection of primary monocytes

Kim

Collins-McMillen

Caposio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Viral spread occurs in a cell-dependent manner, with monocytes serving as direct mediators of viral spread to peripheral tissue (2,32,33). In our investigation of the mechanism for how infected monocytes promote the simultaneous spread of HCMV to biologically distinct tissue, we reported that monocytes acquire a unique chemokinetic phenotype via receptor-ligand interactions during viral binding/entry (4, 7).…”

Section: Discussionmentioning

confidence: 99%

Activation of EGFR on monocytes is required for human cytomegalovirus entry and mediates cellular motility

Chan

Nogalski²,

Yurochko³

2009

Proc. Natl. Acad. Sci. U.S.A.

169

289

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Human cytomegalovirus (HCMV) rapidly induces a mobile and functionally unique proinflammatory monocyte following infection that is proposed to mediate viral spread. The cellular pathways used by HCMV to initiate these biological changes remain unknown. Here, we document the expression of the epidermal growth factor receptor (EGFR) on the surface of human peripheral blood monocytes but not on other blood leukocyte populations. Inhibition of EGFR signaling abrogated viral entry into monocytes, indicating that EGFR can serve as a cellular tropism receptor. Moreover, HCMV-activated EGFR was required for the induction of monocyte motility and transendothelial migration, two biological events required for monocyte extravasation into peripheral tissue, and thus viral spread. Transcriptome analysis revealed that HCMV-mediated EGFR signaling up-regulated neural Wiskott-Aldrich syndrome protein (N-WASP), an actin nucleator whose expression and function are normally limited in leukocytes. Knockdown of N-WASP expression blocked HCMV-induced but not phorbol 12-myristate 13-acetate (PMA)-induced monocyte motility, suggesting that a switch to and/or the distinct use of a new actin nucleator controlling motility occurs during HCMV infection of monocytes. Together, these data provide evidence that EGFR plays an essential role in the immunopathobiology of HCMV by mediating viral entry into monocytes and stimulating the aberrant biological activity that promotes hematogenous dissemination.T he wide range of pathological complications associated with human cytomegalovirus (HCMV) infection is a direct consequence of viral spread to peripheral organ sites and the broad cellular tropism of the virus (1). Monocytes are primary in vivo targets for HCMV and are believed to be responsible for hematogenous dissemination of HCMV to multiple organ systems (2). We previously showed that HCMV infection of monocytes polarized the infected cell toward a distinct proinflammatory phenotype that possessed the distinct biological changes necessary to promote viral spread (3-5). Specifically, HCMV infection induced polarization of infected monocytes toward an M1 proinflammatory cell type that simultaneously exhibited characteristics associated with an M2 antiinflammatory macrophage (6). The infected monocytes also displayed a high level of chemokinesis when compared with monocytes activated by LPS or phorbol 12-myristate 13-acetate (PMA) (4, 5). Moreover, an accelerated rate of differentiation from short-lived monocytes (nonpermissive for HCMV replication) into long-lived macrophages (permissive for HCMV replication) was observed following infection with HCMV (4). Based on our studies, we suggest that during primary infection, newly infected peripheral monocytes acquire a motile phenotype that promotes exit of the infected cell from the circulating blood into multiple organ tissue despite the absence of a chemotactic gradient. Once in the surrounding tissue, differentiation into HCMV replication-competent macrophages occurs, resulting in viral spread...

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“…Whereas a negative PCR test result argues strongly against the presence of CMV replication, a positive PCR result in CMV-seronegative transplant recipients is significant because it indicates primary infection. 45 In other patients, however, the ability of the test to detect very few DNA copies raises the concern that a positive signal may not distinguish between replicating and latent virus. Reverse-transcriptase PCR selectively detects viral messenger RNA (mRNA) and hence is specific for replicating virus.…”

Section: Nucleic Acid Amplificationmentioning

confidence: 99%

Management of cytomegalovirus infection after liver transplantation

Sampathkumar

Payá

2000

Liver Transpl

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Time to Detection of Cytomegalovirus (CMV) DNA in Blood Leukocytes Is a Predictor for the Development of CMV Disease in CMV-Seronegative Recipients of Allografts from CMV-Seropositive Donors following Liver Transplantation

Cited by 50 publications

References 12 publications

Viral binding-induced signaling drives a unique and extended intracellular trafficking pattern during infection of primary monocytes

Viral binding-induced signaling drives a unique and extended intracellular trafficking pattern during infection of primary monocytes

Activation of EGFR on monocytes is required for human cytomegalovirus entry and mediates cellular motility

Management of cytomegalovirus infection after liver transplantation

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